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Szekely AB, Nseir M, Roth B, Ohlsson B. Leptin and PAI-1 Levels Are Decreased After a Dietary Intervention in Patients with Irritable Bowel Syndrome. Int J Mol Sci 2025; 26:4607. [PMID: 40429752 PMCID: PMC12111115 DOI: 10.3390/ijms26104607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/27/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
A diet low in fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) is an established treatment for irritable bowel syndrome (IBS). The starch- and sucrose-reduced diet (SSRD) is a newer, promising diet. Nutrients influence the production of gut hormones, which affect gastrointestinal motility. This study aimed to investigate the changes in copeptin, leptin, PAI-1, C-peptide, and insulin in patients with IBS following a 4-week dietary intervention and to explore whether these hormonal levels correlated with symptom improvements. A total of 142 participants with IBS were randomized to either a 4-week intervention with the SSRD (n = 70) or a low-FODMAP diet (n = 72). Participants completed the study questionnaire, food diary, ROME IV questionnaire, irritable bowel syndrome severity scoring system (IBS-SSS), and visual analog scale for irritable bowel syndrome (VAS-IBS) at baseline and after 4 weeks and 6 months; blood samples were collected at each of these time points. Leptin levels decreased from baseline to 4 weeks in the SSRD group (p = 0.002) but not in the low-FODMAP group (p = 0.153). In the overall study population, leptin (p = 0.001) and PAI-1 (p = 0.019) levels decreased from baseline to 4 weeks. Leptin changes were mainly associated with alterations in carbohydrate intake but not with symptom changes. These findings suggest that the SSRD reduces the levels of leptin in patients with IBS, while PAI-1 levels decrease independently of the dietary intervention, without a corresponding impact on symptoms.
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Affiliation(s)
- Andreas-Balázs Szekely
- Department of Clinical Sciences, Lund University, 22100 Malmö, Sweden; (A.-B.S.); (M.N.); (B.R.)
| | - Mohamed Nseir
- Department of Clinical Sciences, Lund University, 22100 Malmö, Sweden; (A.-B.S.); (M.N.); (B.R.)
| | - Bodil Roth
- Department of Clinical Sciences, Lund University, 22100 Malmö, Sweden; (A.-B.S.); (M.N.); (B.R.)
| | - Bodil Ohlsson
- Department of Clinical Sciences, Lund University, 22100 Malmö, Sweden; (A.-B.S.); (M.N.); (B.R.)
- Department of Internal Medicine, Skåne University Hospital, 20502 Malmö, Sweden
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2
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Zou K, Du L, Qin J, Zhou J, Xiao Y, Song X, Liu H, Wang X. Titanium dioxide nanoparticles disturb glucose homeostasis in association with impaired enteroendocrine cell differentiation. Food Chem Toxicol 2025; 202:115504. [PMID: 40318823 DOI: 10.1016/j.fct.2025.115504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 04/07/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Gut hormones secreted by enteroendocrine cells play a critical role in maintaining glucose homeostasis. However, the adverse endocrine effects related to glucose homeostasis caused by food additives are not well understood. This work aims to investigate the effects of titanium dioxide nanoparticles (TiO2 NPs) in comparison to titanium dioxide microparticles (TiO2 MPs) on glucose homeostasis, with a specific focus on the enteroendocrine cells and gut hormones. Our research found that exposure to 1 % (w/w) TiO2 NPs, unlike TiO2 MPs, resulted in elevated blood glucose levels and impaired glucose tolerance in mice. Notably, 1 % (w/w) TiO2 NPs significantly influenced the differentiation of the intestinal epithelium while not causing any notable histological changes or affecting cell proliferation in the mouse ileum. Furthermore, the levels of gut hormones, including glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and cholecystokinin (CCK), released from mouse ileum tissues were also significantly reduced following exposure to 1 % (w/w) TiO2 NPs. Using the intestinal organoid model, we also discovered that 20 μg/mL TiO2 NPs impaired enteroendocrine cell differentiation, reduced basal GLP-1 secretion levels, and disrupted the GLP-1 secretion response to nutrient stimuli. Our research highlights the detrimental effects of TiO2 NPs as potential intestinal endocrine disruptor and underscores the need to optimize their particle size for safe use in the food industry.
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Affiliation(s)
- Kai Zou
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China; Jiaxing Key Laboratory for Research and Application of Green and Low-carbon Advanced Materials, Jiaxing, 314000, China
| | - Linna Du
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Jing Qin
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Jiacheng Zhou
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Yanping Xiao
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Xixi Song
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Hongxia Liu
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China
| | - Xiu Wang
- School of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314000, China; Jiaxing Key Laboratory for Research and Application of Green and Low-carbon Advanced Materials, Jiaxing, 314000, China.
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3
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Li WY, Chen H, Lin D, Zhang T, Chen YL, Jin T, Cao MJ. Purification, crystal structural characterization of porcine kidney dipeptidyl peptidase IV (PkDPP-IV) and its interaction with oyster derived inhibitory peptide ILAPPER. Int J Biol Macromol 2025; 298:140047. [PMID: 39828169 DOI: 10.1016/j.ijbiomac.2025.140047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 01/01/2025] [Accepted: 01/16/2025] [Indexed: 01/22/2025]
Abstract
Dipeptidyl peptidase IV (DPP-IV) is an important target enzyme for the treatment of type 2 diabetes mellitus (T2DM). Increasing researchers try to screen DPP-IV inhibitory peptides while the cost of DPP-IV is high. In this study, PkDPP-IV was efficiently purified by acid precipitation, ammonium sulfate salting out and gel filtration chromatography with a purification of 283.5 folds and 16.5 % yield. PkDPP-IV is a glycoprotein with molecular weight of 110 kDa and optimal activity at pH 7.0 and 40 °C. Crystal structure indicated that PkDPP-IV is composed of an α/β hydrolase domain and a β-propeller domain, which is highly similar to that of human DPP-IV. A peptide ILAPPER derived from oyster exhibited high inhibitory activity with Ki value of 0.131 μM against PkDPP-IV. The crystal structure of the PkDPP-IV + ILAPPER complex revealed that ILAPPER stably occupy the S1 and S2 catalytic pockets of PkDPP-IV by forming three hydrogen bonds with Tyr-547, Ser-630, and Tyr-662, thereby inhibiting enzyme activity. Analysis of transmembrane transport pathway suggested that ILAPPER is transported by the Caco-2 cell monolayer via the paracellular pathway. All the results provide a new approach for rapid preparation of natural PkDPP-IV, and the potential application of ILAPPER as an antihyperglycemic peptide in functional foods.
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Affiliation(s)
- Wan-Yu Li
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Hong Chen
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Duanquan Lin
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Tuo Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yu-Lei Chen
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Tengchuan Jin
- CAS Key Laboratory of innate immunity and chronic disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230007, China
| | - Min-Jie Cao
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China.
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Lee WD, Weilandt DR, Liang L, MacArthur MR, Jaiswal N, Ong O, Mann CG, Chu Q, Hunter CJ, Ryseck RP, Lu W, Oschmann AM, Cowan AJ, TeSlaa TA, Bartman CR, Jang C, Baur JA, Titchenell PM, Rabinowitz JD. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis. Cell Metab 2025; 37:758-771.e8. [PMID: 39889702 PMCID: PMC11926601 DOI: 10.1016/j.cmet.2024.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 09/19/2024] [Accepted: 12/17/2024] [Indexed: 02/03/2025]
Abstract
Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.
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Affiliation(s)
- Won Dong Lee
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Daniel R Weilandt
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Lingfan Liang
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Michael R MacArthur
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Natasha Jaiswal
- Department of Health and Kinesiology, Purdue University, West Lafayette, IN, USA
| | - Olivia Ong
- Department of Health and Kinesiology, Purdue University, West Lafayette, IN, USA
| | - Charlotte G Mann
- Department of Health Sciences and Technology, ETH Zürich, Schwerzenbach, Switzerland
| | - Qingwei Chu
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Craig J Hunter
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Rolf-Peter Ryseck
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Wenyun Lu
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Anna M Oschmann
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA
| | - Alexis J Cowan
- Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA
| | - Tara A TeSlaa
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Caroline R Bartman
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Cholsoon Jang
- Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
| | - Joseph A Baur
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Paul M Titchenell
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Joshua D Rabinowitz
- Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute of Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA.
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Chaichana C, Pramyothin P, Treesuwan W, Jangtawee P, Yindeengam A, Kaewmanee S, Vanavichit A, Krittayaphong R. Impact of 3 G rice on plasma glucose, insulin, and gastrointestinal hormones in patients with obesity or type 2 diabetes: A non-randomized experimental study. Obes Res Clin Pract 2025; 19:101-107. [PMID: 40037945 DOI: 10.1016/j.orcp.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 02/23/2025] [Accepted: 02/27/2025] [Indexed: 03/06/2025]
Abstract
OBJECTIVE To evaluate the effects of a novel grain variety 3 G rice compared to traditional white rice on postprandial glycemia, insulinemia, and gastrointestinal hormones in individuals with obesity and type 2 diabetes (T2D). METHODS A non-randomized experimental study was conducted with 20 participants with obesity (without diabetes) and 20 patients with T2D. Each participant consumed meals containing 50 g of carbohydrates from either 3 G rice or white rice. Plasma glucose, insulin, and gastrointestinal hormone levels were measured at baseline and intervals up to 120 min post-consumption. RESULTS Among participants with obesity, plasma glucose levels were significantly lower at 90 and 120 after 3 G compared to white rice (0.52 ± 0.04 vs. 2.58 ± 0.37 mmol/L, p < 0.001 at 90 min and 0.06 ± 0.02 vs. 1.47 ± 0.26 mmol/L, p = 0.003 at 120 min). In contrast, plasma insulin levels were markedly higher following 3 G rice consumption at 90-120 min (p = 0.003). Gastrointestinal hormones were significantly elevated after 3 G rice intake compared to white rice, with GLP-1 levels showing sustained increases from 60 to 120 min (p = 0.019). In T2D patients, 3 G rice consumption led to a modest reduction in plasma glucose at 120 min (5.15 ± 0.49 mmol/L for white rice vs. 3.57 ± 0.35 mmol/L for 3 G rice, p = 0.0262) without significant effect on other parameters. CONCLUSION 3 G rice significantly improved postprandial glycemic control and enhanced gastrointestinal hormone responses in individuals with obesity. These findings highlight the promise of 3 G rice as a dietary intervention for managing postprandial glycemia and insulin sensitivity.
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Affiliation(s)
- Chartchai Chaichana
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pornpoj Pramyothin
- Division of Nutrition, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Witcha Treesuwan
- Department of Nutrition and Health, Institute of Food Research and Product Development, Kasetsart University, Bangkok, Thailand
| | - Preechaya Jangtawee
- Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ahthit Yindeengam
- Her Majesty's Cardiac Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Saroch Kaewmanee
- Department of Animal Science, Faculty of Agriculture, Kasetsart University, Bangkok, Thailand
| | - Apichart Vanavichit
- Rice Science Center, Kasetsart University, Kamphangsaen, Nakhon Pathom, Thailand
| | - Rungroj Krittayaphong
- Division of Cardiology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Chen W, Yu S, Webber B, DeWolf EL, Kilmer R, Xian S, Schmidt CR, Power EM, Webber MJ. Supramolecular Peptide Depots for Glucose-Responsive Glucagon Delivery. J Biomed Mater Res A 2025; 113:e37854. [PMID: 39719890 DOI: 10.1002/jbm.a.37854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/04/2024] [Accepted: 12/09/2024] [Indexed: 12/26/2024]
Abstract
Precise blood glucose control continues to be a critical challenge in the treatment and management of type 1 diabetes in order to mitigate both acute and chronic complications. This study investigates the development of a supramolecular peptide amphiphile (PA) material functionalized with phenylboronic acid (PBA) for glucose-responsive glucagon delivery. The PA-PBA system self-assembles into nanofibrillar hydrogels in the presence of physiological glucose levels, resulting in stable hydrogels capable of releasing glucagon under hypoglycemic conditions. Glucose responsiveness is driven by reversible binding between PBA and glucose, which modulates the electrostatic interactions necessary for hydrogel formation and dissolution. Through comprehensive in vitro characterization, including circular dichroism, zeta potential measurements, and rheological assessments, the PA-PBA system is found to exhibit glucose-dependent assembly, enabling controlled glucagon release that is inversely related to glucose concentration. Glucagon release is accelerated under low glucose conditions, simulating a hypoglycemic state, with a reduced rate seen at higher glucose levels. Evaluation of the platform in vivo using a type 1 diabetic mouse model demonstrates the efficacy in protecting against insulin-induced hypoglycemia by restoring blood glucose levels following an insulin overdose. The ability to tailor glucagon release in response to fluctuating glucose concentrations underscores the potential of this platform for improving glycemic control. These findings suggest that glucose-stabilized supramolecular peptide hydrogels hold significant promise for responsive drug delivery applications, offering an approach to manage glucose levels in diabetes and other metabolic disorders.
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Affiliation(s)
- Weike Chen
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
| | - Sihan Yu
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
| | - Bernice Webber
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
| | - Emily L DeWolf
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
| | - Rory Kilmer
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
| | - Sijie Xian
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
| | - Connor R Schmidt
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
| | - Elizabeth M Power
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
| | - Matthew J Webber
- Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, USA
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Li X, Zhang X, Xie X, Dong T, Lv C, Guan R, Zhang W, Ji G, Chen F, Wang S, Wang X. Novel Phenoxyalkanoic Acid Derivatives as Free Fatty Acid Receptor 4 Agonists for Treating Type 2 Diabetes Mellitus. Int J Mol Sci 2024; 25:11476. [PMID: 39519029 PMCID: PMC11547093 DOI: 10.3390/ijms252111476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/20/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Diabetes mellitus (DM) is a common metabolic disease that poses a severe threat to human health. Despite a range of therapeutic approaches, there remains a lack of effective and safe therapies with the existing drugs. Therefore, there is an urgent need to develop novel, effective, and safe therapeutic strategies for DM. Free fatty acid receptor 4 (FFAR4), also known as GPR120, is a member of the G protein-coupled receptor family, which has received considerable attention as an attractive new therapeutic target for treating DM. In the present study, based on the structure of TUG-891, which has excellent activity and selectivity, a series of novel FFAR4 agonists was designed by replacing the phenylpropanoic acid β position carbon atom with an oxygen atom, while replacing the linking oxymethylene with an amide-linking group. The target compounds were evaluated for FFAR4 agonistic activity, and the preferred compounds were evaluated for selectivity, oral glucose tolerance in normal ICR mice, antidiabetic activity in diet-induced obese (DIO) mice, pharmacokinetic properties in ICR mice and molecular modeling studies. The results showed that compound 10f possessed excellent FFAR4 agonistic activity and selectivity, significantly improved glucose tolerance in normal ICR mice, lowered blood glucose and promoted insulin secretion in a dose-dependent manner in DIO mice, and showed favorable pharmacokinetic properties. These results indicate that compound 10f may be a promising compound that deserves further structure-activity relationship and pharmacological studies for the development of antidiabetic drugs.
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Affiliation(s)
- Xu Li
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Xinmeng Zhang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Xueyuan Xie
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Taimin Dong
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Chengxu Lv
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Ranran Guan
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Wenyue Zhang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Guoxia Ji
- School of Chemistry and Chemical Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China;
| | - Fanghui Chen
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Shiben Wang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
| | - Xuekun Wang
- National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China; (X.L.); (X.Z.); (X.X.); (T.D.); (C.L.); (R.G.); (W.Z.); (F.C.)
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8
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Mu X, Li D, Xiao R, Guan K, Ma Y, Wang R, Niu T. Discovery of novel dipeptidyl peptidase-IV inhibitory peptides derived from walnut protein and their bioactivities in vivo and in vitro. Curr Res Food Sci 2024; 9:100893. [PMID: 39555024 PMCID: PMC11567926 DOI: 10.1016/j.crfs.2024.100893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/15/2024] [Accepted: 10/23/2024] [Indexed: 11/19/2024] Open
Abstract
The inhibition of dipeptidyl peptidase IV (DPP-IV) has been regarded as a major target for treating type-2 diabetes (T2D). Food-derived peptides are a great source of DPP-IV inhibitory peptides. In this study, we utilized walnut protein as the raw material and hydrolyzed it using four different proteases. The trypsin hydrolysate exhibited the highest DPP-IV inhibitory activity. A DEAE-52 anion exchange column and a Sephadex G-25 gel filtration column were used to sequentially separate and purify the enzymatic hydrolysates. Mass spectrometry identified 117 peptide sequences, of which LPFA, VPFWA, and WGLP were three highly active DPP-IV inhibitory peptides. Molecular docking results revealed that three peptides primarily bind tightly to DPP-IV through hydrogen bonds and van der Waals forces. The inhibitory activity and absorption transport of the peptides were examined using a Caco-2 cell model. LPFA, VPFWA, and WGLP could cross the Caco-2 cell monolayer intact, with in situ IC50s of 267.9 ± 7.2 μM, 325.0 ± 8.4 μM, and 350.9 ± 8.3 μM, respectively. Oral glucose tolerance tests (OGTT) demonstrated that the three inhibitory peptides significantly improved glucose metabolism in normal ICR mice. This study establishes a theoretical basis for the high-value utilization of walnuts and the therapeutic treatment of T2D.
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Affiliation(s)
- Xinxin Mu
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, 150001, China
| | - Dan Li
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, 150001, China
| | - Ran Xiao
- Mengniu Hi-Tech Dairy Product Beijing Co., Ltd., Beijing, 101100, China
| | - Kaifang Guan
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, 150001, China
| | - Ying Ma
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, 150001, China
| | - Rongchun Wang
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, 150001, China
| | - Tianjiao Niu
- Mengniu Hi-Tech Dairy Product Beijing Co., Ltd., Beijing, 101100, China
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McKimpson WM, Spiegel S, Mukhanova M, Kraakman M, Du W, Kitamoto T, Yu J, Deng Z, Pajvani U, Accili D. Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells. J Cell Biol 2024; 223:e202305093. [PMID: 38958606 PMCID: PMC11222742 DOI: 10.1083/jcb.202305093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 05/02/2024] [Accepted: 06/20/2024] [Indexed: 07/04/2024] Open
Abstract
Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation.
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Affiliation(s)
- Wendy M. McKimpson
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Sophia Spiegel
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Maria Mukhanova
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Michael Kraakman
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Wen Du
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Takumi Kitamoto
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Junjie Yu
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Zhaobin Deng
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Utpal Pajvani
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Domenico Accili
- Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
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10
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Qi Q, Zhang H, Jin Z, Wang C, Xia M, Chen B, Lv B, Peres Diaz L, Li X, Feng R, Qiu M, Li Y, Meseguer D, Zheng X, Wang W, Song W, Huang H, Wu H, Chen L, Schneeberger M, Yu X. Hydrogen sulfide produced by the gut microbiota impairs host metabolism via reducing GLP-1 levels in male mice. Nat Metab 2024; 6:1601-1615. [PMID: 39030389 DOI: 10.1038/s42255-024-01068-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 05/21/2024] [Indexed: 07/21/2024]
Abstract
Dysbiosis of the gut microbiota has been implicated in the pathogenesis of metabolic syndrome (MetS) and may impair host metabolism through harmful metabolites. Here, we show that Desulfovibrio, an intestinal symbiont enriched in patients with MetS, suppresses the production of the gut hormone glucagon-like peptide 1 (GLP-1) through the production of hydrogen sulfide (H2S) in male mice. Desulfovibrio-derived H2S is found to inhibit mitochondrial respiration and induce the unfolded protein response in intestinal L cells, thereby hindering GLP-1 secretion and gene expression. Remarkably, blocking Desulfovibrio and H2S with an over-the-counter drug, bismuth subsalicylate, improves GLP-1 production and ameliorates diet-induced metabolic disorder in male mice. Together, our study uncovers that Desulfovibrio-derived H2S compromises GLP-1 production, shedding light on the gut-relayed mechanisms by which harmful microbiota-derived metabolites impair host metabolism in MetS and suggesting new possibilities for treating MetS.
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Affiliation(s)
- Qingqing Qi
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Huijie Zhang
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Zheyu Jin
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Changchun Wang
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Mengyu Xia
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Bandy Chen
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
| | - Bomin Lv
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Ludmila Peres Diaz
- Department of Immunobiology, Institute for Biomolecular Design and Discovery, Yale University School of Medicine, New Haven, CT, USA
| | - Xue Li
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Ru Feng
- Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengdi Qiu
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Yang Li
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - David Meseguer
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Wang
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
| | - Wei Song
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China
| | - He Huang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China
| | - Hao Wu
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China
- Human Phenome Institute, Fudan University, Shanghai, China
| | - Lei Chen
- Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Marc Schneeberger
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
| | - Xiaofei Yu
- State Key Laboratory of Genetic Engineering, Fudan Microbiome Center, School of Life Sciences, Fudan University, Shanghai, China.
- Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China.
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11
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Singh K, Aulakh SK, Nijjar GS, Singh S, Sandhu APS, Luthra S, Tanvir F, Kaur Y, Singla A, Kaur MS. Rebalancing the Gut: Glucagon-Like Peptide-1 Agonists as a Strategy for Obesity and Metabolic Health. Cureus 2024; 16:e64738. [PMID: 39156410 PMCID: PMC11329331 DOI: 10.7759/cureus.64738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2024] [Indexed: 08/20/2024] Open
Abstract
Obesity significantly impacts gut microbial composition, exacerbating metabolic dysfunction and weight gain. Traditional treatment methods often fall short, underscoring the need for innovative approaches. Glucagon-like peptide-1 (GLP-1) agonists have emerged as promising agents in obesity management, demonstrating significant potential in modulating gut microbiota. These agents promote beneficial bacterial populations, such as Bacteroides, Lactobacillus, and Bifidobacterium, while reducing harmful species like Enterobacteriaceae. By influencing gut microbiota composition, GLP-1 agonists enhance gut barrier integrity, reducing permeability and systemic inflammation, which are hallmarks of metabolic dysfunction in obesity. Additionally, GLP-1 agonists improve metabolic functions by increasing the production of short-chain fatty acids like butyrate, propionate, and acetate, which serve as energy sources for colonocytes, modulate immune responses, and enhance the production of gut hormones that regulate appetite and glucose homeostasis. By increasing microbial diversity, GLP-1 agonists create a more resilient gut microbiome capable of resisting pathogenic invasions and maintaining metabolic balance. Thus, by shifting the gut microbiota toward a healthier profile, GLP-1 agonists help disrupt the vicious cycle of obesity-induced gut dysbiosis and inflammation. This review highlights the intricate relationship between obesity, gut microbiota, and GLP-1 agonists, providing valuable insights into their combined role in effective obesity treatment and metabolic health enhancement.
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Affiliation(s)
| | - Smriti K Aulakh
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | | | - Sumerjit Singh
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Ajay Pal Singh Sandhu
- Internal Medicine, Sri Guru Ram Das University of Health Sciences and Research, Amritsar, IND
| | - Shivansh Luthra
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Fnu Tanvir
- Internal Medicine, Government Medical College, Amritsar, IND
| | - Yasmeen Kaur
- Internal Medicine, Government Medical College, Amritsar, IND
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12
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Gélineau A, Marcelin G, Ouhachi M, Dussaud S, Voland L, Manuel R, Baba I, Rouault C, Yvan-Charvet L, Clément K, Tussiwand R, Huby T, Gautier EL. Fructooligosaccharides benefits on glucose homeostasis upon high-fat diet feeding require type 2 conventional dendritic cells. Nat Commun 2024; 15:5413. [PMID: 38926424 PMCID: PMC11208547 DOI: 10.1038/s41467-024-49820-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
Diet composition impacts metabolic health and is now recognized to shape the immune system, especially in the intestinal tract. Nutritional imbalance and increased caloric intake are induced by high-fat diet (HFD) in which lipids are enriched at the expense of dietary fibers. Such nutritional challenge alters glucose homeostasis as well as intestinal immunity. Here, we observed that short-term HFD induced dysbiosis, glucose intolerance and decreased intestinal RORγt+ CD4 T cells, including peripherally-induced Tregs and IL17-producing (Th17) T cells. However, supplementation of HFD-fed male mice with the fermentable dietary fiber fructooligosaccharides (FOS) was sufficient to maintain RORγt+ CD4 T cell subsets and microbial species known to induce them, alongside having a beneficial impact on glucose tolerance. FOS-mediated normalization of Th17 cells and amelioration of glucose handling required the cDC2 dendritic cell subset in HFD-fed animals, while IL-17 neutralization limited FOS impact on glucose tolerance. Overall, we uncover a pivotal role of cDC2 in the control of the immune and metabolic effects of FOS in the context of HFD feeding.
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Affiliation(s)
- Adélaïde Gélineau
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Geneviève Marcelin
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Nutrition and Obesities: Systemic approaches research group, NutriOmics, Paris, France
| | - Melissa Ouhachi
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Sébastien Dussaud
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Lise Voland
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Nutrition and Obesities: Systemic approaches research group, NutriOmics, Paris, France
| | - Raoul Manuel
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Ines Baba
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Christine Rouault
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Nutrition and Obesities: Systemic approaches research group, NutriOmics, Paris, France
| | - Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale, Inserm, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, Nice, France
| | - Karine Clément
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Nutrition and Obesities: Systemic approaches research group, NutriOmics, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, service de Nutrition, Paris, France
| | - Roxane Tussiwand
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Thierry Huby
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France
| | - Emmanuel L Gautier
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Inserm, Research Unit on Cardiovascular and Metabolic Diseases, Hôpital de la Pitié-Salpêtrière, Paris, France.
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13
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Rochoń J, Kalinowski P, Szymanek-Majchrzak K, Grąt M. Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease. World J Gastroenterol 2024; 30:2964-2980. [PMID: 38946874 PMCID: PMC11212696 DOI: 10.3748/wjg.v30.i23.2964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/08/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.
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Affiliation(s)
- Jakub Rochoń
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
| | - Piotr Kalinowski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
| | | | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland
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14
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Jeong JW, Lee SY, Lee DY, Kim JH, Yun SH, Lee J, Mariano E, Moon SS, Hur SJ. Analytical Methods and Effects of Bioactive Peptides Derived from Animal Products: A Mini-Review. Food Sci Anim Resour 2024; 44:533-550. [PMID: 38765288 PMCID: PMC11097009 DOI: 10.5851/kosfa.2024.e31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/04/2024] [Accepted: 04/09/2024] [Indexed: 05/21/2024] Open
Abstract
Peptides with bioactive effects are being researched for various purposes. However, there is a lack of overall research on pork-derived peptides. In this study, we reviewed the process of obtaining bioactive peptides, available analytical methods, and the study of bioactive peptides derived from pork. Pepsin and trypsin, two representative protein digestive enzymes in the body, are hydrolyzed by other cofactors to produce peptides. Bicinchoninic acid assay, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, chromatography, and in vitro digestion simulation systems are utilized to analyze bioactive peptides for protein digestibility and molecular weight distribution. Pork-derived peptides mainly exhibit antioxidant and antihypertensive activities. The antioxidant activity of bioactive peptides increases the accessibility of amino acid residues by disrupting the three-dimensional structure of proteins, affecting free radical scavenging, reactive oxygen species inactivation, and metal ion chelating. In addition, the antihypertensive activity decreases angiotensin II production by inhibiting angiotensin converting enzyme and suppresses blood pressure by blocking the AT1 receptor. Pork-derived bioactive peptides, primarily obtained using papain and pepsin, exhibit significant antioxidant and antihypertensive activities, with most having low molecular weights below 1 kDa. This study may aid in the future development of bioactive peptides and serve as a valuable reference for pork-derived peptides.
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Affiliation(s)
- Jae Won Jeong
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Seung Yun Lee
- Division of Animal Science, Division of Applied Life Science (BK21 Four), Institute of Agriculture & Life Science, Gyeongsang National University, Jinju 52828, Korea
| | - Da Young Lee
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Jae Hyeon Kim
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Seung Hyeon Yun
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Juhyun Lee
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Ermie Mariano
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
| | - Sung Sil Moon
- Sunjin Technology & Research Institute, Icheon 17332, Korea
| | - Sun Jin Hur
- Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, Korea
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15
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Bhalla D, Dinesh S, Sharma S, Sathisha GJ. Gut-Brain Axis Modulation of Metabolic Disorders: Exploring the Intertwined Neurohumoral Pathways and Therapeutic Prospects. Neurochem Res 2024; 49:847-871. [PMID: 38244132 DOI: 10.1007/s11064-023-04084-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/06/2023] [Accepted: 12/08/2023] [Indexed: 01/22/2024]
Abstract
A significant rise in metabolic disorders, frequently brought on by lifestyle choices, is alarming. A wide range of preliminary studies indicates the significance of the gut-brain axis, which regulates bidirectional signaling between the gastrointestinal tract and the cognitive system, and is crucial for regulating host metabolism and cognition. Intimate connections between the brain and the gastrointestinal tract provide a network of neurohumoral transmission that can transmit in both directions. The gut-brain axis successfully establishes that the wellness of the brain is always correlated with the extent to which the gut operates. Research on the gut-brain axis has historically concentrated on how psychological health affects how well the gastrointestinal system works. The latest studies, however, revealed that the gut microbiota interacts with the brain via the gut-brain axis to control phenotypic changes in the brain and in behavior. This study addresses the significance of the gut microbiota, the role of the gut-brain axis in management of various metabolic disorders, the hormonal and neural signaling pathways and the therapeutic treatments available. Its objective is to establish the significance of the gut-brain axis in metabolic disorders accurately and examine the link between the two while evaluating the therapeutic strategies to be incorporated in the future.
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Affiliation(s)
- Diya Bhalla
- Faculty of Life and Allied Health Sciences, MS Ramaiah University of Applied Science, Bangalore, 560048, India
| | - Susha Dinesh
- Department of Bioinformatics, BioNome, Bangalore, 560043, India
| | - Sameer Sharma
- Department of Bioinformatics, BioNome, Bangalore, 560043, India.
| | - Gonchigar Jayanna Sathisha
- Department of Post Graduate Studies and Research in Biochemistry, Jnanasahyadri, Kuvempu University, Shankaraghatta, Shimoga, 577451, India
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16
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Hryciw DH, Patten RK, Rodgers RJ, Proietto J, Hutchinson DS, McAinch AJ. GPR119 agonists for type 2 diabetes: past failures and future hopes for preclinical and early phase candidates. Expert Opin Investig Drugs 2024; 33:183-190. [PMID: 38372052 DOI: 10.1080/13543784.2024.2321271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/16/2024] [Indexed: 02/20/2024]
Abstract
INTRODUCTION Type 2 diabetes (T2D) is metabolic disorder associated with a decrease in insulin activity and/or secretion from the β-cells of the pancreas, leading to elevated circulating glucose. Current management practices for T2D are complex with varying long-term effectiveness. Agonism of the G protein-coupled receptor GPR119 has received a lot of recent interest as a potential T2D therapeutic. AREAS COVERED This article reviews studies focused on GPR119 agonism in animal models of T2D and in patients with T2D. EXPERT OPINION GPR119 agonists in vitro and in vivo can potentially regulate incretin hormone release from the gut, then pancreatic insulin release which regulates blood glucose concentrations. However, the success in controlling glucose homeostasis in rodent models of T2D and obesity, failed to translate to early-stage clinical trials in patients with T2D. However, in more recent studies, acute and chronic dosing with the GPR119 agonist DS-8500a had increased efficacy, although this compound was discontinued for further development. New trials on GPR119 agonists are needed, however it may be that the future of GPR119 agonists lie in the development of combination therapy with other T2D therapeutics.
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Affiliation(s)
- Deanne H Hryciw
- School of Environment and Science, Griffith University, Nathan, Queensland, Australia
- Griffith Institute of Drug Discovery, Griffith University, Nathan, Queensland, Australia
| | - Rhiannon K Patten
- Institute for Health and Sport, Victoria University, Melbourne, Australia
| | - Raymond J Rodgers
- Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Joseph Proietto
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dana S Hutchinson
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Andrew J McAinch
- Institute for Health and Sport, Victoria University, Melbourne, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Victoria University, Melbourne, VIC, Australia
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17
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Wang S, Liu A, Xu C, Hou J, Hong J. GLP-1(7-36) protected against oxidative damage and neuronal apoptosis in the hippocampal CA region after traumatic brain injury by regulating ERK5/CREB. Mol Biol Rep 2024; 51:313. [PMID: 38374452 PMCID: PMC10876747 DOI: 10.1007/s11033-024-09244-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 01/11/2024] [Indexed: 02/21/2024]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) (7-36) amide, an endogenous active form of GLP-1, has been shown to modulate oxidative stress and neuronal cell survival in various neurological diseases. OBJECTIVE This study investigated the potential effects of GLP-1(7-36) on oxidative stress and apoptosis in neuronal cells following traumatic brain injury (TBI) and explored the underlying mechanisms. METHODS Traumatic brain injury (TBI) models were established in male SD rats for in vivo experiments. The extent of cerebral oedema was assessed using wet-to-dry weight ratios following GLP-1(7-36) intervention. Neurological dysfunction and cognitive impairment were evaluated through behavioural experiments. Histopathological changes in the brain were observed using haematoxylin and eosin staining. Oxidative stress levels in hippocampal tissues were measured. TUNEL staining and Western blotting were employed to examine cell apoptosis. In vitro experiments evaluated the extent of oxidative stress and neural apoptosis following ERK5 phosphorylation activation. Immunofluorescence colocalization of p-ERK5 and NeuN was analysed using immunofluorescence cytochemistry. RESULTS Rats with TBI exhibited neurological deterioration, increased oxidative stress, and enhanced apoptosis, which were ameliorated by GLP-1(7-36) treatment. Notably, GLP-1(7-36) induced ERK5 phosphorylation in TBI rats. However, upon ERK5 inhibition, oxidative stress and neuronal apoptosis levels were elevated, even in the presence of GLP-1(7-36). CONCLUSION In summary, this study suggested that GLP-1(7-36) suppressed oxidative damage and neuronal apoptosis after TBI by activating ERK5/CREB.
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Affiliation(s)
- Shuwei Wang
- Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan, 063000, Hebei, China
| | - Aijun Liu
- Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan, 063000, Hebei, China
| | - Chaopeng Xu
- Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan, 063000, Hebei, China
| | - Jingxuan Hou
- Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan, 063000, Hebei, China
| | - Jun Hong
- Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan, 063000, Hebei, China.
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Abdel-Maksoud FM, Ali S, Abd-Elhafeez HH, Abdalla KEH. Meckel's Diverticulum in Adult Geese (Alopochen egyptiacus): A Comprehensive Study of Structure Using Histological, Electron Microscopy, and Immunohistochemical Methods. Cells Tissues Organs 2024; 213:390-402. [PMID: 38237565 DOI: 10.1159/000536210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 01/08/2024] [Indexed: 10/03/2024] Open
Abstract
INTRODUCTION The intestine plays an important role in mediating between the bird and its nutritional environment. The yolk stalk, also known as Meckel's diverticulum, is a landmark between the jejunum and ileum. This work aimed to investigate the anatomical, histological, and electron microscopical features of cellular components of the Meckel's diverticulum (MD) in adult geese. METHODS The intestine was dissected from the bird's body cavity, and Meckel's diverticulum was exposed and prepared for light and electron microscopical examinations. RESULTS Our results revealed that the MD mucosa is thrown up into villi and crypts, and the mucosal epithelium is a columnar epithelium with goblet cells as well as intraepithelial lymphocytes. Lymphoid follicles and numerous immune cells were demonstrated within the lamina propria. The mucous glands were also observed within the lamina propria and among the lymphoid follicles. The lining epithelium of MD appeared with different staining affinities: dark cells (electron-dense) and light cells (electron-lucent) contained few mitochondria and more secretory vesicles, while dark cells contained more mitochondria and fewer secretory vesicles. Immunohistochemical analysis of MD revealed positive immunoreactivity for several markers, such as CD117, chromogranin, PLCβ, cytokeratin, MHC II, and S100. CONCLUSION Taken together, our findings suggest that MD is considered an immune organ in adult geese.
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Affiliation(s)
- Fatma M Abdel-Maksoud
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sphinx University, Assiut, Egypt
| | - Shimaa Ali
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt
| | - Hanan H Abd-Elhafeez
- Department of Cell and Tissues, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - Kamal E H Abdalla
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
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Mariam Z, Niazi SK. Glucagon-like peptide agonists: A prospective review. Endocrinol Diabetes Metab 2024; 7:e462. [PMID: 38093651 PMCID: PMC10782143 DOI: 10.1002/edm2.462] [Citation(s) in RCA: 38] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/03/2023] [Accepted: 11/19/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising therapeutic options for addressing Type-2 diabetes, obesity, and related conditions. Among these, semaglutide, tirzepatide, liraglutide etc., all notable GLP-1RA, have gained attention owing to their favourable pharmacological properties and clinical efficacy. AIMS This comprehensive review aims to provide a detailed analysis of both the currently available GLP-1RAs in the market and those undergoing clinical trials. The focus is on examining their mechanism of action, pharmacokinetics, efficacy in glycemic control and weight management, safety profile, and potential applications. MATERIALS & METHODS The review employs a systematic approach to gather information on GLP-1RAs. Relevant literature from the currently literature and ongoing clinical trials is thoroughly examined. Detailed scrutiny is applied to understand the mechanism of action, pharmacokinetic properties, and clinical outcomes of these agents. RESULTS The review presents a comprehensive overview of the GLP-1RAs, highlighting their distinct mechanisms of action, pharmacokinetic profiles, and clinical effectiveness in glycemic control and weight management. Safety profiles are also discussed, providing a holistic understanding of these therapeutic agents. DISCUSSION The findings are discussed in the context of advancements in the field of GLP-1RAs. Potential applications beyond diabetes and obesity are explored, shedding light on the broader implications of these agents in managing related conditions. CONCLUSION In conclusion, this review underscores the significance of GLP-1RAs, with a specific focus on semaglutide, in the management of type 2 diabetes, obesity, and beyond. By synthesizing information on their mechanisms, pharmacokinetics, efficacy, and safety, this review provides valuable insights into the potential benefits these agents offer, contributing to the ongoing discourse in the field.
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Ozeki T, Muramatsu K, Yoshimoto N, Ujiie I, Izumi K, Iwata H, Mushiroda T, Ujiie H. Association of Genetic Variants of HLA-DQA1 with Bullous Pemphigoid Induced by Dipeptidyl Peptidase-4 Inhibitors. J Invest Dermatol 2023; 143:2219-2225.e5. [PMID: 37156394 DOI: 10.1016/j.jid.2023.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 03/24/2023] [Accepted: 04/17/2023] [Indexed: 05/10/2023]
Abstract
Bullous pemphigoid (BP) is the most common autoimmune blistering disorder. Several factors, including an antidiabetic (dipeptidyl peptidase-4 inhibitor [DPP-4i]), have been reported to trigger BP. To identify the genetic variants associated with BP, GWAS and HLA fine-mapping analyses were conducted. The 21 cases of noninflammatory BP induced by DPP-4i (i.e., DPP-4i-induced noninflammatory BP) and 737 controls (first cohort) and the 8 cases and 164 controls (second cohort) were included in the GWAS. Combining GWAS satisfied the genome-wide significant association of HLA-DQA1 (chromosome 6, rs3129763 [T/C]) with the risk of DPP-4i-induced noninflammatory BP (allele T carrier of 72.4% [21 of 29] in cases vs. 15.3% [138 of 901] in controls; dominant model, OR = 14, P = 1.8 × 10-9). HLA fine mapping revealed that HLA-DQA1∗05 with serine at position 75 of HLA-DQα1 (Ser75) had the most significant association with the combined cohort of DPP-4i-induced noninflammatory BP (79.3% [23 of 29] cases vs. 16.1% [145 of 901] controls; dominant model, OR = 21, P = 2.0 × 10-10). HLA-DQα1 Ser75 polymorphism was located inside the functional pocket of HLA-DQ molecules, suggesting the impact of HLA-DQα1 Ser75 on DPP-4i-induced noninflammatory BP.
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Affiliation(s)
- Takeshi Ozeki
- Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Ken Muramatsu
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Norihiro Yoshimoto
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Inkin Ujiie
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kentaro Izumi
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroaki Iwata
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Taisei Mushiroda
- Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hideyuki Ujiie
- Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
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Zhou Y, Huang S, Li C, Qiao Y, Liu Q, Chen T, Wang J, Liu Y. Glucagon-Like Peptide-1 (GLP-1) Rescue Diabetic Cardiac Dysfuntions in Human iPSC-Derived Cardiomyocytes. Adv Biol (Weinh) 2023; 7:e2200130. [PMID: 36373695 DOI: 10.1002/adbi.202200130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/29/2022] [Indexed: 11/16/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) can improve cardiac function and cardiovascular outcomes in diabetic cardiomyopathy; however, the beneficial effect of GLP-1 on human diabetic cardiomyocytes (DCMs) and its mechanism have not been fully elucidated. Here, the DCMs model by human-induced pluripotent stem cells-derived cardiomyocytes is developed. Two subtypes of GLP-1, GLP-17-36 and GLP-19-36 , are evaluated for their efficacy on the DCMs model. Diabetogenic condition is sufficient to induce most characteristics of diabetic cardiomyopathy in vitro, such as cardiac hypertrophy, lipid accumulation, impaired calcium transients, and abnormal electrophysiological properties. GLP-17-36 and GLP-19-36 can restore cardiomyocyte hypertrophic phenotype, impaired calcium transient frequency, abnormal action potential amplitude, depolarization, and repolarization velocity. Interestingly, RNA-seq reveals different pathways altered by GLP-17-36 and GLP-19-36 , respectively. Differentially expressed gene analysis reveals that possible targets of GLP-17-36 involve the regulation of mitotic nuclear division and extracellular matrix-receptor interaction, while possible targets of GLP-19-36 involve kinetochore assembly, and the complement and coagulation cascades. This study demonstrates the therapeutic effects of GLP-1 on human DCMs and provides a novel platform to unveil the cellular mechanisms of diabetic cardiomyopathy, shedding light on discovering better targets for novel therapeutic interventions.
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Affiliation(s)
- Ying Zhou
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, 109 Longmian Avenue, Nanjing, 211166, China
| | - Shuting Huang
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, 109 Longmian Avenue, Nanjing, 211166, China
| | - Chengwu Li
- HELP Therapeutics, 568 Longmian Avenue, Nanjing, 211166, China
| | - Yue Qiao
- Department of Endocrinology, The Second Hospital of Jilin University, 218 Ziqiang Street, Changchun, 210031, China
| | - Qing Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, 109 Longmian Avenue, Nanjing, 211166, China
| | - Taotao Chen
- HELP Therapeutics, 568 Longmian Avenue, Nanjing, 211166, China
| | - Jiaxian Wang
- HELP Therapeutics, 568 Longmian Avenue, Nanjing, 211166, China
| | - Yu Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, 109 Longmian Avenue, Nanjing, 211166, China
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Miura M, Igarashi M, Isotani R, Nakagawa-Nagahama Y, Kuranami S, Naruse K, Kadowaki T, Yamauchi T. SIRT1 Controls Enteroendocrine Progenitor Cell Proliferation in High-Fat Diet-Fed Mice. Cell Mol Gastroenterol Hepatol 2023; 16:1040-1057. [PMID: 37598893 PMCID: PMC10685171 DOI: 10.1016/j.jcmgh.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND & AIMS We aimed to investigate how sirtuin 1 (SIRT1), a conserved mammalian Nicotinamide adenine dinucleotide+-dependent protein deacetylase, regulates the number of enteroendocrine cells (EECs). EECs benefit metabolism, and their increase potentially could treat type 2 diabetes and obesity. METHODS We used mice with specific Sirt1 disruption in the intestinal epithelium (VilKO, villin-Cre+, and Sirt1flox/flox mice) or enteroendocrine progenitor cells (EEPCs) (NgnKO, neurogenin 3-Cre+, Sirt1flox/flox mice) and mice with increased SIRT1 activity owing to overexpression (Sir2d mice) or 24-hour fasting. Mice were fed a high-fat diet (HFD), and blood glucagon-like peptide 1 (GLP-1) and glucose levels were measured. Intestinal tissues, EECs, and formed organoids were analyzed using quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In HFD-fed VilKO and NgnKO mice, an increase in EECs (42.3% and 37.2%), GLP-1- or GLP-2-producing L cells (93.0% and 61.4%), and GLP-1 (85.7% and 109.6%) was observed after glucose loading, explaining the improved metabolic phenotype of HFD-VilKO mice. These increases were associated with up-regulated expression of neurogenin 3 (EEPC marker) in crypts of HFD-VilKO and HFD-NgnKO mice, respectively. Conversely, Sir2d or 24-hour fasted mice showed a decrease in EECs (21.6%), L cells (41.6%), and proliferative progenitor cells. SIRT1 overexpression- or knockdown-mediated change in the progenitor cell proliferation was associated with Wnt/β-catenin activity changes. Notably, Wnt/β-catenin inhibitor completely suppressed EEC and L-cell increases in HFD-VilKO mice or organoids from HFD-VilKO and HFD-NgnKO mice. CONCLUSIONS Intestinal SIRT1 in EECs modulates the EEPC cycle by regulating β-catenin activity and can control the number of EECs in HFD-fed mice, which is a previously unknown role.
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Affiliation(s)
- Masaomi Miura
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaki Igarashi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Biology, Koch Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts.
| | - Ryosuke Isotani
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshiko Nakagawa-Nagahama
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Satoshi Kuranami
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kyoko Naruse
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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Wang Y, Lopez-Bellido R, Huo X, Kavelaars A, Galko MJ. The insulin receptor regulates the persistence of mechanical nociceptive sensitization in flies and mice. Biol Open 2023; 12:bio059864. [PMID: 37259940 PMCID: PMC10245137 DOI: 10.1242/bio.059864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 04/28/2023] [Indexed: 05/10/2023] Open
Abstract
Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent mechanical hypersensitivity. Mice with a specific deletion of the Insr gene in Nav1.8+ nociceptive sensory neurons showed nociceptive thermal and mechanical baselines similar to controls. In an inflammatory paradigm, however, these mutant mice showed persistent mechanical (but not thermal) hypersensitivity, particularly in female mice. Mice with the Nav1.8+ sensory neuron-specific deletion of Insr did not show metabolic abnormalities typical of a defect in systemic insulin signaling. Our results show that some aspects of the regulation of nociceptive hypersensitivity by the insulin receptor are shared between flies and mice and that this regulation is likely independent of metabolic effects.
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Affiliation(s)
- Yan Wang
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Roger Lopez-Bellido
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Xiaojiao Huo
- Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Annemieke Kavelaars
- Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Neuroscience Graduate Program, The MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Michael J. Galko
- Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Neuroscience Graduate Program, The MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
- Genetics & Epigenetics Graduate Program, The MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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Mu X, Wang R, Cheng C, Ma Y, Zhang Y, Lu W. Preparation, structural properties, and in vitro and in vivo activities of peptides against dipeptidyl peptidase IV (DPP-IV) and α-glucosidase: a general review. Crit Rev Food Sci Nutr 2023; 64:9844-9858. [PMID: 37310013 DOI: 10.1080/10408398.2023.2217444] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Diabetes is one of the fastest-growing and most widespread diseases worldwide. Approximately 90% of diabetic patients have type 2 diabetes. In 2019, there were about 463 million diabetic patients worldwide. Inhibiting the dipeptidyl peptidase IV (DPP-IV) and α-glucosidase activity is an effective strategy for the treatment of type 2 diabetes. Currently, various anti-diabetic bioactive peptides have been isolated and identified. This review summarizes the preparation methods, structure-effect relationships, molecular binding sites, and effectiveness validation of DPP-IV and α-glucosidase inhibitory peptides in cellular and animal models. The analysis of peptides shows that the DPP-IV inhibitory peptides, containing 2-8 amino acids and having proline, leucine, and valine at their N-terminal and C-terminal, are the highly active peptides. The more active α-glucosidase inhibitory peptides contain 2-9 amino acids and have valine, isoleucine, and proline at the N-terminal and proline, alanine, and serine at the C-terminal.
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Affiliation(s)
- Xinxin Mu
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, China
| | - Rongchun Wang
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, China
- Zhengzhou Institute, Harbin Institute of Technology, Zhengzhou, China
- Qiongqing Institute, Harbin Institute of Technology, Qiongqing, China
| | - Cuilin Cheng
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, China
- Qiongqing Institute, Harbin Institute of Technology, Qiongqing, China
- National and Local Joint Engineering Laboratory for Synthesis, Transformation and Separation of Extreme Environmental Nutrients, Harbin Institute of Technology, Harbin, China
| | - Ying Ma
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, China
- Zhengzhou Institute, Harbin Institute of Technology, Zhengzhou, China
- Qiongqing Institute, Harbin Institute of Technology, Qiongqing, China
| | - Yingchun Zhang
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, China
- Zhengzhou Institute, Harbin Institute of Technology, Zhengzhou, China
- Qiongqing Institute, Harbin Institute of Technology, Qiongqing, China
| | - Weihong Lu
- Department of Food Nutrition and Health, School of Medicine and Health, Harbin Institute of Technology, Harbin, China
- Zhengzhou Institute, Harbin Institute of Technology, Zhengzhou, China
- Qiongqing Institute, Harbin Institute of Technology, Qiongqing, China
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25
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Biomedical importance of the ubiquitin-proteasome system in diabetes and metabolic transdifferentiation of pancreatic duct epithelial cells into β-cells. Gene 2023; 858:147191. [PMID: 36632913 DOI: 10.1016/j.gene.2023.147191] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 01/05/2023] [Accepted: 01/06/2023] [Indexed: 01/09/2023]
Abstract
The ubiquitin-proteasome system (UPS) is a major pathway for cellular protein degradation. The molecular function of the UPS is the removal of damaged proteins, and this function is applied in many biological processes, including inflammation, proliferation, and apoptosis. Accumulating evidence also suggests that the UPS also has a key role in pancreatic β-cell transdifferentiation in diabetes and can be targeted for treatment of diabetic diseases. In this review, we summarized the mechanistic roles of the UPS in the biochemical activities of pancreatic β-cells, including the role of the UPS in insulin synthesis and secretion, as well as β-cell degradation. Also, we discuss how the UPS mediates the transdifferentiation of pancreatic duct epithelial cells into β-cells as the experimental basis for the development of new strategies for the treatment of diabetes in regenerative medicine.
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McKimpson WM, Spiegel S, Mukhanova M, Kraakman M, Du W, Kitamoto T, Yu J, Pajvani U, Accili D. Calorie Restriction activates a gastric Notch-FOXO1 pathway to expand Ghrelin cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.06.531352. [PMID: 36945500 PMCID: PMC10028817 DOI: 10.1101/2023.03.06.531352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Calorie restriction increases lifespan. While some tissue-specific protective effects of calorie restriction have been described, the impact of calorie restriction on the gastrointestinal tract remains unclear. We found increased abundance of chromogranin A+, including orexigenic ghrelin+, endocrine cells in the stomach of calorie-restricted mice. This effect coincided with increased Notch target Hes1 and Notch ligand Jag1 and was reversed when Notch signaling was blocked using the γ-secretase inhibitor DAPT. Using primary cultures and genetically-modified reporter mice, we determined that increased endocrine cell abundance was due to altered stem and progenitor proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, calorie restriction triggered nuclear localization of FOXO1, which was sufficient to promote endocrine cell differentiation. Taken together, the data indicate that calorie restriction promotes gastric endocrine cell differentiation triggered by active Notch signaling and regulated by FOXO1.
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Komatsu T, Abe S, Nakashima S, Sasaki K, Higaki Y, Saku K, Miura SI, Uehara Y. Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Phosphate Accelerates Cellular Cholesterol Efflux in THP-1 Cells. Biomolecules 2023; 13:228. [PMID: 36830597 PMCID: PMC9953524 DOI: 10.3390/biom13020228] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/11/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
Cholesterol efflux is a major atheroprotective function of high-density lipoproteins (HDLs) which removes cholesterol from the foam cells of lipid-rich plaques in Type 2 diabetes. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin phosphate increases plasma glucagon-like peptide-1 (GLP-1) concentrations and is used to treat Type 2 diabetes. GLP-1 plays an important role in regulating insulin secretion and expression via the GLP-1 receptor (GLP-1R), which is expressed in pancreatic islets as well as freshly isolated human monocytes and THP-1 cells. Here, we identified a direct role of GLP-1 and DPP-4 inhibition in HDL function. Cholesterol efflux was measured in cultivated phorbol 12-myristate 13-acetate-treated THP-1 cells radiolabeled with 3H-cholesterol and stimulated with liver X receptor/retinoid X receptor agonists. Contrary to vildagliptin, sitagliptin phosphate together with GLP-1 significantly (p < 0.01) elevated apolipoprotein (apo)A1-mediated cholesterol efflux in a dose-dependent manner. The sitagliptin-induced increase in cholesterol efflux did not occur in the absence of GLP-1. In contrast, adenosine triphosphate-binding cassette transporter A1 (ABCA1) mRNA and protein expressions in the whole cell fraction were not changed by sitagliptin in the presence of GLP-1, although sitagliptin treatment significantly increased ABCA1 protein expression in the membrane fraction. Furthermore, the sitagliptin-induced, elevated efflux in the presence of GLP-1 was significantly decreased by a GLP-1R antagonist, an effect that was not observed with a protein kinase A inhibitor. To our knowledge, the present study reports for the first time that sitagliptin elevates cholesterol efflux in cultivated macrophages and may exert anti-atherosclerotic actions that are independent of improvements in glucose metabolism. Our results suggest that sitagliptin enhances HDL function by inducing a de novo HDL synthesis via cholesterol efflux.
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Affiliation(s)
- Tomohiro Komatsu
- Research Institute for Physical Activity, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
- Center for Preventive, Anti-Aging and Regenerative Medicine, Fukuoka University Hospital, 7-45-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
| | - Satomi Abe
- Research Institute for Physical Activity, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
| | - Shihoko Nakashima
- Faculty of Sports and Health Science, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
| | - Kei Sasaki
- Center for Preventive, Anti-Aging and Regenerative Medicine, Fukuoka University Hospital, 7-45-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
| | - Yasuki Higaki
- Research Institute for Physical Activity, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
- Faculty of Sports and Health Science, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
| | - Keijiro Saku
- Department of Cardiology, Fukuoka University Hospital, 7-45-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
| | - Shin-ichiro Miura
- Department of Cardiology, Fukuoka University Hospital, 7-45-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
| | - Yoshinari Uehara
- Research Institute for Physical Activity, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
- Center for Preventive, Anti-Aging and Regenerative Medicine, Fukuoka University Hospital, 7-45-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
- Faculty of Sports and Health Science, Fukuoka University, 8-19-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
- Department of Cardiology, Fukuoka University Hospital, 7-45-1 Nanakuma, Johnan-ku, Fukuoka 814-0180, Japan
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Baafi K, March JC. Harnessing gut cells for functional insulin production: Strategies and challenges. BIOTECHNOLOGY NOTES (AMSTERDAM, NETHERLANDS) 2022; 4:7-13. [PMID: 39416909 PMCID: PMC11446352 DOI: 10.1016/j.biotno.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/30/2022] [Accepted: 11/30/2022] [Indexed: 10/19/2024]
Abstract
Reprogrammed glucose-responsive, insulin + cells ("β-like") exhibit the potential to bypass the hurdles of exogenous insulin delivery in treating diabetes mellitus. Current cell-based therapies-transcription factor regulation, biomolecule-mediated enteric signaling, and transgenics - have demonstrated the promise of reprogramming either mature or progenitor gut cells into surrogate "β-like" cells. However, there are predominant challenges impeding the use of gut "β-like" cells as clinical replacements for insulin therapy. Reprogrammed "β-like" gut cells, even those of enteroendocrine origin, mostly do not exhibit glucose - potentiated insulin secretion. Despite the exceptionally low conversion rate of gut cells into surrogate "β-like" cells, the therapeutic quantity of gut "β-like" cells needed for normoglycemia has not even been established. There is also a lingering uncertainty regarding the functionality and bioavailability of gut derived insulin. Herein, we review the strategies, challenges, and opportunities in the generation of functional, reprogrammed "β-like" cells.
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Affiliation(s)
- Kelvin Baafi
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, 14853, USA
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RNA binding protein HuD mediates the crosstalk between β cells and islet endothelial cells by the regulation of Endostatin and Serpin E1 expression. Cell Death Dis 2022; 13:1019. [PMID: 36470872 PMCID: PMC9722926 DOI: 10.1038/s41419-022-05465-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022]
Abstract
RNA binding protein HuD plays essential roles in gene expression by regulating RNA metabolism, and its dysregulation is involved in the pathogenesis of several diseases, including tumors, neurodegenerative diseases, and diabetes. Here, we explored HuD-mediated differential expression of secretory proteins in mouse insulinoma βTC6 cells using a cytokine array. Endostatin and Serpin E1 that play anti-angiogenic roles were identified as differentially expressed proteins by HuD. HuD knockdown increased the expression of α chain of collagen XVIII (Col18a1), a precursor form of endostatin, and Serpin E1 by associating with the 3'-untranslated regions (UTRs) of Col18a1 and Serpin E1 mRNAs. Reporter analysis revealed that HuD knockdown increased the translation of EGFP reporters containing 3'UTRs of Col18a1 and Serpin E1 mRNAs, which suggests the role of HuD as a translational repressor. Co-cultures of βTC6 cells and pancreatic islet endothelial MS1 cells were used to assess the crosstalk between β cells and islet endothelial cells, and the results showed that HuD downregulation in βTC6 cells inhibited the growth and migration of MS1 cells. Ectopic expression of HuD decreased Col18a1 and Serpin E1 expression, while increasing the markers of islet vascular cells in the pancreas of db/db mice. Taken together, these results suggest that HuD has the potential to regulate the crosstalk between β cells and islet endothelial cells by regulating Endostatin and Serpin E1 expression, thereby contributing to the maintenance of homeostasis in the islet microenvironment.
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Sharif A. Interventions Against Posttransplantation Diabetes: A Scientific Rationale for Treatment Hierarchy Based on Literature Review. Transplantation 2022; 106:2301-2313. [PMID: 35696695 DOI: 10.1097/tp.0000000000004198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Posttransplant diabetes (PTD) is a common medical complication after solid organ transplantation. Because of adverse outcomes associated with its development and detrimental impact on long-term survival, strategies to prevent or manage PTD are critically important but remain underresearched. Treatment hierarchies of antidiabetic therapies in the general population are currently being revolutionized based on cardiovascular outcome trials, providing evidence-based rationale for optimization of medical management. However, opportunities for improving medical management of PTD are challenged by 2 important considerations: (1) translating clinical evidence data from the general population to underresearched solid organ transplant cohorts and (2) targeting treatment based on primary underlying PTD pathophysiology. In this article, the aim is to provide an overview of PTD treatment options from a new angle. Rationalized by a consideration of underlying PTD pathophysiological defects, which are heterogeneous among diverse transplant patient cohorts, a critical appraisal of the published literature and summary of current research in progress will be reviewed. The aim is to update transplant professionals regarding medical management of PTD from a new perspective tailored therapeutic intervention based on individualized characteristics. As the gap in clinical evidence between management of PTD versus type 2 diabetes widens, it is imperative for the transplant community to bridge this gap with targeted clinical trials to ensure we optimize outcomes for solid organ transplant recipients who are at risk or develop PTD. This necessary clinical research should help efforts to improve long-term outcomes for solid transplant patients from both a patient and graft survival perspective.
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Affiliation(s)
- Adnan Sharif
- Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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Nibali L, Gkranias N, Mainas G, Di Pino A. Periodontitis and implant complications in diabetes. Periodontol 2000 2022; 90:88-105. [PMID: 35913467 DOI: 10.1111/prd.12451] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Epidemiologic evidence indicates that periodontitis is more frequent in patients with uncontrolled diabetes mellitus than in healthy controls, suggesting that it could be considered the "sixth complication" of diabetes. Actually, diabetes mellitus and periodontitis are two extraordinarily prevalent chronic diseases that share a number of comorbidities all converging toward an increased risk of cardiovascular disease. Periodontal treatment has recently been shown to have the potential to improve the metabolic control of diabetes, although long-term studies are lacking. Uncontrolled diabetes also seems to affect the response to periodontal treatment, as well as the risk to develop peri-implant diseases. Mechanisms of associations between diabetes mellitus and periodontal disease include the release of advanced glycation end products as a result of hyperglycemia and a range of shared predisposing factors of genetic, microbial, and lifestyle nature. This review discusses the evidence for the risk of periodontal and peri-implant disease in diabetic patients and the potential role of the dental professional in the diabetes-periodontal interface.
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Affiliation(s)
- Luigi Nibali
- Periodontology Unit, Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Nikolaos Gkranias
- Centre for Immunobiology and Regenerative Medicine and Centre for Oral Clinical Research, Institute of Dentistry, Queen Mary University London (QMUL), London, UK
| | - Giuseppe Mainas
- Periodontology Unit, Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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Abstract
We are host to an assembly of microorganisms that vary in structure and function along the length of the gut and from the lumen to the mucosa. This ecosystem is collectively known as the gut microbiota and significant efforts have been spent during the past 2 decades to catalog and functionally describe the normal gut microbiota and how it varies during a wide spectrum of disease states. The gut microbiota is altered in several cardiometabolic diseases and recent work has established microbial signatures that may advance disease. However, most research has focused on identifying associations between the gut microbiota and human diseases states and to investigate causality and potential mechanisms using cells and animals. Since the gut microbiota functions on the intersection between diet and host metabolism, and can contribute to inflammation, several microbially produced metabolites and molecules may modulate cardiometabolic diseases. Here we discuss how the gut bacterial composition is altered in, and can contribute to, cardiometabolic disease, as well as how the gut bacteria can be targeted to treat and prevent metabolic diseases.
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Affiliation(s)
- Louise E Olofsson
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sweden
| | - Fredrik Bäckhed
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sweden.,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Denmark.,Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden
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Reprogramming—Evolving Path to Functional Surrogate β-Cells. Cells 2022; 11:cells11182813. [PMID: 36139388 PMCID: PMC9496933 DOI: 10.3390/cells11182813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 12/04/2022] Open
Abstract
Numerous cell sources are being explored to replenish functional β-cell mass since the proof-of -concept for cell therapy of diabetes was laid down by transplantation of islets. Many of these cell sources have been shown to possess a degree of plasticity permitting differentiation along new lineages into insulin-secreting β-cells. In this review, we explore emerging reprograming pathways that aim to generate bone fide insulin producing cells. We focus on small molecules and key transcriptional regulators that orchestrate phenotypic conversion and maintenance of engineered cells.
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Kang B, Liu XY, Cheng YX, Tao W, Peng D. Factors associated with hypertension remission after gastrectomy for gastric cancer patients. World J Gastrointest Surg 2022; 14:743-753. [PMID: 36157372 PMCID: PMC9453326 DOI: 10.4240/wjgs.v14.i8.743] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 06/24/2022] [Accepted: 08/05/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Previous studies reported hypertension remission after gastrectomy for gastric cancer patients, and the remission rate was 11.1%-93.8%. We have reported the factors of hypertension remission previously, however, the follow-up time was six months. It is necessary to identify risk factors for hypertension for a relatively longer follow-up time.
AIM To analyze the predictive factors for hypertension remission one year after gastrectomy of gastric cancer patients and to construct a risk model for hypertension remission.
METHODS We retrospectively collected the medical information of patients with concurrent gastric cancer and hypertension in a single clinical center from January 2013 to December 2020. Univariate and multivariate logistic regression of hypertension remission were conducted, and a nomogram model was established.
RESULTS A total of 209 patients with concurrent gastric cancer and hypertension were included in the current study. There were 108 patients in the remission group and 101 patients in the non-remission group. The hypertension remission rate was 51.7% one year after gastrectomy. The remission group had younger aged patients (P = 0.001), larger weight loss (P = 0.001), lower portion of coronary heart disease (P = 0.017), higher portion of II-degree hypertension (P = 0.033) and higher portion of total gastrectomy (P = 0.008) than the non-remission group. Younger age (P = 0.011, odds ratio = 0.955, 95%CI: 0.922-0.990), higher weight loss (P = 0.019, odds ratio = 0.937, 95%CI: 0.887-0.989) and total gastrectomy (P = 0.039, odds ratio = 2.091, 95%CI: 1.037-4.216) were independent predictors for hypertension remission. The concordance index of the model was 0.769 and the calibration curve suggested great agreement. Furthermore, decision curve analysis showed that the model was clinically useful.
CONCLUSION Younger age, higher weight loss and total gastrectomy were independent predictors for hypertension remission after gastrectomy for gastric cancer patients. The nomogram could visually display these results.
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Affiliation(s)
- Bing Kang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Clinical Nutrition, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Xiao-Yu Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yu-Xi Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Tao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Dong Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Li S, Liu J, Wang Z, Duan F, Jia Z, Chen X, Li S. The promising role of probiotics/prebiotics/synbiotics in energy metabolism biomarkers in patients with NAFLD: A systematic review and meta-analysis. Front Public Health 2022; 10:862266. [PMID: 35958869 PMCID: PMC9358257 DOI: 10.3389/fpubh.2022.862266] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with a high prevalence worldwide, seriously harming human health, and its pathogenesis remains unclear. In recent years, increasing evidence has indicated that intestinal microbiota plays an important role in the occurrence and development of NAFLD. The regulation method of probiotics/prebiotics/synbiotics can alter the intestinal microbiota and has been suggested as an option in the treatment of NAFLD. Methods Five databases of PubMed, Embase, the Cochrane Library, clinicaltrails.gov, and China National Knowledge Infrastructure were searched initially, and then the eligible studies were screened. Finally, the data of included studieswere extracted, combined and analyzed Results A total of 29 randomized controlled trials involving 2,110 patients were included in this study. The results showed that using probiotics/prebiotics/synbiotics in the intervention group could reduce the levels of glucose (SMD = −0.23, 95% CI [−0.45, −0.01], P = 0.04), HOMA-IR (SMD = −0.47, 95% CI [−0.63, −0.31], P < 0.00001) and insulin (SMD = −0.46, 95% CI [−0.76, −0.16], P = 0.002) in sugar metabolism; in terms of lipid metabolism, the levels of TC (SMD = −0.62, 95%CI [−0.87, −0.36], P < 0.00001), and LDL-C (SMD = −0.57, 95%CI [−0.85, −0.28], P < 0.00001) were decreased; and the level of ALB was decreased in protein metabolism (SMD = −0.34, 95%CI [−0.61, −0.06], P = 0.02). Conclusions Based on the current evidence, probiotics/prebiotics/synbiotics may improve energy metabolism biomarkers in the NAFLD population, but these effects still need to be confirmed by further research. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/#aboutpage.
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Affiliation(s)
- Shudi Li
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Jiangkai Liu
- The First Affiliated Hospital of Henan University of TCM, Zhengzhou, China
| | - Zhen Wang
- The First Affiliated Hospital of Henan University of TCM, Zhengzhou, China
| | - Fei Duan
- The First Affiliated Hospital of Henan University of TCM, Zhengzhou, China
| | - Zi Jia
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Xinju Chen
- The First Affiliated Hospital of Henan University of TCM, Zhengzhou, China
| | - Suling Li
- The First Affiliated Hospital of Henan University of TCM, Zhengzhou, China
- *Correspondence: Suling Li
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Ma C, Liu D, Hao H, Wu X. Identification of the DPP-IV Inhibitory Peptides from Donkey Blood and Regulatory Effect on the Gut Microbiota of Type 2 Diabetic Mice. Foods 2022; 11:foods11142148. [PMID: 35885395 PMCID: PMC9316604 DOI: 10.3390/foods11142148] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/11/2022] [Accepted: 07/16/2022] [Indexed: 02/06/2023] Open
Abstract
After being treated with protease K, peptides extracted from donkey blood were separated, identified, and characterized. The results showed that Sephadex G-25 medium purified with MW < 3 kDa had the highest dipeptidyl peptidase IV (DPP-IV) inhibition capacity. Three-hundred-and-thirty-four peptides were identified with UPLC−MS/MS. Peptide Ranker and molecular docking analysis were used to screen active peptides, and 16 peptides were finalized out of the 334. The results showed that the lowest binding energy between P7(YPWTQ) and DPP-IV was −9.1, and the second-lowest binding energy between P1(VDPENFRLL) and DPP-IV was −8.7. The active peptides(MW < 3 kDa) could cause a reduction in the fasting blood glucose levels of type 2 diabetic mice, improve glucose tolerance, and facilitate healing of the damaged structure of diabetic murine liver and pancreas. Meanwhile, the peptides were found to ameliorate the diabetic murine intestinal micro-ecological environment to a certain extent.
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37
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Choi YS, Yi JW, Shin WY, Heo Y. Oncometabolic surgery in gastric cancer patients with type 2 diabetes. Sci Rep 2022; 12:11853. [PMID: 35831319 PMCID: PMC9279435 DOI: 10.1038/s41598-022-15404-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 06/23/2022] [Indexed: 12/04/2022] Open
Abstract
The rates of early gastric cancer and type 2 diabetes mellitus(T2DM) are sharply increasing in Korea. Oncometabolic surgery in which metabolic surgery is conducted along with cancer surgery is a method used to treat gastric cancer and T2DM in one-stage operation. From 2011 to 2019, a total of 48 patients underwent long-limb Roux-en-Y gastrectomy (LRYG) in Inha University Hospital, and all data were reviewed retrospectively. A 75 g oral glucose tolerance test and serum insulin level test were performed before and 1 week and 1 year after surgery. One year after LRYG operation, 25 of 48 patients showed complete or partial remission and 23 patients showed non-remission of T2DM. The preoperative HbA1c level was significantly lower and the change in HbA1c was significantly greater in the T2DM remission group. Insulin secretion indices(insulinogenic index and disposition index) were increased significantly in the T2DM remission group. In contrast, the insulin resistance indices (homeostatic model assessment of insulin resistance (HOMA-IR) and Matsuda index) changed minimal. In the case of LRYG in T2DM patients, remnant β cell function is an important predictor of favorable glycemic control.
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Affiliation(s)
- Yun Suk Choi
- Department of Surgery, Inha University Hospital & College of Medicine, 27, Inhang-ro, Jung-gu, Inchon, 22332, Republic of Korea
| | - Jin Wook Yi
- Department of Surgery, Inha University Hospital & College of Medicine, 27, Inhang-ro, Jung-gu, Inchon, 22332, Republic of Korea
| | - Woo Young Shin
- Department of Surgery, Inha University Hospital & College of Medicine, 27, Inhang-ro, Jung-gu, Inchon, 22332, Republic of Korea
| | - Yoonseok Heo
- Department of Surgery, Inha University Hospital & College of Medicine, 27, Inhang-ro, Jung-gu, Inchon, 22332, Republic of Korea.
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Sun G, Song X, Zou Y, Teng T, Jiang L, Shi B. Dietary Glucose Ameliorates Impaired Intestinal Development and Immune Homeostasis Disorders Induced by Chronic Cold Stress in Pig Model. Int J Mol Sci 2022; 23:ijms23147730. [PMID: 35887078 PMCID: PMC9317271 DOI: 10.3390/ijms23147730] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/11/2022] [Accepted: 07/11/2022] [Indexed: 01/03/2023] Open
Abstract
Endotherms are easily challenged by chronic cold stress. In this study, the development and injury of the small intestine in the Min pig model and Yorkshire pig model under chronic cold stress, and the molecular mechanisms by which glucose supplementation reduces small intestinal mucosal damage were investigated. The results showed that morphological structure lesions of the jejunal mucosa and ileal mucosa were visible in Yorkshire pigs under chronic cold stress. Meanwhile, the Occludin mRNA and protein expression in jejunal mucosa of Yorkshire pigs was decreased. Chronic cold stress enhanced the expression of Toll-like receptor 4 (TLR4), the myeloid differentiation main response 88 (MyD88), nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3), cleaved caspase-1, mature-IL-1β, and high-mobility group box 1 (HMGB 1) mRNA and protein expression in jejunal mucosa of Yorkshire pigs, whereas the mRNA and protein of Bax was triggered in ileal mucosa. In Min pigs, no such deleterious consequences were observed. Dietary glucose supplementation ameliorates small intestinal mucosal injury, declined TLR4 and MyD88 expression in jejunal mucosa. In conclusion, chronic cold stress induced the small intestinal mucosa damage in Yorkshire pigs, whereas glucose supplementation mitigated the deleterious effects of chronic cold stress on the small intestine.
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Chen YC, Walhin JP, Hengist A, Gonzalez JT, Betts JA, Thompson D. Interrupting Prolonged Sitting with Intermittent Walking Increases Postprandial Gut Hormone Responses. Med Sci Sports Exerc 2022; 54:1183-1189. [PMID: 35389963 DOI: 10.1249/mss.0000000000002903] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Continuous exercise can increase postprandial gut hormone such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) responses, but it is unknown whether interrupting prolonged sitting with intermittent walking elicits this effect. METHOD Ten participants with central overweight/obesity (7 men and 3 postmenopausal women, 51 ± 5 yr; mean ± SD) completed a randomized crossover study in which they consumed breakfast and lunch in the laboratory while either sitting continuously for the entire 5.5-h period (SIT) or the prolonged sitting interrupted every 20 min by walking briskly (6.4 km·h-1) for 2 min (BREAKS). Blood samples were collected at regular intervals to examine postprandial plasma GLP-1, PYY, and glucose-dependent insulinotropic polypeptide concentrations. Adipose tissue samples were collected at baseline and at the end of the trials to examine changes in net dipeptidyl peptidase 4 secretion from primary explants. RESULTS Mean (95% confidence interval) postprandial GLP-1 and PYY incremental area under curve values were elevated by 26% and 31% in the BREAKS trial versus SIT (8.4 [0.7, 16.1] vs 6.7 [-0.8, 14.2], P = 0.001, and 26.9 [8.1, 45.6] vs 20.4 [5.1, 35.8] nmol·330 min·L-1, P = 0.024, respectively) but without any such effect on glucose-dependent insulinotropic polypeptide (P = 0.076) or net adipose tissue dipeptidyl peptidase 4 secretion (P > 0.05). CONCLUSIONS Interrupting prolonged sitting with regular short bouts of brisk walking increases postprandial GLP-1 and PYY concentrations in healthy middle-age men and women with central adiposity.
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Affiliation(s)
- Yung-Chih Chen
- Department of Physical Education and Sport Sciences, National Taiwan Normal University, Taipei, TAIWAN
| | | | - Aaron Hengist
- Department for Health, University of Bath, Bath, UNITED KINGDOM
| | | | - James A Betts
- Department for Health, University of Bath, Bath, UNITED KINGDOM
| | - Dylan Thompson
- Department for Health, University of Bath, Bath, UNITED KINGDOM
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Ataeinosrat A, Haghighi MM, Abednatanzi H, Soltani M, Ghanbari-Niaki A, Nouri-Habashi A, Amani-Shalamzari S, Mossayebi A, Khademosharie M, Johnson KE, VanDusseldorp TA, Saeidi A, Zouhal H. Effects of Three Different Modes of Resistance Training on Appetite Hormones in Males With Obesity. Front Physiol 2022; 13:827335. [PMID: 35264977 PMCID: PMC8900747 DOI: 10.3389/fphys.2022.827335] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/31/2022] [Indexed: 12/19/2022] Open
Abstract
Purpose This study explored the effect of three different modes of resistance training on appetite hormones [leptin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine–tyrosine (PYY)], cardiometabolic and anthropometric measures in males with obesity. Methods Forty-four males with obesity (age: 27.5 ± 9.4 yrs.; mean weight: 93.2 ± 2.2 kg, body mass index: 32.9 ± 1.2 kg/m2) were randomized to traditional resistance training (TRT, n = 11), circuit resistance training (CRT, n = 11), interval resistance training (IRT, n = 11) or control (C, n = 11) groups. All resistance training groups received 50 min of supervised training per session, three days per week, for 12 weeks. Measurements were taken at baseline and after 12 weeks of training. Results Plasma levels of leptin, ghrelin, CCK, and PYY decreased significantly in all three different modalities of resistance training groups when compared to the control group (p < 0.05). GLP-1 increased significantly in both CRT and IRT groups compared to TRT and C groups (p < 0.05). Glucose-dependent insulinotropic polypeptide decreased significantly in CRT and IRT groups compared to the C group (p < 0.05). Adiponectin levels increased significantly in all resistance training groups compared to the C group (p < 0.05). Conclusion Overall, CRT and IRT protocols had the greatest impact on appetite hormones compared to individuals who engaged in TRT or did not exercise (C).
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Affiliation(s)
- Ali Ataeinosrat
- Department of Physical Education and Sport Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Hossein Abednatanzi
- Department of Physical Education and Sport Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Soltani
- Department of Biological Sciences in Sport, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | - Abbass Ghanbari-Niaki
- Exercise Biochemistry Division, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran
| | - Akbar Nouri-Habashi
- Department of Exercise Physiology and Corrective Movements, Faculty of Sport Sciences, Urmia University, Urmia, Iran
| | - Sadegh Amani-Shalamzari
- Department of Exercise Physiology, Faculty of Physical Education and Sports Science, Kharazmi University, Tehran, Iran
| | - Ali Mossayebi
- Department of Kinesiology, College of Health Sciences, University of Texas at El Paso, El Paso, TX, United States
| | - Mitra Khademosharie
- Department of Physical Education, Faculty of Literature, Kosar University of Bojnord, Bojnord, Iran
| | - Kelly E Johnson
- Department of Kinesiology, Coastal Carolina University, Conway, SC, United States
| | - Trisha A VanDusseldorp
- Department of Exercise Science and Sport Management, Kennesaw State University, Kennesaw, GA, United States
| | - Ayoub Saeidi
- Department of Physical Education and Sport Sciences, Faculty of Humanities and Social Sciences, University of Kurdistan, Sanandaj, Iran
| | - Hassane Zouhal
- Laboratoire Mouvement, Sport, Santé (M2S), University of Rennes, Rennes, France.,Institut International des Sciences du Sport (2I2S), Iroduer, France
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Adansonia digitata L. (Baobab Fruit) Effect on Postprandial Glycemia in Healthy Adults: A Randomized Controlled Trial. Nutrients 2022; 14:nu14020398. [PMID: 35057579 PMCID: PMC8778021 DOI: 10.3390/nu14020398] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/06/2022] [Accepted: 01/13/2022] [Indexed: 02/01/2023] Open
Abstract
Baobab fruits have been traditionally used in Africa due to their therapeutic properties attributed to their high polyphenol content. The aim of the study was to investigate the effect of baobab fruit on postprandial glycaemia in healthy adults and to measure its bioactive compounds and antioxidant activity. The study (NCT05140629) was conducted on 31 healthy subjects. The participants were randomly allocated in the control group (oral glucose tolerance test (OGTT); n = 16) and in the intervention group (OGTT, followed by administration of 250 mL baobab aqueous extract (BAE); n = 15). Total phenols, proanthocyanins, hydrolyzable tannins, and antioxidant activity (FRAP, DPPH, ABTS, and inhibition of O2•− and NO• methods) were quantified. Repeated measures ANOVA of mixed type and independent samples t-test were used. Glycemia incremental area under the curve (p = 0.012) and glucose maximum concentration (p = 0.029) was significantly lower in the intervention group compared to the control group. The BAE revealed high total contents of phenols, proanthocyanins, and hydrolyzable tannins, as well as a strong capacity to scavenge superoxide anions and nitric oxide radicals and a high antioxidant activity. In conclusion, this study encourages the use of this food component as a promising source of natural antioxidants and a hypoglycemic agent under glucose load acute conditions.
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Mooli RGR, Mukhi D, Pasupulati AK, Evers SS, Sipula IJ, Jurczak M, Seeley RJ, Shah YM, Ramakrishnan SK. Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells. Cell Mol Gastroenterol Hepatol 2021; 13:1057-1072. [PMID: 34902628 PMCID: PMC8873605 DOI: 10.1016/j.jcmgh.2021.12.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/04/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Compelling evidence shows that glucagon-like peptide-1 (GLP-1) has a profound effect in restoring normoglycemia in type 2 diabetic patients by increasing pancreatic insulin secretion. Although L-cells are the primary source of circulating GLP-1, the current therapies do not target L-cells to increase GLP-1 levels. Our study aimed to determine the molecular underpinnings of GLP-1 secretion as an impetus to identify new interventions to target endogenous L-cells. METHODS We used genetic mouse models of intestine-specific overexpression of hypoxia-inducible factor (HIF)-1α and HIF-2α (VhlΔIE), conditional overexpression of intestinal HIF-2α (Hif-2αLSL;Vilin-Cre/ERT2), and intestine-specific HIF-2α knockout mice (Hif-2αΔIE) to show that HIF signaling, especially HIF-2α, regulates GLP-1 secretion. RESULTS Our data show that intestinal HIF signaling improved glucose homeostasis in a GLP-1-dependent manner. Intestinal HIF potentiated GLP-1 secretion via the lipid sensor G-protein-coupled receptor (GPR)40 enriched in L-cells. We show that HIF-2α regulates GPR40 in L-cells and potentiates fatty acid-induced GLP-1 secretion via extracellular regulated kinase (ERK). Using a genetic model of intestine-specific overexpression of HIF-2α, we show that HIF-2α is sufficient to increase GLP-1 levels and attenuate diet-induced metabolic perturbations such as visceral adiposity, glucose intolerance, and hepatic steatosis. Lastly, we show that intestinal HIF-2α signaling acts as a priming mechanism crucial for postprandial lipid-mediated GLP-1 secretion. Thus, disruption of intestinal HIF-2α decreases GLP-1 secretion. CONCLUSIONS In summary, we show that intestinal HIF signaling, particularly HIF-2α, regulates the lipid sensor GPR40, which is crucial for the lipid-mediated GLP-1 secretion, and suggest that HIF-2α is a potential target to induce endogenous GLP-1 secretion.
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Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Anil K Pasupulati
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Ian J Sipula
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael Jurczak
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Yatrik M Shah
- Department of Molecular and Integrative Physiology, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Ibeh LN, Ijioma SN, Emmanuel O, Timothy CO, Ugbogu EA. Psidium guajava leaf extract improves gastrointestinal functions in rats and rabbits: an implication for ulcer and diarrhoea management. Biomarkers 2021; 26:737-746. [PMID: 34634977 DOI: 10.1080/1354750x.2021.1992651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 10/09/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Psidium guajava L. (Family, Myrtaceae) is reportedly used in ethnomedicine for the treatment of diarrhoea, inflammation, and gastroenteritis. OBJECTIVE This study evaluated the gastrointestinal function of Psidium guajava leaf extract (PGLE) in rats and rabbits. MATERIALS AND METHODS Crude ethanolic PGLE was subjected to phytochemical and toxicity tests (acute and sub-acute). Standard analytical procedures were employed to evaluate the in vivo gastrointestinal motility, and gastroprotective effect of PGLE against aspirin-induced ulcers. RESULTS In the phytochemical analysis, phenols were the highest (48.32 mg) followed by flavonoids (32.74 mg) and least in tannins (7.31 mg). The acute toxicity of PGLE was >6000 mg/kg. Administration of PGLE decreased significantly (p < 0.05) the body weight, while the liver biomarkers were not significantly altered (p > 0.05) when compared to the control. PGLE significantly increased extractible mucus weight and lowered gastric acid secretion in rats (p < 0.05). PGLE decreased significantly (p < 0.05) ulcer scores and indexes, and increased percentage ulcer inhibition in a dose-dependent manner compared to the negative and omeprazole-treated groups. PGLE dose-dependently inhibited basal amplitudes of contractions, and significantly inhibited acetylcholine-induced contractions, terminating them completely at higher doses. CONCLUSION PGLE may be a good anti-ulcer and anti-diarrhoeal agent, raising the prospect of novel drug development for such applications.
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Affiliation(s)
- Lilian Ngozi Ibeh
- Department of Physiology, College of Basic Medical Sciences, Abia State University, Uturu, Nigeria
| | - Solomon Nnah Ijioma
- Department of Zoology and Environmental Biology, Michael Okpara University of Agriculture, Umudike, Nigeria
| | - Okezie Emmanuel
- Department of Biochemistry, Abia State University, Uturu, Nigeria
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Prasad RB, Kristensen K, Katsarou A, Shaat N. Association of single nucleotide polymorphisms with insulin secretion, insulin sensitivity, and diabetes in women with a history of gestational diabetes mellitus. BMC Med Genomics 2021; 14:274. [PMID: 34801028 PMCID: PMC8606068 DOI: 10.1186/s12920-021-01123-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 11/10/2021] [Indexed: 12/23/2022] Open
Abstract
Background This study investigated whether single nucleotide polymorphisms (SNPs) reported by previous genome-wide association studies (GWAS) to be associated with impaired insulin secretion, insulin resistance, and/or type 2 diabetes are associated with disposition index, the homeostasis model assessment of insulin resistance (HOMA-IR), and/or development of diabetes following a pregnancy complicated by gestational diabetes mellitus (GDM). Methods Seventy-two SNPs were genotyped in 374 women with previous GDM from Southern Sweden. An oral glucose tolerance test was performed 1–2 years postpartum, although data on the diagnosis of diabetes were accessible up to 5 years postpartum. HOMA-IR and disposition index were used to measure insulin resistance and secretion, respectively. Results The risk A-allele in the rs11708067 polymorphism of the adenylate cyclase 5 gene (ADCY5) was associated with decreased disposition index (beta = − 0.90, SE 0.38, p = 0.019). This polymorphism was an expression quantitative trait loci (eQTL) in islets for both ADCY5 and its antisense transcript. The risk C-allele in the rs2943641 polymorphism, near the insulin receptor substrate 1 gene (IRS1), showed a trend towards association with increased HOMA-IR (beta = 0.36, SE 0.18, p = 0.050), and the T-allele of the rs4607103 polymorphism, near the ADAM metallopeptidase with thrombospondin type 1 motif 9 gene (ADAMTS9), was associated with postpartum diabetes (OR = 2.12, SE 0.22, p = 0.00055). The genetic risk score (GRS) of the top four SNPs tested for association with the disposition index using equal weights was associated with the disposition index (beta = − 0.31, SE = 0.29, p = 0.00096). In addition, the GRS of the four SNPs studied for association with HOMA-IR using equal weights showed an association with HOMA-IR (beta = 1.13, SE = 0.48, p = 9.72874e−11). All analyses were adjusted for age, body mass index, and ethnicity. Conclusions This study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity and, ultimately, to diabetes development.
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Affiliation(s)
- Rashmi B Prasad
- Genomics, Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Karl Kristensen
- Genomics, Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden.,Department of Obstetrics and Gynaecology, Skåne University Hospital, Malmö, Sweden
| | - Anastasia Katsarou
- Genomics, Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden.,Department of Endocrinology, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Nael Shaat
- Genomics, Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden. .,Department of Endocrinology, Skåne University Hospital, 205 02, Malmö, Sweden.
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Wu CC, Lee CH, Hsu TW, Yeh CC, Lin MC, Chang CM, Tsai JH. Is Colectomy Associated with the Risk of Type 2 Diabetes in Patients without Colorectal Cancer? A Population-Based Cohort Study. J Clin Med 2021; 10:jcm10225313. [PMID: 34830601 PMCID: PMC8622203 DOI: 10.3390/jcm10225313] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 12/22/2022] Open
Abstract
Type 2 diabetes might be influenced by colonic disease; however, the association between colonic resection and type 2 diabetes has rarely been discussed. This population-based cohort study explored the association between colectomy and type 2 diabetes in patients without colorectal cancer. A total of 642 patients who underwent colectomy for noncancerous diseases at any time between 2000 and 2012 in the National Health Insurance Research Database of Taiwan were enrolled. The enrolled patients were matched with 2568 patients without colectomy at a 1:4 ratio using a propensity score that covered age, sex, and comorbidities. The risk of type 2 diabetes was assessed using a Cox proportional hazards model. The mean (standard deviation) follow-up durations in colectomy cases and non-colectomy controls were 4.9 (4.0) and 5.6 (3.6) years, respectively; 65 (10.1%) colectomy cases and 342 (15.5%) non-colectomy controls developed type 2 diabetes. After adjustment, colectomy cases still exhibited a decreased risk of type 2 diabetes (adjusted HR = 0.80, 95% CI: 0.61–1.04). A stratified analysis for colectomy type indicated that patients who underwent right or transverse colectomy had a significantly lower risk of developing type 2 diabetes (adjusted HR = 0.57, 95% CI: 0.34–0.98). In the present study, colectomy tended to be at a reduced risk of type 2 diabetes in patients without colorectal cancer, and right or transverse colectomies were especially associated with a significantly reduced risk of type 2 diabetes.
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Affiliation(s)
- Chin-Chia Wu
- Division of Colorectal Surgery, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 622, Taiwan; (C.-C.W.); (T.-W.H.)
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 970, Taiwan; (C.-H.L.); (C.-C.Y.)
| | - Cheng-Hung Lee
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 970, Taiwan; (C.-H.L.); (C.-C.Y.)
- Division of General Surgery, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 622, Taiwan
| | - Ta-Wen Hsu
- Division of Colorectal Surgery, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 622, Taiwan; (C.-C.W.); (T.-W.H.)
- College of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Chia-Chou Yeh
- School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 970, Taiwan; (C.-H.L.); (C.-C.Y.)
- Department of Chinese Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 622, Taiwan
| | - Mei-Chen Lin
- Management Office for Health Data, China Medical University Hospital, Taichung 404, Taiwan;
- College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Chun-Ming Chang
- College of Medicine, Tzu Chi University, Hualien 970, Taiwan
- Department of General Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- Correspondence: (C.-M.C.); (J.-H.T.)
| | - Jui-Hsiu Tsai
- College of Medicine, Tzu Chi University, Hualien 970, Taiwan
- Department of Psychiatry, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi 622, Taiwan
- Ph.D. Program in Environmental and Occupation Medicine, National Health Research Institutes and Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: (C.-M.C.); (J.-H.T.)
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Ohlsson B. Theories behind the effect of starch‑ and sucrose‑reduced diets on gastrointestinal symptoms in irritable bowel syndrome (Review). Mol Med Rep 2021; 24:732. [PMID: 34414452 PMCID: PMC8404103 DOI: 10.3892/mmr.2021.12372] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/22/2021] [Indexed: 12/13/2022] Open
Abstract
Increased amounts of starch and sugar have been added to the diet in the Western world during the last decades. Undigested carbohydrates lead to bacterial fermentation and gas production with diffusion of water, causing abdominal bloating, pain and diarrhea. Therefore, dietary advice is the first line of treatment of irritable bowel syndrome (IBS), a disease characterized by abdominal pain and altered bowel habits without any organic findings. Recently, a diet with a reduction of starch and sucrose led to a marked effect on gastrointestinal (GI) symptoms. The mechanism is unknown, but three possible mechanisms are presented in the present review. First, functional variants of the enzyme sucrase‑isomaltase (SI) have been described in IBS. A subgroup of patients with IBS may thus suffer from partial SI deficiency with reduced digestion of starch and sucrose. Second, fructose absorption is less efficient than glucose absorption, which may lead to a physiological fructose malabsorption when ingesting high amounts of sucrose. A third mechanism is that high‑sugar diets causing hyperglycemia, hyperinsulinemia and weight gain have led to painful neuropathy in animal models; whereas, improved metabolic control in humans has led to improvement of neuropathy. Starch‑ and sucrose‑reduced diets lead to decreased levels of C‑peptide, insulin, gastric inhibitory peptide, leptin and weight reduction. These metabolic changes may reduce the excitability of the hypersensitive nervous system often found in IBS and, thereby, lead to the reduced symptoms found after the diet. In conclusion, further studies are needed to investigate the pathophysiology behind development of symptoms after starch and sucrose intake, and the mechanisms behind symptom relief after reduced intake.
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Affiliation(s)
- Bodil Ohlsson
- Department of Internal Medicine, Lund University, Skåne University Hospital, 20502 Malmö, Sweden
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Jin ZL, Liu W. Progress in treatment of type 2 diabetes by bariatric surgery. World J Diabetes 2021; 12:1187-1199. [PMID: 34512886 PMCID: PMC8394224 DOI: 10.4239/wjd.v12.i8.1187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/29/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
The incidence of type 2 diabetes (T2D) is increasing at an alarming rate worldwide. Bariatric surgical procedures, such as the vertical sleeve gastrectomy and Roux-en-Y gastric bypass, are the most efficient approaches to obtain substantial and durable remission of T2D. The benefits of bariatric surgery are realized through the consequent increased satiety and alterations in gastrointestinal hormones, bile acids, and the intestinal microbiota. A comprehensive understanding of the mechanisms by which various bariatric surgical procedures exert their benefits on T2D could contribute to the design of better non-surgical treatments for T2D. In this review, we describe the classification and evolution of bariatric surgery and explore the multiple mechanisms underlying the effect of bariatric surgery on insulin resistance. Based upon our summarization of the current knowledge on the underlying mechanisms, we speculate that the gut might act as a new target for improving T2D. Our ultimate goal with this review is to provide a better understanding of T2D pathophysiology in order to support development of T2D treatments that are less invasive and more scalable.
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Affiliation(s)
- Zhang-Liu Jin
- Department of General Surgery & Department of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Wei Liu
- Department of General Surgery & Department of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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Ansari P, Flatt PR, Harriott P, Hannan JMA, Abdel-Wahab YHA. Identification of Multiple Pancreatic and Extra-Pancreatic Pathways Underlying the Glucose-Lowering Actions of Acacia arabica Bark in Type-2 Diabetes and Isolation of Active Phytoconstituents. PLANTS (BASEL, SWITZERLAND) 2021; 10:1190. [PMID: 34208010 PMCID: PMC8230611 DOI: 10.3390/plants10061190] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/20/2022]
Abstract
Acacia arabica is used traditionally to treat a variety of ailments, including diabetes. This study elucidated the antidiabetic actions of A. arabica bark together with the isolation of bioactive molecules. Insulin secretion and signal transduction were measured using clonal β cells and mouse islets. Glucose uptake was assessed using 3T3-L1 adipocytes, and in vitro systems assessed additional glucose-lowering actions. High-fat-fed (HFF) obese rats were used for in vivo evaluation, and phytoconstituents were isolated and characterised by RP-HPLC followed by LC-MS and NMR. Hot-water extract of A. arabica (HWAA) increased insulin release from clonal β cells and mouse islets by 1.3-6.8-fold and 1.6-3.2-fold, respectively. Diazoxide, verapamil and calcium-free conditions decreased insulin-secretory activity by 30-42%. In contrast, isobutylmethylxanthine (IBMX), tolbutamide and 30 mM KCl potentiated the insulin-secretory effects. The mechanism of actions of HWAA involved membrane depolarisation and elevation of intracellular Ca2+ together with an increase in glucose uptake by 3T3-L1 adipocytes, inhibition of starch digestion, glucose diffusion, dipeptidyl peptidase-IV (DPP-IV) enzyme activity and protein glycation. Acute HWAA administration (250 mg/5 mL/kg) enhanced glucose tolerance and plasma insulin in HFF obese rats. Administration of HWAA (250 mg/5 mL/kg) for 9 days improved glucose homeostasis and β-cell functions, thereby improving glycaemic control, and circulating insulin. Isolated phytoconstituents, including quercetin and kaempferol, increased insulin secretion in vitro and improved glucose tolerance. The results indicate that HWAA has the potential to treat type 2 diabetes as a dietary supplement or as a source of antidiabetic agents, including quercetin and kaempferol.
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Affiliation(s)
- Prawej Ansari
- School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK; (P.R.F.); (P.H.); (Y.H.A.A.-W.)
- Department of Pharmacy, Independent University, Dhaka 1229, Bangladesh;
| | - Peter R. Flatt
- School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK; (P.R.F.); (P.H.); (Y.H.A.A.-W.)
| | - Patrick Harriott
- School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK; (P.R.F.); (P.H.); (Y.H.A.A.-W.)
| | - J. M. A. Hannan
- Department of Pharmacy, Independent University, Dhaka 1229, Bangladesh;
| | - Yasser H. A. Abdel-Wahab
- School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK; (P.R.F.); (P.H.); (Y.H.A.A.-W.)
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Therapeutic potential of targeting intestinal bitter taste receptors in diabetes associated with dyslipidemia. Pharmacol Res 2021; 170:105693. [PMID: 34048925 DOI: 10.1016/j.phrs.2021.105693] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 05/23/2021] [Accepted: 05/23/2021] [Indexed: 12/19/2022]
Abstract
Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis. The impaired incretin effects observed in the pathophysiologic abnormality of type 2 diabetes have triggered the pharmacological development of incretin-based therapy through the activation of glucagon-like peptide-1 (GLP-1) receptor, including GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP4) inhibitors. In the light of the mechanisms involved in the stimulation of GLP-1 secretion, it is a fundamental question to explore whether glucose and lipid homeostasis can be manipulated by the digestive system in response to nutrient ingestion and taste perception along the gastrointestinal tract. While glucose is a potent stimulant of GLP-1 secretion, emerging evidence highlights the importance of bitter tastants in the enteroendocrine secretion of gut hormones through activation of bitter taste receptors. This review summarizes bitter chemosensation in the intestines for GLP-1 secretion and metabolic regulation based on recent advances in biological research of bitter taste receptors and preclinical and clinical investigation of bitter medicinal plants, including bitter melon, hops strobile, and berberine-containing herbs (e.g. coptis rhizome and barberry root). Multiple mechanisms of action of relevant bitter phytochemicals are discussed with the consideration of pharmacokinetic studies. Current evidence suggests that specific agonists targeting bitter taste receptors, such as human TAS2R1 and TAS2R38, may provide both metabolic benefits and anti-inflammatory effects with the modulation of the enteroendocrine hormone secretion and bile acid turnover in metabolic syndrome individuals or diabetic patients with dyslipidemia-related comorbidities.
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50
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Heiss CN, Mannerås-Holm L, Lee YS, Serrano-Lobo J, Håkansson Gladh A, Seeley RJ, Drucker DJ, Bäckhed F, Olofsson LE. The gut microbiota regulates hypothalamic inflammation and leptin sensitivity in Western diet-fed mice via a GLP-1R-dependent mechanism. Cell Rep 2021; 35:109163. [PMID: 34038733 DOI: 10.1016/j.celrep.2021.109163] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 04/06/2021] [Accepted: 04/29/2021] [Indexed: 12/14/2022] Open
Abstract
Mice lacking a microbiota are protected from diet-induced obesity. Previous studies have shown that feeding a Western diet causes hypothalamic inflammation, which in turn can lead to leptin resistance and weight gain. Here, we show that wild-type (WT) mice with depleted gut microbiota, i.e., germ-free (GF) and antibiotic-treated mice, have elevated levels of glucagon-like peptide-1 (GLP-1), are protected against diet-induced hypothalamic inflammation, and have enhanced leptin sensitivity when fed a Western diet. Using GLP-1 receptor (GLP-1R)-deficient mice and pharmacological inhibition of the GLP-1R in WT mice, we demonstrate that intact GLP-1R signaling is required for preventing hypothalamic inflammation and enhancing leptin sensitivity. Furthermore, we show that astrocytes express the GLP-1R, and deletion of the receptor in glial fibrillary acidic protein (GFAP)-expressing cells diminished the antibiotic-induced protection against diet-induced hypothalamic inflammation. Collectively, our results suggest that depletion of the gut microbiota attenuates diet-induced hypothalamic inflammation and enhances leptin sensitivity via GLP-1R-dependent mechanisms.
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Affiliation(s)
- Christina N Heiss
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Louise Mannerås-Holm
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Ying Shiuan Lee
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Julia Serrano-Lobo
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Anna Håkansson Gladh
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Randy J Seeley
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, ON M5G 1X5, Canada
| | - Fredrik Bäckhed
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 41345 Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Physiology, Region Västra Götaland, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden
| | - Louise E Olofsson
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, 41345 Gothenburg, Sweden.
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