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Stefanaki K, Karagiannakis DS, Peppa M, Vryonidou A, Kalantaridou S, Goulis DG, Psaltopoulou T, Paschou SA. Food Cravings and Obesity in Women with Polycystic Ovary Syndrome: Pathophysiological and Therapeutic Considerations. Nutrients 2024; 16:1049. [PMID: 38613082 PMCID: PMC11013286 DOI: 10.3390/nu16071049] [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: 01/12/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, constitutes a metabolic disorder frequently associated with obesity and insulin resistance (IR). Furthermore, women with PCOS often suffer from excessive anxiety and depression, elicited by low self-esteem due to obesity, acne, and hirsutism. These mood disorders are commonly associated with food cravings and binge eating. Hypothalamic signaling regulates appetite and satiety, deteriorating excessive food consumption. However, the hypothalamic function is incapable of compensating for surplus food in women with PCOS, leading to the aggravation of obesity and a vicious circle. Hyperandrogenism, IR, the reduced secretion of cholecystokinin postprandially, and leptin resistance defined by leptin receptors' knockout in the hypothalamus have been implicated in the pathogenesis of hypothalamic dysfunction and appetite dysregulation. Diet modifications, exercise, and psychological and medical interventions have been applied to alleviate food disorders, interrupting the vicious circle. Cognitive-behavioral intervention seems to be the mainstay of treatment, while the role of medical agents, such as GLP-1 analogs and naltrexone/bupropion, has emerged.
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Affiliation(s)
- Katerina Stefanaki
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.S.); (T.P.); (S.A.P.)
| | - Dimitrios S. Karagiannakis
- Academic Department of Gastroenterology, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Melpomeni Peppa
- Endocrine Unit and Diabetes Center, Second Department of Internal Medicine, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- 3rd Department of Internal Medicine, Sotiria Chest Disease Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Andromachi Vryonidou
- Department of Endocrinology and Diabetes Center, Hellenic Red Cross Hospital, 11526 Athens, Greece;
| | - Sophia Kalantaridou
- 3rd Department of Obstetrics and Gynecology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios G. Goulis
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki, 57001 Thessaloniki, Greece
| | - Theodora Psaltopoulou
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.S.); (T.P.); (S.A.P.)
| | - Stavroula A. Paschou
- Endocrine Unit and Diabetes Center, Department of Clinical Therapeutics, Alexandra Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.S.); (T.P.); (S.A.P.)
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Szablewski L. Changes in Cells Associated with Insulin Resistance. Int J Mol Sci 2024; 25:2397. [PMID: 38397072 PMCID: PMC10889819 DOI: 10.3390/ijms25042397] [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: 01/06/2024] [Revised: 02/10/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. It is involved in fat metabolism, increasing the storage of triglycerides and decreasing lipolysis. Ketone body metabolism also depends on insulin action, as insulin reduces ketone body concentrations and influences protein metabolism. It increases nitrogen retention, facilitates the transport of amino acids into cells and increases the synthesis of proteins. Insulin also inhibits protein breakdown and is involved in cellular growth and proliferation. On the other hand, defects in the intracellular signaling pathways of insulin may cause several disturbances in human metabolism, resulting in several chronic diseases. Insulin resistance, also known as impaired insulin sensitivity, is due to the decreased reaction of insulin signaling for glucose levels, seen when glucose use in response to an adequate concentration of insulin is impaired. Insulin resistance may cause, for example, increased plasma insulin levels. That state, called hyperinsulinemia, impairs metabolic processes and is observed in patients with type 2 diabetes mellitus and obesity. Hyperinsulinemia may increase the risk of initiation, progression and metastasis of several cancers and may cause poor cancer outcomes. Insulin resistance is a health problem worldwide; therefore, mechanisms of insulin resistance, causes and types of insulin resistance and strategies against insulin resistance are described in this review. Attention is also paid to factors that are associated with the development of insulin resistance, the main and characteristic symptoms of particular syndromes, plus other aspects of severe insulin resistance. This review mainly focuses on the description and analysis of changes in cells due to insulin resistance.
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Affiliation(s)
- Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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Patil RS, Tupe RS. Communal interaction of glycation and gut microbes in diabetes mellitus, Alzheimer's disease, and Parkinson's disease pathogenesis. Med Res Rev 2024; 44:365-405. [PMID: 37589449 DOI: 10.1002/med.21987] [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: 09/23/2022] [Revised: 07/12/2023] [Accepted: 08/06/2023] [Indexed: 08/18/2023]
Abstract
Diabetes and its complications, Alzheimer's disease (AD), and Parkinson's disease (PD) are increasing gradually, reflecting a global threat vis-à-vis expressing the essentiality of a substantial paradigm shift in research and remedial actions. Protein glycation is influenced by several factors, like time, temperature, pH, metal ions, and the half-life of the protein. Surprisingly, most proteins associated with metabolic and neurodegenerative disorders are generally long-lived and hence susceptible to glycation. Remarkably, proteins linked with diabetes, AD, and PD share this characteristic. This modulates protein's structure, aggregation tendency, and toxicity, highlighting renovated attention. Gut microbes and microbial metabolites marked their importance in human health and diseases. Though many scientific shreds of evidence are proposed for possible change and dysbiosis in gut flora in these diseases, very little is known about the mechanisms. Screening and unfolding their functionality in metabolic and neurodegenerative disorders is essential in hunting the gut treasure. Therefore, it is imperative to evaluate the role of glycation as a common link in diabetes and neurodegenerative diseases, which helps to clarify if modulation of nonenzymatic glycation may act as a beneficial therapeutic strategy and gut microbes/metabolites may answer some of the crucial questions. This review briefly emphasizes the common functional attributes of glycation and gut microbes, the possible linkages, and discusses current treatment options and therapeutic challenges.
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Affiliation(s)
- Rahul Shivaji Patil
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Rashmi Santosh Tupe
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Pune, Maharashtra, India
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Sinha SK, Nicholas SB. Pathomechanisms of Diabetic Kidney Disease. J Clin Med 2023; 12:7349. [PMID: 38068400 PMCID: PMC10707303 DOI: 10.3390/jcm12237349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 03/15/2024] Open
Abstract
The worldwide occurrence of diabetic kidney disease (DKD) is swiftly rising, primarily attributed to the growing population of individuals affected by type 2 diabetes. This surge has been transformed into a substantial global concern, placing additional strain on healthcare systems already grappling with significant demands. The pathogenesis of DKD is intricate, originating with hyperglycemia, which triggers various mechanisms and pathways: metabolic, hemodynamic, inflammatory, and fibrotic which ultimately lead to renal damage. Within each pathway, several mediators contribute to the development of renal structural and functional changes. Some of these mediators, such as inflammatory cytokines, reactive oxygen species, and transforming growth factor β are shared among the different pathways, leading to significant overlap and interaction between them. While current treatment options for DKD have shown advancement over previous strategies, their effectiveness remains somewhat constrained as patients still experience residual risk of disease progression. Therefore, a comprehensive grasp of the molecular mechanisms underlying the onset and progression of DKD is imperative for the continued creation of novel and groundbreaking therapies for this condition. In this review, we discuss the current achievements in fundamental research, with a particular emphasis on individual factors and recent developments in DKD treatment.
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Affiliation(s)
- Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
- College of Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Susanne B. Nicholas
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
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Li H, Chen W, Lin X, Chen W, Xie T, Chen K, Hou S, Li H. Influence of renal function on the ability of TyG Index to predict all-cause mortality. Lipids Health Dis 2023; 22:193. [PMID: 37951945 PMCID: PMC10638822 DOI: 10.1186/s12944-023-01958-1] [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: 09/08/2023] [Accepted: 10/30/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND The association between triglyceride-glucose (TyG) index and poor prognosis remains controversial. Whether renal function status affects the ability of the TyG index to predict poor prognosis has not yet been elucidated and merits further studies. METHODS This retrospective cohort study included 22,031 participants from communities in the U.S. By juxtaposing the TyG categories with the estimated glomerular filtration rate (eGFR, either < 60 mL/min/1.73m2 or ≥ 60 mL/min/1.73m2), participants were categorized into four distinct groups: (1) TyG_L/eGFR_H; (2) TyG_H/eGFR_H; (3) TyG_L/eGFR_L; and (4) TyG_H/eGFR_L. The endpoint was the all-cause mortality rate. Standard Kaplan-Meier plots were constructed and multifactor Cox regression analyses were carried out and restricted cubic spline regression analysis was utilized to assess the association between death and the TyG index for different renal function statuses. RESULTS No statistical differences were found in the TyG groups in participants with normal renal function after adjustment for all covariates (P = 0.070). However, in the high TyG index group with renal insufficiency, the risk of all-cause mortality rates was reduced by 18%. (HR, 0.82; CI, 0.69-0.98). The TyG index (high vs. low) and renal function (eGFR < 60 vs. eGFR ≥ 60) had statistically significant interactions with death (P < 0.001). When all covariates were adjusted, the risk of mortality for the TyG_L combined with eGFR_L group was 56% higher than that for the TyG_L combined with eGFR_H group (HR, 1.56; CI, 1.33-1.82). In the renal insufficiency population, a nonlinear relationship was observed between mortality and the TyG index, albeit with a differing pattern (P for nonlinearity < 0.001). CONCLUSIONS While it has been known that TyG index was a prognosis marker of CVD, this research highlights that higher TyG index was associated with higher all-cause mortality rates for all participants. Furthermore, renal function status significantly moderates the effect of the TyG index on all-cause mortality in community-dwelling adults.
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Affiliation(s)
- Huilan Li
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Weihua Chen
- Beijing Friendship Hospital, Capital Medical University, Beijing, 100053, China
| | - Xueqin Lin
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Weiqin Chen
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Tingzheng Xie
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350000, China
| | - Kaihong Chen
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Shuhong Hou
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China.
| | - Huaqing Li
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China.
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Daza-Arnedo R, Rico-Fontalvo J, Aroca-Martínez G, Rodríguez-Yanez T, Martínez-Ávila MC, Almanza-Hurtado A, Cardona-Blanco M, Henao-Velásquez C, Fernández-Franco J, Unigarro-Palacios M, Osorio-Restrepo C, Uparella-Gulfo I. Insulin and the kidneys: a contemporary view on the molecular basis. FRONTIERS IN NEPHROLOGY 2023; 3:1133352. [PMID: 37675359 PMCID: PMC10479562 DOI: 10.3389/fneph.2023.1133352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 07/07/2023] [Indexed: 09/08/2023]
Abstract
Insulin is a hormone that is composed of 51 amino acids and structurally organized as a hexamer comprising three heterodimers. Insulin is the central hormone involved in the control of glucose and lipid metabolism, aiding in processes such as body homeostasis and cell growth. Insulin is synthesized as a large preprohormone and has a leader sequence or signal peptide that appears to be responsible for transport to the endoplasmic reticulum membranes. The interaction of insulin with the kidneys is a dynamic and multicenter process, as it acts in multiple sites throughout the nephron. Insulin acts on a range of tissues, from the glomerulus to the renal tubule, by modulating different functions such as glomerular filtration, gluconeogenesis, natriuresis, glucose uptake, regulation of ion transport, and the prevention of apoptosis. On the other hand, there is sufficient evidence showing the insulin receptor's involvement in renal functions and its responsibility for the regulation of glucose homeostasis, which enables us to understand its contribution to the insulin resistance phenomenon and its association with the progression of diabetic kidney disease.
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Affiliation(s)
- Rodrigo Daza-Arnedo
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
| | - Jorge Rico-Fontalvo
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
- Faculty of Medicine, Universidad Simón Bolívar, Barranquilla, Colombia
| | - Gustavo Aroca-Martínez
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
- Faculty of Medicine, Universidad Simón Bolívar, Barranquilla, Colombia
| | | | | | | | - María Cardona-Blanco
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
| | | | - Jorge Fernández-Franco
- Department of Internal Medicine, Endocrinology Fellowship, Fundación Universitaria de Ciencias de la Salud—Hospital San José, Bogotá, Colombia
| | - Mario Unigarro-Palacios
- Department of Internal Medicine, Endocrinology Fellowship, Fundación Universitaria de Ciencias de la Salud—Hospital San José, Bogotá, Colombia
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Sohail S, Akkawi G, Rechter T, Fluitt MB, Ecelbarger CM. Sex Modulates Response to Renal-Tubule-Targeted Insulin Receptor Deletion in Mice. Int J Mol Sci 2023; 24:8056. [PMID: 37175762 PMCID: PMC10178497 DOI: 10.3390/ijms24098056] [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: 02/28/2023] [Revised: 04/19/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Insulin facilitates renal sodium reabsorption and attenuates gluconeogenesis. Sex differences in this regulation have not been well characterized. Using tetracycline-inducible Cre-lox recombination, we knocked out (KO) the insulin receptor (InsR) from the renal tubule in adult male (M) and female (F) mice (C57Bl6 background) with a paired box 8 (PAX8) promoter. Body weights were not affected by the KO, but mean kidney weights were reduced in the KO mice (13 and 3%, in M and F, respectively, relative to wild-type (WT) mice). A microscopic analysis revealed 25 and 19% reductions in the proximal tubule (PT) and cortical collecting duct cell heights, respectively, in KOMs relative to WTMs. The reductions were 5 and 11% for KOFs. Western blotting of renal cortex homogenates showed decreased protein levels for the β and γ subunits of the epithelial sodium channel (ENaC) and the sodium-potassium-2-chloride cotransporter type 2 (NKCC2) in both sexes of KO mice; however, α-ENaC was upregulated in KOMs and downregulated in KOFs. Both sexes of KO mice cleared exogenously administered glucose faster than the WT mice and had lower semi-fasted, anesthetized blood glucose levels. However, KOMs (but not KOFs) demonstrated evidence of enhanced renal gluconeogenesis, including higher levels of renal glucose-6-phosphatase, the PT's production of glucose, post-prandial blood glucose, and plasma insulin, whereas KOFs exhibited downregulation of renal high-capacity sodium glucose cotransporter (SGLT2) and upregulation of SGLT1; these changes appeared to be absent in the KOM. Overall, these findings suggest a sex-differential reliance on intact renal tubular InsR signaling which may be translationally important in type 2 diabetes, obesity, or insulin resistance when renal insulin signaling is reduced.
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Affiliation(s)
- Soha Sohail
- Department of Medicine, Georgetown University, Washington, DC 20057, USA
| | - Gabriella Akkawi
- Department of Medicine, Georgetown University, Washington, DC 20057, USA
| | - Taylor Rechter
- Department of Medicine, Georgetown University, Washington, DC 20057, USA
| | - Maurice B. Fluitt
- Department of Medicine, Georgetown University, Washington, DC 20057, USA
- Department of Medicine, Howard University, Washington, DC 20059, USA
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Rebelos E, Mari A, Oikonen V, Iida H, Nuutila P, Ferrannini E. Evaluation of renal glucose uptake with [ 18F]FDG-PET: Methodological advancements and metabolic outcomes. Metabolism 2023; 141:155382. [PMID: 36565992 DOI: 10.1016/j.metabol.2022.155382] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/06/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND/PURPOSE Studying renal glucose metabolism non-invasively in humans is an unmet need. Positron emission tomography (PET) is the current gold standard for measuring regional tissue glucose uptake rates, but the most widely used glucose analog ([18F]FDG) is not a good substrate for sodium-glucose cotransporters (SGLTs). As a consequence, [18F]FDG spills over into the urine and [18F]FDG-PET considerably underestimates published rates of whole renal glucose uptake obtained using the arterial-venous difference technique. Our aim was to assess whether [18F]FDG-PET can be used in the study of renal glucose metabolism in humans. METHODS We measured individual [18F]FDG radioactivity in the urine and estimated intraluminal [18F]FDG radioactivity concentration; these values were used to correct renal [18F]FDG-PET data acquired ∼90 min from tracer injection under fasting conditions and during an insulin clamp in 9 lean and 16 obese subjects. RESULTS We found that the corrected glucose uptake is consistently higher in the medulla than cortex and that both cortical and medullary glucose uptake are higher in lean than obese participants under both fasting and insulinized conditions. Moreover, cortical but not medullary glucose uptake is increased from the fasting to the insulinized condition. CONCLUSION The data show for the first time that [18F]FDG-PET can still provide relevant physiological information on regional renal glucose uptake on the condition that [18F]FDG uptake is corrected for tubular radioactivity.
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Affiliation(s)
- Eleni Rebelos
- Turku PET Centre, University of Turku, Turku, Finland; CNR Institute of Clinical Physiology, Pisa, Italy.
| | - Andrea Mari
- CNR Institute of Neuroscience, Padova, Italy
| | - Vesa Oikonen
- Turku PET Centre, University of Turku, Turku, Finland
| | - Hidehiro Iida
- Turku PET Centre, University of Turku, Turku, Finland
| | - Pirjo Nuutila
- Turku PET Centre, University of Turku, Turku, Finland; Department of Endocrinology, Turku University Hospital, Turku, Finland
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Antimicrobial Peptide LCN2 Inhibited Uropathogenic Escherichia coli Infection in Bladder Cells in a High-Glucose Environment through JAK/STAT Signaling Pathway. Int J Mol Sci 2022; 23:ijms232415763. [PMID: 36555403 PMCID: PMC9779052 DOI: 10.3390/ijms232415763] [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: 09/14/2022] [Revised: 11/08/2022] [Accepted: 12/02/2022] [Indexed: 12/15/2022] Open
Abstract
JAK/STAT plays a key role in regulating uropathogenic Escherichia coli (UPEC) infection in urothelial cells, probably via antimicrobial peptide (AMP) production, in diabetic patients with urinary tract infections. Whether multiple pathways regulate AMPs, especially lipid-carrying protein-2 (LCN2), to achieve a vital effect is unknown. We investigated the effects of an LCN2 pretreatment on the regulation of the JAK/STAT pathway in a high-glucose environment using a bladder cell model with GFP-UPEC and phycoerythrin-labeled TLR-4, STAT1, and STAT3. Pretreatment with 5 or 25 μg/mL LCN2 for 24 h dose-dependently suppressed UPEC infections in bladder cells. TLR-4, STAT1, and STAT3 expression were dose-dependently downregulated after LCN2 pretreatment. The LCN2-mediated alleviation of UPEC infection in a high-glucose environment downregulated TLR-4 and the JAK/STAT transduction pathway and decreased the UPEC-induced secretion of exogenous inflammatory interleukin (IL)-6 and IL-8. Our study provides evidence that LCN2 can alleviate UPEC infection in bladder epithelial cells by decreasing JAK/STAT pathway activation in a high-glucose environment. LCN2 dose-dependently inhibits UPEC infection via TLR-4 expression and JAK/STAT pathway modulation. These findings may provide a rationale for targeting LCN2/TLR-4/JAK/STAT regulation in bacterial cystitis treatment. Further studies should explore specific mechanisms by which the LCN2, TLR-4, and JAK/STAT pathways participate in UPEC-induced inflammation to facilitate the development of effective therapies for cystitis.
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Alqallaf A, Swan P, Docherty NG. Renal insulin resistance in type 2 diabetes mellitus and progression of chronic kidney disease: potential pathogenic mechanisms. Expert Rev Endocrinol Metab 2022; 17:523-532. [PMID: 36203374 DOI: 10.1080/17446651.2022.2131534] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/28/2022] [Indexed: 01/06/2023]
Abstract
INTRODUCTION A bidirectional association exists between insulin resistance (IR) and chronic kidney disease (CKD) in Type 2 Diabetes Mellitus (T2DM). Baseline measures of IR are predictive of CKD progression, and uremia in progressive CKD is itself, in turn, associated with a worsening of IR. Pre-clinical research reveals that intrinsic IR in glomerular podocytes and the renal tubule may serve as a pathogenic driver of CKD in T2DM. AREAS COVERED The present manuscript takes as its point of departure, the recently identified prognostic utility of severe insulin resistance as a predictor of CKD in T2DM. Findings from a series of studies describing the association of IR with pathological alterations in both established, and less commonly assessed dynamic measures of renal impairment are discussed. Drawing upon the pre-clinical mechanistic evidence base, the cellular and molecular basis of intrinsic renal IR as a promoter of CKD is considered. EXPERT OPINION Measurement of insulin sensitivity may add value to profiling of renal risk in T2DM. Rational selection of therapeutic strategies targeting the enhancement of insulin sensitivity merits special attention regarding the personalized management of CKD in insulin resistance predominant T2DM.
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Affiliation(s)
- Alrataj Alqallaf
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Patrick Swan
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Neil G Docherty
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
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Insulin Resistance and High Blood Pressure: Mechanistic Insight on the Role of the Kidney. Biomedicines 2022; 10:biomedicines10102374. [PMID: 36289636 PMCID: PMC9598512 DOI: 10.3390/biomedicines10102374] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/08/2022] [Accepted: 09/15/2022] [Indexed: 12/03/2022] Open
Abstract
The metabolic effects of insulin predominate in skeletal muscle, fat, and liver where the hormone binds to its receptor, thereby priming a series of cell-specific and biochemically diverse intracellular mechanisms. In the presence of a good secretory reserve in the pancreatic islets, a decrease in insulin sensitivity in the metabolic target tissues leads to compensatory hyperinsulinemia. A large body of evidence obtained in clinical and experimental studies indicates that insulin resistance and the related hyperinsulinemia are causally involved in some forms of arterial hypertension. Much of this involvement can be ascribed to the impact of insulin on renal sodium transport, although additional mechanisms might be involved. Solid evidence indicates that insulin causes sodium and water retention, and both endogenous and exogenous hyperinsulinemia have been correlated to increased blood pressure. Although important information was gathered on the cellular mechanisms that are triggered by insulin in metabolic tissues and on their abnormalities, knowledge of the insulin-related mechanisms possibly involved in blood pressure regulation is limited. In this review, we summarize the current understanding of the cellular mechanisms that are involved in the pro-hypertensive actions of insulin, focusing on the contribution of insulin to the renal regulation of sodium balance and body fluids.
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12
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Zhong B, Ma S, Wang DH. Activation of TRPV1 improves natriuresis and salt sensitivity in high-fat diet fed mice. Biochem Pharmacol 2022; 203:115190. [PMID: 35905972 DOI: 10.1016/j.bcp.2022.115190] [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: 06/03/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/02/2022]
Abstract
Western diet (WD) intake increases morbidity of obesity and salt-sensitive hypertension albeit mechanisms are largely unknown. We investigated the role of transient receptor potential vanilloid 1 (TRPV1) in WD intake-induced hypertension. TRPV1-/- and wild-type (WT) mice were fed a normal (CON) or Western diet (WD) for 16-18 weeks. Mean arterial pressure (MAP) after normal sodium glucose (NSG) loading with or without L-NAME (a NO synthase inhibitor) or N-oleoyldopamine (OLDA, a TRPV1agonist) was not different between the two strains on CON.WT or TRPV1-/- mice fed WD had increased MAP after NSG, with a greater magnitude in TRPV1-/- mice. OLDA decreased while L-NAME increased MAP in WT-WD but not in TRPV1-/--WD mice. The urinary nitrates plus nitrites excretion (UNOx), an indicator of renal NO production, was increased in both strains on CON after NSG. TRPV1 ablation with WD intake abolished NSG-induced increment in UNOx. OLDA further increased while L-NAME prevented NSG-induced increment in UNOx in WT-WD mice. Urinary sodium excretion was increased in both strains on CON and in WT-WD mice but not in TRPV1-/--WD mice after NSG. OLDA further increased while L-NAME prevented NSG-induced increases in sodium excretion in WT-WD but not in TRPV1-/--WD mice. Thus, TRPV1 ablation increases salt sensitivity during WD intake possibly via impaired renal NO production and sodium excretion. Activation of TRPV1 enhances renal NO production and sodium excretion, resulting in prevention of increased salt sensitivity during WD intake.
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Affiliation(s)
- Beihua Zhong
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Shuangtao Ma
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Donna H Wang
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA; Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA; Cell & Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.
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Sharma R, Sahoo B, Srivastava A, Tiwari S. Reduced insulin signaling and high glucagon in early insulin resistance impaired fast-fed regulation of renal gluconeogenesis via insulin receptor substrate. J Cell Biochem 2022; 123:1327-1339. [PMID: 35644013 DOI: 10.1002/jcb.30294] [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: 10/28/2021] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 11/08/2022]
Abstract
Gluconeogenesis is one of the key processes through which the kidney contributes to glucose homeostasis. Urinary exosomes (uE) have been used to study renal gene regulation noninvasively in humans and rodents. Recently, we demonstrated fast-fed regulation of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme for gluconeogenesis, in human uE. The regulation was impaired in subjects with early insulin resistance. Here, we studied primary human proximal tubule cells (hPT) and human uE to elucidate a potential link between insulin resistance and fast-fed regulation of renal PEPCK. We demonstrate that fasted hPTs had higher PEPCK and insulin receptor substrate-2 (IRS2) mRNA and protein levels, relative to fed cells. The fast-fed regulation was, however, attenuated in insulin receptor knockdown (IRKO) hPTs. The IRKO was confirmed by the blunted insulin-induced response on PEPCK, PGC1α, p-IR, and p-AKT expression in IRKO cells. Exosomes secreted by the wild-type or IRKO hPT showed similar regulation to the respective hPT. Similarly, in human uE, the relative abundance of IRS-2 mRNA (to IRS1) was higher in the fasted state relative to the fed condition. However, the fast-fed difference was absent in subjects with early insulin resistance. These subjects had higher circulating glucagon levels relative to subjects with optimal insulin sensitivity. Furthermore, in hPT cells, glucagon significantly induced PEPCK and IRS2 gene, and gluconeogenesis. IR knockdown in hPT cells further increased the gene expression levels. Together the data suggest that reduced insulin sensitivity and high glucagon in early insulin resistance may impair renal gluconeogenesis via IRS2 regulation.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Biswajit Sahoo
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Aneesh Srivastava
- Department of Urology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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14
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Fan C, Zhang D, Zhang J, Li J, Wang Y, Gao L, Han S. The effect of D-chiro-inositol on renal protection in diabetic mice. Aging (Albany NY) 2022; 14:3416-3424. [PMID: 35439732 PMCID: PMC9085239 DOI: 10.18632/aging.204019] [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: 01/22/2022] [Accepted: 03/28/2022] [Indexed: 12/02/2022]
Abstract
D-Chiro-inositol (DCI) exerts a hypoglycaemic effect, participates in lipid metabolism and reduces kidney damage. In this study, we preliminarily explored the protective effect of DCI on renal injury in diabetic mice. Male db/db mice were used in this study. After treatment with DCI (35 and 70 mg/kg/d) for 6 consecutive weeks, random blood glucose (RBG) measurements were conducted at 0 and 6 weeks. Creatinine (Cr) and serum blood urea nitrogen (BUN) levels were measured using assay kit, and morphological changes in the kidneys were observed by HE staining, Masson staining and electron microscopy. Immunohistochemical and Western blot experiments were used to examine the protein expression of matrix metalloproteinase-9 (MMP-9), nuclear factor-κB (NF-κB) and peroxisome proliferator-activated receptor-γ (PPAR-γ). We discovered that the increased RBG levels were alleviated after treatment with DCI. Moreover, the Cr and BUN levels were reduced, glomerular mesangial hyperplasia was alleviated, and the degree of renal fibrosis was reduced. In addition, DCI improved the protein expression of MMP-9 and PPAR-γ in kidney tissue, which in turn inhibited NF-κB protein expression, as shown by immunohistochemistry and Western blotting. Our findings showed that DCI ameliorated the renal injury induced by diabetes by upregulating MMP-9 and PPAR-γ expression and downregulating NF-κB expression. We preliminarily concluded that the renal protective effect of DCI on diabetic mice may occurs through the MMP-9/NF-κB signalling pathway.
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Affiliation(s)
- Chunxue Fan
- School of Pharmacy, North China University of Science and Technology, Tangshan 063210, Hebei, PR China.,Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, Hebei, PR China
| | - Dandan Zhang
- Clinical Medical College, North China University of Science and Technology, Tangshan 063210, Hebei, PR China
| | - Junling Zhang
- School of Nursing and Health, Caofeidian College of Technology, Tangshan 063210, Hebei, PR China
| | - Jinwei Li
- School of Nursing and Health, Caofeidian College of Technology, Tangshan 063210, Hebei, PR China
| | - Yu Wang
- School of Nursing and Health, Caofeidian College of Technology, Tangshan 063210, Hebei, PR China
| | - Linghuan Gao
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, Hebei, PR China.,Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, Hebei, PR China
| | - Shuying Han
- School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, Hebei, PR China.,Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, Hebei, PR China.,School of Nursing and Health, Caofeidian College of Technology, Tangshan 063210, Hebei, PR China
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15
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Jeddi S, Gheibi S, Kashfi K, Ghasemi A. Sodium hydrosulfide has no additive effects on nitrite-inhibited renal gluconeogenesis in type 2 diabetic rats. Life Sci 2021; 283:119870. [PMID: 34352258 DOI: 10.1016/j.lfs.2021.119870] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/20/2021] [Accepted: 07/25/2021] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Increased renal and hepatic gluconeogenesis are important sources of fasting hyperglycemia in type 2 diabetes (T2D). The inhibitory effect of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on hepatic but not renal gluconeogenesis has been reported in rats with T2D. The present study aimed to determine the effects of co-administration of sodium nitrite and NaSH on the expression of genes involved in renal gluconeogenesis in rats with T2D. METHODS T2D was induced by a combination of a high-fat diet and low-dose streptozotocin (30 mg/kg). Male Wistar rats were divided into 5 groups (n = 6/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite and NaSH were administered for nine weeks at a dose of 50 mg/L (in drinking water) and 0.28 mg/kg (daily intraperitoneal injection), respectively. Serum levels of urea and creatinine, and mRNA expressions of PEPCK, G6Pase, FBPase, PC, PI3K, AKT, PGC-1α, and FoxO1 in the renal tissue, were measured at the end of the study. RESULTS Nitrite decreased mRNA expression of PEPCK by 39%, G6Pase by 43%, FBPase by 41%, PC by 63%, PGC-1α by 45%, and FoxO1 by 27% in the renal tissue of rats with T2D; co-administration of nitrite and NaSH further decreases FoxO1, while had no additive effects on the tissue expression of the other genes. In addition, nitrite+NaSH decreased elevated serum urea levels by 58% and creatinine by 37% in rats with T2D. CONCLUSION The inhibitory effect of nitrite on gluconeogenesis in T2D rats is at least in part due to decreased mRNA expressions of renal gluconeogenic genes. Unlike effects on hepatic gluconeogenesis, co-administration of nitrite and NaSH has no additive effects on genes involved in renal gluconeogenesis in rats with T2D.
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Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sevda Gheibi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Lund University, Malmö, Sweden
| | - Khosrow Kashfi
- Department of Molecular, Cellular, Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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16
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Rahman MS, Hossain KS, Das S, Kundu S, Adegoke EO, Rahman MA, Hannan MA, Uddin MJ, Pang MG. Role of Insulin in Health and Disease: An Update. Int J Mol Sci 2021; 22:6403. [PMID: 34203830 PMCID: PMC8232639 DOI: 10.3390/ijms22126403] [Citation(s) in RCA: 132] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/12/2021] [Accepted: 06/14/2021] [Indexed: 02/06/2023] Open
Abstract
Insulin is a polypeptide hormone mainly secreted by β cells in the islets of Langerhans of the pancreas. The hormone potentially coordinates with glucagon to modulate blood glucose levels; insulin acts via an anabolic pathway, while glucagon performs catabolic functions. Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue, resulting in overall weight gain. The modulation of a wide range of physiological processes by insulin makes its synthesis and levels critical in the onset and progression of several chronic diseases. Although clinical and basic research has made significant progress in understanding the role of insulin in several pathophysiological processes, many aspects of these functions have yet to be elucidated. This review provides an update on insulin secretion and regulation, and its physiological roles and functions in different organs and cells, and implications to overall health. We cast light on recent advances in insulin-signaling targeted therapies, the protective effects of insulin signaling activators against disease, and recommendations and directions for future research.
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Affiliation(s)
- Md Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong 17546, Korea; (M.S.R.); (E.O.A.)
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
| | - Khandkar Shaharina Hossain
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
| | - Sharnali Das
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
| | - Sushmita Kundu
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
| | - Elikanah Olusayo Adegoke
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong 17546, Korea; (M.S.R.); (E.O.A.)
| | - Md. Ataur Rahman
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Md. Abdul Hannan
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
| | - Md Jamal Uddin
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Woman’s University, Seoul 03760, Korea
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong 17546, Korea; (M.S.R.); (E.O.A.)
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Unluhizarci K, Karaca Z, Kelestimur F. Role of insulin and insulin resistance in androgen excess disorders. World J Diabetes 2021; 12:616-629. [PMID: 33995849 PMCID: PMC8107978 DOI: 10.4239/wjd.v12.i5.616] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/13/2021] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Insulin has complex effects on cell growth, metabolism and differentiation, and these effects are mediated by a cell-surface bound receptor and eventually a cascade of intracellular signaling events. Among the several metabolic and growth-promoting effects of insulin, insulin resistance is defined as an attenuated effect of insulin on glucose metabolism, primarily the limited export of blood glucose into skeletal muscle and adipose tissue. On the other hand, not all the signaling pathways and insulin-responsive tissues are equally affected, and some effects other than the metabolic actions of insulin are overexpressed. Ovaries and the adrenal glands are two examples of tissues remaining sensitive to insulin actions where insulin may contribute to increased androgen secretion. Polycystic ovary syndrome (PCOS) is the most common form of androgen excess disorder (AED), and its pathogenesis is closely associated with insulin resistance. Patients with idiopathic hirsutism also exhibit insulin resistance, albeit lower than patients with PCOS. Although it is not as evident as in PCOS, patients with congenital adrenal hyperplasia may have insulin resistance, which may be further exacerbated with glucocorticoid overtreatment and obesity. Among patients with severe insulin resistance syndromes, irrespective of the type of disease, hyperinsulinemia promotes ovarian androgen synthesis independently of gonadotropins. It is highly debated in whom and how insulin resistance should be diagnosed and treated among patients with AEDs, including PCOS. It is not suitable to administer an insulin sensitizer relying on only some mathematical models used for estimating insulin resistance. Instead, the treatment decision should be based on the constellation of the signs, symptoms and presence of obesity; acanthosis nigricans; and some laboratory abnormalities such as impaired glucose tolerance and impaired fasting glucose.
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Affiliation(s)
- Kursad Unluhizarci
- Department of Endocrinology, Erciyes University Medical School, Kayseri, 38039, Turkey
| | - Zuleyha Karaca
- Department of Endocrinology, Erciyes University Medical School, Kayseri, 38039, Turkey
| | - Fahrettin Kelestimur
- Department of Endocrinology, Yeditepe University Medical School, Istanbul, 34755, Turkey
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18
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Sharma R, Tiwari S. Renal gluconeogenesis in insulin resistance: A culprit for hyperglycemia in diabetes. World J Diabetes 2021; 12:556-568. [PMID: 33995844 PMCID: PMC8107972 DOI: 10.4239/wjd.v12.i5.556] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/27/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Renal gluconeogenesis is one of the major pathways for endogenous glucose production. Impairment in this process may contribute to hyperglycemia in cases with insulin resistance and diabetes. We reviewed pertinent studies to elucidate the role of renal gluconeogenesis regulation in insulin resistance and diabetes. A consensus on the suppressive effect of insulin on kidney gluconeogenesis has started to build up. Insulin-resistant models exhibit reduced insulin receptor (IR) expression and/or post-receptor signaling in their kidney tissue. Reduced IR expression or post-receptor signaling can cause impairment in insulin’s action on kidneys, which may increase renal gluconeogenesis in the state of insulin resistance. It is now established that the kidney contributes up to 20% of all glucose production via gluconeogenesis in the post-absorptive phase. However, the rate of renal glucose release excessively increases in diabetes. The rise in renal glucose release in diabetes may contribute to fasting hyperglycemia and increased postprandial glucose levels. Enhanced glucose release by the kidneys and renal expression of the gluconeogenic-enzyme in diabetic rodents and humans further point towards the significance of renal gluconeogenesis. Overall, the available literature suggests that impairment in renal gluconeogenesis in an insulin-resistant state may contribute to hyperglycemia in type 2 diabetes.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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19
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Ecelbarger CM. Diabetic Kidney Disease Represents a Locus of Opportunity. Front Physiol 2021; 12:650503. [PMID: 33762972 PMCID: PMC7982870 DOI: 10.3389/fphys.2021.650503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/01/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Carolyn Mary Ecelbarger
- Department of Medicine/Division of Endocrinology and Metabolism, Georgetown University, Washington, DC, United States
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20
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Aljaylani A, Fluitt M, Piselli A, Shepard BD, Tiwari S, Ecelbarger CM. Acid Loading Unmasks Glucose Homeostatic Instability in Proximal-Tubule-Targeted Insulin/Insulin-Like-Growth-Factor-1 Receptor Dual Knockout Mice. Cell Physiol Biochem 2021; 54:682-695. [PMID: 32678535 DOI: 10.33594/000000248] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2020] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND/AIMS Metabolic syndrome and type 2 diabetes are associated with some degree of acidosis. Acidosis has also been shown to upregulate renal gluconeogenesis. Whether impaired insulin or insulin-like-growth factor 1 receptor (IGF1) signaling alter this relationship is not known. Our aim was to determine the effects of deletion of insulin and IGF1 receptors (Insr and Igf1r) from renal proximal tubule (PT) on the gluconeogenic response to acidosis. METHODS We developed a mouse model with PT-targeted dual knockout (KO) of the Insr/Igf1r by driving Cre-recombinase with the gamma-glutamyl transferase (gGT) promoter. Male and female mice were maintained as control or acidotic by treatment with NH4Cl in the drinking water for 1-week. RESULTS Acidosis in both genotypes increased renal expression of phosphoenolpyruvate carboxykinase (PEPCK) and fructose-1-bisphosphatase (FBP1), but not glucose-6-phosphatase catalytic subunit (G6PC), which showed significantly lower expression in the KO regardless of treatment. Several differences between KO and WT suggested a protective role for insulin/IGF1 receptor signaling in maintaining relative euglycemia in the face of acidosis. First, the increase in FBP1 with acid was greater in the KO (significant interactive term). Secondly, proximal-tubule-associated FOXO1 and AKT overall protein levels were suppressed by acid loading in the KO, but not in the WT. Robust intact insulin signaling would be needed to reduce gluconeogenesis in PT. Third, phosphorylated FOXO1 (pS256) levels were markedly reduced by acid loading in the KO PT, but not in the WT. This reduction would support greater gluconeogenesis. Fourth, the sodium-glucose cotransporter (SGLT1) was increased by acid loading in the KO kidney, but not the WT. While this would not necessarily affect gluconeogenesis, it could result in increased circulatory glucose via renal reabsorption. Reduced susceptibility to glucose-homeostatic dysregulation in the WT could potentially relate to the sharp (over 50%) reduction in renal levels of sirtuin-1 (SIRT1), which deacetylates and regulates transcription of a number of genes. This reduction was absent in the KO. CONCLUSION Insulin resistance of the kidney may increase whole-body glucose instability a major risk factor for morbidity in diabetes. High dietary acid loads provide a dilemma for the kidney, as ammoniagenesis liberates α-ketoglutarate, which is a substrate for gluconeogenesis. We demonstrate an important role for insulin and/or IGF1 receptor signaling in the PT to facilitate this process and reduce excursions in blood glucose. Thus, medications and lifestyle changes that improve renal insulin sensitivity may also provide added benefit in type 2 diabetes especially when coupled with metabolic acidosis.
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Affiliation(s)
- Abdullah Aljaylani
- Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, D.C., USA
| | - Maurice Fluitt
- Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, D.C., USA
| | - Alexandra Piselli
- Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, D.C., USA
| | - Blythe D Shepard
- School of Nursing and Health Studies, Department of Human Science, Georgetown University, Washington, D.C., USA
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Utter Pradesh, India
| | - Carolyn M Ecelbarger
- Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, D.C., USA,
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Jeddi S, Gheibi S, Carlström M, Kashfi K, Ghasemi A. Long-term co-administration of sodium nitrite and sodium hydrosulfide inhibits hepatic gluconeogenesis in male type 2 diabetic rats: Role of PI3K-Akt-eNOS pathway. Life Sci 2020; 265:118770. [PMID: 33212150 DOI: 10.1016/j.lfs.2020.118770] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/05/2020] [Accepted: 11/13/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVE A deficiency in hydrogen sulfide (H2S) and nitric oxide (NO) contributes to the development of type 2 diabetes (T2D). An inhibitory effect on liver gluconeogenesis has been reported in rats with T2D with co-administration of sodium nitrite and sodium hydrosulfide (NaSH); the underlying mechanisms have however not yet been elucidated. The aim of this study is to determine the long-term effects of co-administering sodium nitrite and NaSH on expression of genes involved in liver gluconeogenesis in rats with T2D. METHODS T2D was induced using a high fat diet combined with low-dose of streptozotocin (30 mg/kg). Rats were divided into 5 groups (n = 7/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite (50 mg/L) and NaSH (0.28 mg/kg) were administered for 9 weeks. Intraperitoneal pyruvate tolerance test (PTT) was performed at the end of the ninth week and mRNA expressions of PI3K, Akt, eNOS, PEPCK, G6Pase, and FBPase were measured in the liver. RESULTS Co-administration of nitrite and NaSH decreased elevated serum glucose concentrations during PTT. Compared to T2D + nitrite, co-administration of nitrite and NaSH resulted in significant increases in mRNA expression of PI3K, Akt, and eNOS and significant decreases in mRNA expression of G6Pase and FBPase but had no effect on PEPCK expression. CONCLUSION Long-term NaSH administration at low-dose, potentiated the inhibitory effects of nitrite on mRNA expression of key liver gluconeogenic enzymes in rats with T2D. This inhibitory effect of nitrite and NaSH co-administration on gluconeogenesis were associated with increased gene expression of PI3K, Akt, and eNOS in the liver.
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Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sevda Gheibi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Mattias Carlström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA.
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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22
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Gao L, Yuan P, Zhang Q, Fu Y, Hou Y, Wei Y, Zheng X, Feng W. Taxifolin improves disorders of glucose metabolism and water-salt metabolism in kidney via PI3K/AKT signaling pathway in metabolic syndrome rats. Life Sci 2020; 263:118713. [PMID: 33157091 DOI: 10.1016/j.lfs.2020.118713] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/23/2020] [Accepted: 11/02/2020] [Indexed: 12/16/2022]
Abstract
AIMS Our study was designed to explore the function and mechanism of taxifolin on glucose metabolism and water-salt metabolism in kidney with metabolic syndrome (MS) rats. MAIN METHODS Spontaneous hypertensive rats were induced by fructose to establish MS model. Systolic blood pressure (SBP) and homeostasis model assessment of insulin resistance (HOMA-IR) were measured after 7 weeks of continuous administration with taxifolin. Kidney injury indices and histopathological evaluation were done. The apoptosis rate of primary kidney cells was detected by flow cytometry. Insulin signaling pathway related proteins and renal glucose transport-related proteins were detected by western blotting. We assessed the effects of taxifolin on sodium water retention and renin-angiotensin-aldosterone system (RAAS) in MS rats. We examined not only changes in urine volume, osmotic pressure, urinary sodium and urinary chloride excretion, but also the effects on NA+/K+-ATPase and RAAS indicators. We also detected changes in inflammatory factors by immunohistochemical staining and immunofluorescence. In vitro experiment, high glucose and salt stimulated NRK-52E cells. By adding the PI3K inhibitor (wortmannin) to inhibit the PI3K, the effects of inhibiting the PI3K/AKT signaling pathway on glucose metabolism, water-sodium retention and inflammatory response were discussed. KEY FINDINGS Taxifolin effectively reversed SBP, HOMA-IR, the kidney indices and abnormal histopathological changes induced by MS. Besides, taxifolin called back the protein associated with the downstream glucose metabolism pathway of PI3K/AKT. It also inhibited overactivation of RAAS and inflammatory response. In vitro experiments have demonstrated that the PI3K/AKT signaling pathway plays an important role in this process. SIGNIFICANCE Taxifolin can improve homeostasis of glucose, inhibit overactivation of RAAS and reduce inflammatory response by PI3K/AKT signaling pathway.
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Affiliation(s)
- Liyuan Gao
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Peipei Yuan
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Qi Zhang
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yang Fu
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Ying Hou
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yaxin Wei
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Xiaoke Zheng
- Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
| | - Weisheng Feng
- Henan University of Chinese Medicine, Zhengzhou 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, Zhengzhou 450046, China.
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Rani L, Saini S, Shukla N, Chowdhuri DK, Gautam NK. High sucrose diet induces morphological, structural and functional impairments in the renal tubules of Drosophila melanogaster: A model for studying type-2 diabetes mediated renal tubular dysfunction. INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY 2020; 125:103441. [PMID: 32735915 DOI: 10.1016/j.ibmb.2020.103441] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 07/13/2020] [Accepted: 07/20/2020] [Indexed: 06/11/2023]
Abstract
Continuous feeding of high dietary sugar is strongly associated with type 2 diabetes (T2D) and its secondary complications. Diabetic nephropathy (DN) is a major secondary complication that leads to glomerular and renal tubular dysfunction. The present study is aimed to investigate the effects of chronic exposure of high sugar diet (HSD) on renal tubules. Malpighian tubules (MTs), a renal organ of Drosophila, were used as a model in the study. Feeding of HSD develops T2D condition in Drosophila. The MTs showed structural abnormalities in 20 days of HSD fed flies. Impaired insulin signaling, oxidative stress, enhanced levels of AGE-RAGE and induction of apoptosis were observed in the MTs of these flies. Further, altered expression of transporters, enhanced uric acid level and reduced fluid secretion rate confirmed the impaired function of MTs in these flies. RNA-seq and RT-PCR analyses in the MTs of HSD fed-and control-flies revealed the altered expression of candidate genes that regulate several important pathways including extracellular matrix (ECM), advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE), transforming growth factor β (TGF-β), galactose, starch and sucrose metabolism that are well known mediators of renal tubular dysfunction in DN patients. Disruption of insulin signaling in the MTs also causes renal tubular dysfunction similar to HSD fed flies. Overall, the study suggests that phenotypes observed in the MTs of HSD fed flies recapitulate several hallmarks of renal tubular dysfunction in DN patients. Therefore, we conclude that MTs of HSD fed flies may be used for deciphering the underlying mechanisms of T2D mediated renal tubular dysfunction.
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Affiliation(s)
- Lavi Rani
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India
| | - Sanjay Saini
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, 226007, India
| | - Neha Shukla
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India
| | - Debapratim Kar Chowdhuri
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India
| | - Naveen Kumar Gautam
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India; Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India.
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24
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Ferrannini E, Pereira-Moreira R, Seghieri M, Rebelos E, Souza AL, Chueire VB, Arvia C, Muscelli E. Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport. BMJ Open Diabetes Res Care 2020; 8:8/1/e001178. [PMID: 32423964 PMCID: PMC7245398 DOI: 10.1136/bmjdrc-2020-001178] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/27/2020] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Insulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known. METHODS We applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects. Each participant received a somatostatin infusion and a variable glucose infusion to achieve (within 1 hour) and maintain glycemia at 22 mmol/L for 3 hours; next, a constant insulin infusion (240 pmol/min/kg) was added for another 3 hours. Urine was collected separately in each period for glucose and creatinine determination. RESULTS During saline, glucose excretion was lower in T2D than controls in absolute terms (0.49 (0.32) vs 0.69 (0.18) mmol/min, median (IQR), p=0.01) and as a fraction of filtered glucose (16.2 (6.4) vs 19.9 (7.5)%, p<0.001). With insulin, whole-body glucose disposal rose more in controls than T2D (183 (48) vs 101 (48) µmol/kgFFM/min, p<0.0003). Insulin stimulated absolute and fractional glucose excretion in controls (p<0.01) but not in T2D. Sodium excretion paralleled glucose excretion. In the pooled data, fractional glucose excretion was directly related to whole-body glucose disposal and to fractional sodium excretion (r=0.52 and 0.54, both p<0.01). In another group of healthy controls, empagliflozin was administered before starting the pancreatic clamp to block sodium-glucose cotransporter 2 (SGLT2). Under these conditions, insulin still enhanced both glucose and sodium excretion. CONCLUSIONS Acute exogenous insulin infusion jointly stimulates renal glucose and sodium excretion, indicating that the effect may be mediated by SGLTs. This action is resistant in patients with diabetes, accounting for their increased retention of glucose and sodium, and is not abolished by partial SGLT2 inhibition by empagliflozin.
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Affiliation(s)
| | - Ricardo Pereira-Moreira
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Marta Seghieri
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Eleni Rebelos
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Aglécio L Souza
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Valeria B Chueire
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | | | - Elza Muscelli
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
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25
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Sharma R, Kumari M, Prakash P, Gupta S, Tiwari S. Phosphoenolpyruvate carboxykinase in urine exosomes reflect impairment in renal gluconeogenesis in early insulin resistance and diabetes. Am J Physiol Renal Physiol 2020; 318:F720-F731. [PMID: 32036699 DOI: 10.1152/ajprenal.00507.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Impaired insulin-induced suppression of renal gluconeogenesis could be a risk for hyperglycemia. Diabetes is associated with elevated renal gluconeogenesis; however, its regulation in early insulin resistance is unclear in humans. A noninvasive marker of renal gluconeogenesis would be helpful. Here, we show that human urine exosomes (uE) contain three gluconeogenic enzymes: phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Their protein levels were positively associated with whole body insulin sensitivity. PEPCK protein in uE exhibited a meal-induced suppression. However, subjects with lower insulin sensitivity had blunted meal-induced suppression. Also, uE from subjects with prediabetes and diabetic rats had higher PEPCK relative to nondiabetic controls. Moreover, uE-PEPCK was higher in drug-naïve subjects with diabetes relative to drug-treated subjects with diabetes. To determine whether increased renal gluconeogenesis is associated with hyperglycemia or PEPCK expression in uE, acidosis was induced in rats by 0.28 M NH4Cl with 0.5% sucrose in drinking water. Control rats were maintained on 0.5% sucrose. At the seventh day posttreatment, gluconeogenic enzyme activity in the kidneys, but not in the liver, was higher in acidotic rats. These rats had elevated PEPCK in their uE and a significant rise in blood glucose relative to controls. The induction of gluconeogenesis in human proximal tubule cells increased PEPCK expression in both human proximal tubules and human proximal tubule-secreted exosomes in the media. Overall, gluconeogenic enzymes are detectable in human uE. Elevated PEPCK and its blunted meal-induced suppression in human urine exosomes are associated with diabetes and early insulin resistance.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Manju Kumari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Prem Prakash
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sushil Gupta
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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26
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Pereira-Moreira R, Muscelli E. Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review. J Diabetes Res 2020; 2020:8492467. [PMID: 32377524 PMCID: PMC7180501 DOI: 10.1155/2020/8492467] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 12/18/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023] Open
Abstract
Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na+K+ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.
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Affiliation(s)
- Ricardo Pereira-Moreira
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Zip Code: 13083-887, Brazil
| | - Elza Muscelli
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Zip Code: 13083-887, Brazil
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27
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Permyakova A, Gammal A, Hinden L, Weitman M, Weinstock M, Tam J. A Novel Indoline Derivative Ameliorates Diabesity-Induced Chronic Kidney Disease by Reducing Metabolic Abnormalities. Front Endocrinol (Lausanne) 2020; 11:91. [PMID: 32218769 PMCID: PMC7078689 DOI: 10.3389/fendo.2020.00091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/13/2020] [Indexed: 12/13/2022] Open
Abstract
Both diabetes and obesity (diabesity) contribute significantly to the development of chronic kidney disease (CKD). In search of new remedies to reverse or arrest the progression of CKD, we examined the therapeutic potential of a novel compound, AN1284, in a mouse model of CKD induced by type 2 diabetes with obesity. Six-week-old BKS Cg-Dock 7m+/+ Leprdb/J mice with type 2 diabetes and obesity were treated with AN1284 (2.5 or 5 mg kg-1 per day) via micro-osmotic pumps implanted subcutaneously for 3 months. Measures included renal, pancreatic, and liver assessment as well as energy utilization. AN1284 improved kidney function in BSK-db/db animals by reducing albumin and creatinine and preventing renal inflammation and morphological changes. The treatment was associated with weight loss, decreased body fat mass, increased utilization of body fat toward energy, preservation of insulin sensitivity and pancreatic β cell mass, and reduction of dyslipidemia, hepatic steatosis, and liver injury. This indoline derivative protected the kidney from the deleterious effects of hyperglycemia by ameliorating the metabolic abnormalities of diabetes. It could have therapeutic potential for preventing CKD in human subjects with diabesity.
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Affiliation(s)
- Anna Permyakova
- Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Asaad Gammal
- Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Liad Hinden
- Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Michal Weitman
- Department of Chemistry, Bar Ilan University, Ramat Gan, Israel
| | - Marta Weinstock
- Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Joseph Tam
- Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
- *Correspondence: Joseph Tam
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28
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Mitrofanova A, Sosa MA, Fornoni A. Lipid mediators of insulin signaling in diabetic kidney disease. Am J Physiol Renal Physiol 2019; 317:F1241-F1252. [PMID: 31545927 PMCID: PMC6879940 DOI: 10.1152/ajprenal.00379.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/19/2019] [Accepted: 09/19/2019] [Indexed: 12/30/2022] Open
Abstract
Diabetic kidney disease (DKD) affects ∼40% of patients with diabetes and is associated with high mortality rates. Among different cellular targets in DKD, podocytes, highly specialized epithelial cells of the glomerular filtration barrier, are injured in the early stages of DKD. Both clinical and experimental data support the role of preserved insulin signaling as a major contributor to podocyte function and survival. However, little is known about the key modulators of podocyte insulin signaling. This review summarizes the novel knowledge that intracellular lipids such as cholesterol and sphingolipids are major determinants of podocyte insulin signaling. In particular, the implications of these lipids on DKD development, progression, and treatment will be addressed.
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Affiliation(s)
- Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, Florida
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - Marie Anne Sosa
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida
- Peggy and Harold Katz Family Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, Florida
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29
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Wang Y, Zhou H, Palyha O, Mu J. Restoration of insulin receptor improves diabetic phenotype in T2DM mice. JCI Insight 2019; 4:124945. [PMID: 31391336 DOI: 10.1172/jci.insight.124945] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 06/27/2019] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM), also known as adult-onset diabetes, is characterized by ineffective insulin action due to insulin resistance in key metabolic tissues. Insulin receptor (IR) plays an important role in insulin signal transduction, defect of which has been considered the fundamental cause of T2DM. IR content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation has not been considered as a treatment option because it is limited by uncontrollable expression level, tissue selectivity, or developmental defects. In the current study, we demonstrated that single-dose adeno-associated virus (AAV) vector delivered expression of human IR (hIR) in the liver of inducible IR-knockout mice and significantly improved the diabetic phenotype caused by IR deletion during adulthood. Such an approach was also applied, for the first time to our knowledge, to treating ob/ob mice, a model of severe T2DM attributed to superfluous calorie intake and insulin resistance. Interestingly, similar treatment with AAV-hIR had no obvious effect in healthy animals, indicative of low hypoglycemic risk as a consequence of potential excessive insulin action. The results described here support restoration of IR expression as a safe and effective T2DM therapeutic with a long-lasting profile.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Blood Glucose/analysis
- Dependovirus/genetics
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/pathology
- Diabetes Mellitus, Type 2/therapy
- Disease Models, Animal
- Genetic Therapy/adverse effects
- Genetic Therapy/methods
- Genetic Vectors/administration & dosage
- Genetic Vectors/adverse effects
- Genetic Vectors/genetics
- Humans
- Hypoglycemia/blood
- Hypoglycemia/diagnosis
- Hypoglycemia/genetics
- Insulin/metabolism
- Male
- Mice
- Mice, Knockout
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
- Treatment Outcome
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30
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Álvarez-Cilleros D, López-Oliva E, Goya L, Martín MÁ, Ramos S. Cocoa intake attenuates renal injury in Zucker Diabetic fatty rats by improving glucose homeostasis. Food Chem Toxicol 2019; 127:101-109. [DOI: 10.1016/j.fct.2019.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 03/01/2019] [Accepted: 03/02/2019] [Indexed: 12/26/2022]
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31
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Singh S, Sharma R, Kumari M, Tiwari S. Insulin receptors in the kidneys in health and disease. World J Nephrol 2019; 8:11-22. [PMID: 30705868 PMCID: PMC6354081 DOI: 10.5527/wjn.v8.i1.11] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/15/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023] Open
Abstract
Insulin is an important hormone that affects various metabolic processes, including kidney function. Impairment in insulin’s action leads to insulin resistance in the target tissue. Besides defects in post-receptor insulin signaling, impairment at the receptor level could significantly affect insulin sensitivity of the target tissue. The kidney is a known target of insulin; however, whether the kidney develops “insulin resistance” is debatable. Regulation of the insulin receptor (IR) expression and its function is very well studied in major metabolic tissues like liver, skeletal muscles, and adipose tissue. The physiological relevance of IRs in the kidney has recently begun to be clarified. The credit goes to studies that showed a wide distribution of IR throughout the nephron segments and their reduced expression in the insulin resistance state. Moreover, altered renal and systemic metabolism observed in mice with targeted deletion of the IR from various epithelial cells of the kidney has strengthened this proposition. In this review, we recapitulate the crucial findings from literature that have expanded our knowledge regarding the significance of the renal IR in normal- and insulin-resistance states.
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Affiliation(s)
- Sarojini Singh
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Manju Kumari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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32
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Kumari M, Sharma R, Pandey G, Ecelbarger CM, Mishra P, Tiwari S. Deletion of insulin receptor in the proximal tubule and fasting augment albumin excretion. J Cell Biochem 2019; 120:10688-10696. [PMID: 30644120 DOI: 10.1002/jcb.28359] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Accepted: 11/29/2018] [Indexed: 12/29/2022]
Abstract
The contribution of proximal tubules (PT) to albumin uptake is now well recognized, however, its regulation is understudied area. There are reports suggesting that insulin resistance is associated with the development of albuminuria in nondiabetic individuals. We have previously reported reduced insulin receptor (IR) expression in renal-tubular-epithelial cells, including PT in various models of insulin resistance. However, the effect of a physiological fall in insulin levels and the role for IR in PT in tubular albumin uptake is not clear. To address these gaps in our understanding, we estimated urine excretion and renal uptake of albumin in fasted and fed C57Bl/6 mice injected with fluorescein isothiocyanate (FITC)-albumin (5 µg/mL/kg body weight, intraperitoneal, n = 6 per group). In addition, we compared spot urine analysis from 33 clinically healthy humans after overnight fasting (when insulin levels are lower than in the fed state) and then at 2 hours after 75 g oral glucose challenge (postprandial). Fasted mice had attenuated renal uptake of FITC-albumin and higher excretion in urine, relative to fed mice ( P = 0.04). Moreover, a significant drop in urine albumin-to-creatinine ratio (ACR) and urine albumin concentration (UAC) was observed in the postprandial state in these subjects ( P = 0.001 and P = 0.017, for ACR and UAC, respectively). The drop was negatively associated with postprandial blood glucose levels (ρ = -0.36, P = 0.03 for ΔUAC and ρ = -0.34, P = 0.05 for ΔACR). To test the role of IR in PT, we analyzed 24-hour urine albumin excretion in male mice with targeted deletion of IR from PT (insulin receptor knockout [IRKO]) and their wild-type (WT) littermates ( n = 7 per group). IRKO mice had significantly higher 24-hour urine albumin excretion relative to WT. Moreover, kidneys from KO mice revealed reduced expression of megalin and cubulin proteins in the PT relative to the WT. We also demonstrated insulin (100 nM) induced albumin internalization in human proximal tubule cells (hPT) and this effect of insulin was attenuated in hydroxy-2-naphthalenylmethylphosphonic acid (100 µM), a tyrosine kinase inhibitor, pretreated hPT. Our findings revealed albumin excretion was attenuated by glucose administration to fasting individuals implying a regulatory role for insulin in PT albumin reabsorption. Thus albuminuria associated with insulin resistance/diabetes may relate not only to glomerular dysfunction but also to impairment in insulin-mediated reabsorption.
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Affiliation(s)
- Manju Kumari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Gaurav Pandey
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Carolyn M Ecelbarger
- Department of Medicine, Division of Endocrinology and Metabolism, Georgetown University, Washington, District of Columbia
| | - Prabhaker Mishra
- Department of Biostatistics and Health Informatics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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33
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Murtha MJ, Eichler T, Bender K, Metheny J, Li B, Schwaderer AL, Mosquera C, James C, Schwartz L, Becknell B, Spencer JD. Insulin receptor signaling regulates renal collecting duct and intercalated cell antibacterial defenses. J Clin Invest 2018; 128:5634-5646. [PMID: 30418175 DOI: 10.1172/jci98595] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 09/20/2018] [Indexed: 12/14/2022] Open
Abstract
People with diabetes mellitus have increased infection risk. With diabetes, urinary tract infection (UTI) is more common and has worse outcomes. Here, we investigate how diabetes and insulin resistance impact the kidney's innate defenses and urine sterility. We report that type 2 diabetic mice have increased UTI risk. Moreover, insulin-resistant prediabetic mice have increased UTI susceptibility, independent of hyperglycemia or glucosuria. To identify how insulin resistance affects renal antimicrobial defenses, we genetically deleted the insulin receptor in the kidney's collecting tubules and intercalated cells. Intercalated cells, located within collecting tubules, contribute to epithelial defenses by acidifying the urine and secreting antimicrobial peptides (AMPs) into the urinary stream. Collecting duct and intercalated cell-specific insulin receptor deletion did not impact urine acidification, suppressed downstream insulin-mediated targets and AMP expression, and increased UTI susceptibility. Specifically, insulin receptor-mediated signaling regulates AMPs, including lipocalin 2 and ribonuclease 4, via phosphatidylinositol-3-kinase signaling. These data suggest that insulin signaling plays a critical role in renal antibacterial defenses.
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Affiliation(s)
- Matthew J Murtha
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.,The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Tad Eichler
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kristin Bender
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Jackie Metheny
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Birong Li
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Andrew L Schwaderer
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.,The Ohio State University College of Medicine, Columbus, Ohio, USA.,Division of Nephrology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Claudia Mosquera
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Cindy James
- Mass Spectrometry and Proteomics Facility, The Ohio State University, Columbus, Ohio, USA
| | - Laura Schwartz
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Brian Becknell
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.,The Ohio State University College of Medicine, Columbus, Ohio, USA.,Division of Nephrology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - John David Spencer
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.,The Ohio State University College of Medicine, Columbus, Ohio, USA.,Division of Nephrology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA
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34
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Álvarez-Cilleros D, Martín MÁ, Ramos S. Protective effects of (-)-epicatechin and the colonic metabolite 3,4-dihydroxyphenylacetic acid against glucotoxicity-induced insulin signalling blockade and altered glucose uptake and production in renal tubular NRK-52E cells. Food Chem Toxicol 2018; 120:119-128. [PMID: 29981789 DOI: 10.1016/j.fct.2018.07.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 06/26/2018] [Accepted: 07/02/2018] [Indexed: 01/24/2023]
Abstract
Glucotoxicity (high levels of glucose) is a major cause in the pathogenesis of diabetes. Evidences indicate that (-)-epicatechin (EC) and colonic metabolites derived from flavonoid intake could possess antidiabetic effects, but the mechanisms for their preventive activities related to glucose homeostasis and insulin signalling in the kidney remain largely unknown. This work is aimed to investigate the effect of EC and main colonic phenolic acids derived from flavonoid intake, i.e. 2,3-dihydroxybenzoic-acid, 3,4-dihydroxyphenylacetic-acid (DHPAA) and 3-hydroxyphenylpropionic-acid, on insulin signalling, and glucose production and uptake in renal tubular proximal NRK-52E cells treated with high glucose. Pre-treatment with EC or DHPAA prevented the decreased tyrosine-phosphorylated and total levels of IR caused by high glucose. EC and DHPAA pre-treatment also avoided the inactivation of the PI3K/AKT pathway and AMPK, and the elevation of PEPCK levels induced by high glucose. Additionally, EC and DHPAA pre-treatment alleviated the altered glucose uptake and production caused by high glucose, although this protective effect was abrogated when AKT and AMPK were inhibited. These results suggest EC and DHPAA prevent or delay a potential dysfunction of NRK-52E cells treated with high glucose through the attenuation of the insulin signalling blockade and the modulation of glucose homeostasis via AKT and AMPK.
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Affiliation(s)
- David Álvarez-Cilleros
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040, Madrid, Spain
| | - María Ángeles Martín
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
| | - Sonia Ramos
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040, Madrid, Spain.
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Gandhi VD, Shrestha Palikhe N, Hamza SM, Dyck JRB, Buteau J, Vliagoftis H. Insulin decreases expression of the proinflammatory receptor proteinase-activated receptor-2 on human airway epithelial cells. J Allergy Clin Immunol 2018; 142:1003-1006.e8. [PMID: 29890235 DOI: 10.1016/j.jaci.2018.04.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Revised: 04/05/2018] [Accepted: 04/29/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Vivek D Gandhi
- Division of Pulmonary Medicine, Department of Medicine, Alberta Respiratory Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Nami Shrestha Palikhe
- Division of Pulmonary Medicine, Department of Medicine, Alberta Respiratory Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Shereen M Hamza
- Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Jason R B Dyck
- Department of Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Jean Buteau
- Alberta Diabetes Institute, Li Ka Shing Centre, University of Alberta, Edmonton, Alberta, Canada; Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Harissios Vliagoftis
- Division of Pulmonary Medicine, Department of Medicine, Alberta Respiratory Centre, University of Alberta, Edmonton, Alberta, Canada.
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Nizar JM, Bouby N, Bankir L, Bhalla V. Improved protocols for the study of urinary electrolyte excretion and blood pressure in rodents: use of gel food and stepwise changes in diet composition. Am J Physiol Renal Physiol 2018; 314:F1129-F1137. [PMID: 29357416 PMCID: PMC6032076 DOI: 10.1152/ajprenal.00474.2017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 12/28/2017] [Accepted: 12/31/2017] [Indexed: 11/22/2022] Open
Abstract
Many experimental protocols in rodents require the comparison of groups that are fed different diets. Changes in dietary electrolyte and/or fat content can influence food intake, which can potentially introduce bias or confound the results. Unpalatable diets slow growth or cause weight loss, which is exacerbated by housing the animals in individual metabolic cages or by surgery. For balance studies in mice, small changes in body weight and food intake and low urinary flow can amplify these challenges. Powder food can be administered as gel with the addition of a desired amount of water, electrolytes, drugs (if any), and a small amount of agar. We describe here how the use of gel food to vary water, Na, K, and fat content can reduce weight loss and improve reproducibility of intake, urinary excretion, and blood pressure in rodents. In addition, mild food restriction reduces the interindividual variability and intergroup differences in food intake and associated variables, thus improving the statistical power of an experiment. Finally, we also demonstrate the advantages of using gel food for weight-based drug dosing. These protocols can improve the accuracy and reproducibility of experimental data where dietary manipulations are needed and are especially advisable in rodent studies related to water balance, obesity, and blood pressure.
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Affiliation(s)
- Jonathan M Nizar
- Department of Medicine, Division of Nephrology, Stanford University School of Medicine , Palo Alto, California
| | - Nadine Bouby
- Institut National de la Santé et de la Recherche Médicale, UMRS 1138, Centre de Recherché des Cordeliers , Paris , France
- Université Pierre et Marie Curie , Paris , France
| | - Lise Bankir
- Institut National de la Santé et de la Recherche Médicale, UMRS 1138, Centre de Recherché des Cordeliers , Paris , France
- Université Pierre et Marie Curie , Paris , France
| | - Vivek Bhalla
- Department of Medicine, Division of Nephrology, Stanford University School of Medicine , Palo Alto, California
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Renoprotective Effect of Danhong Injection on Streptozotocin-Induced Diabetic Rats through a Peroxisome Proliferator-Activated Receptor γ Mediated Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:3450141. [PMID: 29849705 PMCID: PMC5925177 DOI: 10.1155/2018/3450141] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 12/10/2017] [Accepted: 01/11/2018] [Indexed: 01/13/2023]
Abstract
The aim of the study was to investigate the protective effect of Danhong injection (DHI) on diabetic kidney disease and explore the potential mechanisms. Diabetic kidney disease was induced by unilateral nephrectomy, high-fat diet, and streptozotocin. After DHI administration, the renal function deterioration, 24-hour total urine protein excretion, and elevated serum lipid levels were reversed to some extent, and the renal pathological damage was also ameliorated. The KEGG pathway enrichment analysis demonstrated that the PPARγ signal pathway was significantly upregulated in DH group. And the increased expressions of PPARγ and UCP-1 were confirmed by immunohistochemistry, whereas the p38MAPK was significantly decreased. These data show that DHI could delay the progress of DKD, and the effect might be achieved in part by activating the PPARγ signaling pathway.
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Belani M, Deo A, Shah P, Banker M, Singal P, Gupta S. Differential insulin and steroidogenic signaling in insulin resistant and non-insulin resistant human luteinized granulosa cells-A study in PCOS patients. J Steroid Biochem Mol Biol 2018; 178:283-292. [PMID: 29339197 DOI: 10.1016/j.jsbmb.2018.01.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 01/05/2018] [Accepted: 01/11/2018] [Indexed: 12/15/2022]
Abstract
Insulin resistance (IR) is one of the significant aberrations in polycystic ovarian syndrome (PCOS), however is only observed in 70%-80% of obese PCOS and 20%-25% of lean PCOS. Hyperinsulinemia accompanies PCOS-IR along with hyperandrogenemia against normal insulin and androgen levels in PCOS-non insulin resistance (NIR). This could possibly be due to defects in the downstream signaling pathways. The study thus aims to unravel insulin and steroidogenic signaling pathways in luteinized granulosa cells isolated from PCOS-IR and NIR vs matched controls. Luteinized granulosa cells from 30 controls and 39 PCOS were classified for IR based on a novel method of down regulation of protein expression of insulin receptor-β (INSR- β) as shown in our previous paper. We evaluated expression of molecules involved in insulin, steroidogenic signaling and lipid metabolism in luteinized granulosa cells followed by analysis of estradiol, progesterone and testosterone in follicular fluid. Protein expression of INSR- β, pIRS (ser 307), PI(3)K, PKC-ζ, pAkt, ERK1/2, pP38MAPK and gene expression of IGF showed differential expression in the two groups. Increased protein expression of PPAR-γ was accompanied by up regulation in SREBP1c, FAS, CPT-1 and ACC-1 genes in PCOS-IR group. Expression of StAR, CYP19A1, 17 β- HSD and 3 β- HSD demonstrated significant decrease along with increase in CYP11A1, FSH-R and LH-R in both the groups. Follicular fluid testosterone increased and progesterone decreased in PCOS-IR group. This study shows how candidate molecules that were differentially expressed, aid in designing targeted therapy against the two phenotypes of PCOS.
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Affiliation(s)
- Muskaan Belani
- Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, 390 002, Gujarat, India
| | - Abhilash Deo
- Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, 390 002, Gujarat, India
| | - Preeti Shah
- Nova IVI Fertility, Behind Xavier's Ladies Hostel, 108, Swastik Society Rd, Navrangpura, Ahmedabad, 390009, Gujarat, India
| | - Manish Banker
- Nova IVI Fertility, Behind Xavier's Ladies Hostel, 108, Swastik Society Rd, Navrangpura, Ahmedabad, 390009, Gujarat, India
| | - Pawan Singal
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Winnipeg MB, Canada
| | - Sarita Gupta
- Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, 390 002, Gujarat, India.
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Li F, Yang J, Villar VAM, Asico LD, Ma X, Armando I, Sanada H, Yoneda M, Felder RA, Jose PA, Wang X. Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice. Diabetologia 2018; 61:727-737. [PMID: 29080975 PMCID: PMC6342204 DOI: 10.1007/s00125-017-4482-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 10/02/2017] [Indexed: 01/16/2023]
Abstract
AIMS/HYPOTHESIS We hypothesised that renal sorting nexin 5 (SNX5) regulates the insulin-degrading enzyme (IDE) and, thus, circulating insulin levels. We therefore studied the dynamic interaction between SNX5 and IDE in human renal proximal tubule cells (hRPTCs), as well as in rat and mouse kidneys. METHODS The regulation of IDE by SNX5 expressed in the kidney was studied in vitro and in vivo. Snx5 or mock siRNA was added to immortalised hRPTCs (passage <20) in culture or selectively infused, via osmotic mini-pump, into the remnant kidney of uninephrectomised mice and rats. RESULTS SNX5 co-localised with IDE at the plasma membrane and perinuclear area of hRPTCs and in the brush border membrane of proximal tubules of human, rat, and mouse kidneys. Insulin increased the co-localisation and co-immunoprecipitation of SNX5 and IDE in hRPTCs. Silencing SNX5 in hRPTCs decreased IDE expression and activity. Renal-selective silencing of Snx5 (SNX5 protein: 100 ± 25 vs 29 ± 10, p < 0.05 [% of control]) in C57Bl/6J mice decreased IDE protein (100 ± 13 vs 57 ± 6, p < 0.05 [% of control]) and urinary insulin excretion, impaired the responses to insulin and glucose, and increased blood insulin and glucose levels. Spontaneously hypertensive rats (SHRs) had increased blood insulin and glucose levels and decreased renal SNX5 (100 ± 27 vs 29 ± 6, p < 0.05 [% of control]) and IDE (100 ± 5 vs 75 ± 4, p < 0.05 [% of control]) proteins, compared with normotensive Wistar-Kyoto (WKY) rats. Kidney Snx5-depleted WKY rats also had increased blood insulin and glucose levels. The expression of SNX5 and IDE was decreased in RPTCs from SHRs and hypertensive humans compared with cells from normotensive volunteers, indicating a common cause for hyperinsulinaemia and hypertension. CONCLUSIONS/INTERPRETATION Renal SNX5 positively regulates IDE expression and function. This study is the first to demonstrate the novel and crucial role of renal SNX5 in insulin and glucose metabolism.
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Affiliation(s)
- Fengmin Li
- Department of Physiology and Biophysics, Georgetown University Medical Center, Washington, DC, USA
| | - Jian Yang
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Nutrition, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China
| | - Van Anthony M Villar
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
- Division of Renal Diseases and Hypertension, Department of Medicine, The George Washington University, Walter G. Ross Hall, Suite 740-C, 2300 I Street, N.W., Washington, DC, 20037, USA
| | - Laureano D Asico
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
- Division of Renal Diseases and Hypertension, Department of Medicine, The George Washington University, Walter G. Ross Hall, Suite 740-C, 2300 I Street, N.W., Washington, DC, 20037, USA
| | - Xiaobo Ma
- Division of Renal Diseases and Hypertension, Department of Medicine, The George Washington University, Walter G. Ross Hall, Suite 740-C, 2300 I Street, N.W., Washington, DC, 20037, USA
| | - Ines Armando
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
- Division of Renal Diseases and Hypertension, Department of Medicine, The George Washington University, Walter G. Ross Hall, Suite 740-C, 2300 I Street, N.W., Washington, DC, 20037, USA
| | - Hironobu Sanada
- Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan
| | - Minoru Yoneda
- Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan
| | - Robin A Felder
- Department of Pathology, The University of Virginia, Charlottesville, VA, USA
| | - Pedro A Jose
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
- Division of Renal Diseases and Hypertension, Department of Medicine, The George Washington University, Walter G. Ross Hall, Suite 740-C, 2300 I Street, N.W., Washington, DC, 20037, USA
- Department of Pharmacology and Physiology, The George Washington University, Washington, DC, USA
| | - Xiaoyan Wang
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
- Division of Renal Diseases and Hypertension, Department of Medicine, The George Washington University, Walter G. Ross Hall, Suite 740-C, 2300 I Street, N.W., Washington, DC, 20037, USA.
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Li J, Xue YM, Zhu B, Pan YH, Zhang Y, Wang C, Li Y. Rosiglitazone Elicits an Adiponectin-Mediated Insulin-Sensitizing Action at the Adipose Tissue-Liver Axis in Otsuka Long-Evans Tokushima Fatty Rats. J Diabetes Res 2018; 2018:4627842. [PMID: 30225267 PMCID: PMC6129789 DOI: 10.1155/2018/4627842] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/15/2018] [Accepted: 06/25/2018] [Indexed: 01/07/2023] Open
Abstract
Rosiglitazone is an agonist of peroxisome proliferator-activated receptor- (PPAR-) γ that is principally associated with insulin action. The exact mechanisms underlying its insulin-sensitizing action are still not fully elucidated. It is well known that adiponectin mostly secreted in adipose tissue is an insulin sensitizer. Here, we found that treatment of Otsuka Long-Evans Tokushima Fatty (OLETF) rats with rosiglitazone (3 mg/kg, once daily, by oral gavage for 33 weeks) attenuated the increase in fasting plasma insulin concentrations and the index of the homeostasis model assessment of insulin resistance along with the age growth and glucose concentrations during an oral glucose tolerance test. In addition, the increase in plasma alanine aminotransferase activity, concentrations of fasting plasma nonesterified fatty acids and triglyceride, and hepatic triglyceride content was also suppressed. The hepatic protein expression profile revealed that rosiglitazone increased the downregulated total protein expression of insulin receptor substrate 1 (IRS-1) and IRS-2. Furthermore, the treatment suppressed the upregulated phosphorylation of IRS-1 at Ser307 and IRS-2 at Ser731. The results indicate that rosiglitazone ameliorates hepatic and systemic insulin resistance, hepatic inflammation, and fatty liver. Mechanistically, rosiglitazone suppressed hepatic protein overexpression of both phosphorylated nuclear factor- (NF-) κBp65 and inhibitory-κB kinase-α/β, a transcription factor that primarily regulates chronic inflammatory responses and the upstream NF-κB signal transduction cascades which are necessary for activating NF-κB, respectively. More importantly, rosiglitazone attenuated the decreases in adipose adiponectin mRNA level, plasma adiponectin concentrations, and hepatic protein expression of adiponectin receptor-1 and receptor-2. Thus, we can draw the conclusion that rosiglitazone elicits an adiponectin-mediated insulin-sensitizing action at the adipose tissue-liver axis in obese rats. Our findings may provide new insights into the mechanisms of action of rosiglitazone.
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Affiliation(s)
- Jia Li
- Department of Endocrinology, General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010, China
| | - Yao-Ming Xue
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bo Zhu
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yong-Hua Pan
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yan Zhang
- Department of Endocrinology & Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chunxia Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yuhao Li
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, NSW 2000, Australia
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Guina J, Roy S, Gupta A, Langleben DD, Elman I. Oral glucose tolerance test performance in olanzapine-treated schizophrenia-spectrum patients is predicted by BMI and triglycerides but not olanzapine dose or duration. Hum Psychopharmacol 2017; 32. [PMID: 28573760 DOI: 10.1002/hup.2604] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 02/03/2017] [Accepted: 04/22/2017] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Olanzapine, an atypical antipsychotic, is associated with glucoregulatory abnormalities, but the nature of this link is not fully elucidated. This is the first olanzapine oral glucose tolerance test (oGTT) study to consider treatment dose and duration, and to compare complementary indices respectively assessing insulin sensitivity (Matsuda index) and resistance (homeostasis model assessment). METHODS Body mass index (BMI), body composition, plasma lipids, and oGTT were measured in olanzapine-treated nondiabetic patients with DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder (n = 35). RESULTS While only one previously undiagnosed participant met diabetes criteria based on fasting plasma glucose alone (≥126 mg/dL), seven were diagnosed with oGTT (2-hr plasma glucose ≥200 mg/dL). Multiple regression analyses revealed that the Matsuda index correlated with BMI (p < 0.0001) and plasma triglycerides (p = 0.01), but not with age, olanzapine dose, olanzapine treatment duration, or plasma cholesterol. Homeostasis model assessment and fasting plasma glucose correlated with triglycerides only (p < 0.0001 for both). CONCLUSIONS Our data suggest that BMI and triglycerides may be implicated in olanzapine-related glucoregulatory abnormalities. The lack of correlation between glucoregulatory abnormalities and olanzapine dose or treatment duration suggests preexisting metabolic disturbances and/or disturbances arising early in the course of treatment. Clinicians prescribing antipsychotics should consider oGTT, especially in patients with obesity and/or hypertriglyceridemia.
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Affiliation(s)
- Jeffrey Guina
- Department of Psychiatry, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA.,Wright-Patterson Medical Center, Wright-Patterson Air Force Base, Dayton, Ohio, USA
| | - Sayon Roy
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Ankur Gupta
- Department of Medicine, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.,VA Medical Center, Dayton, Ohio, USA
| | - Daniel D Langleben
- Department of Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Igor Elman
- Department of Psychiatry, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA.,VA Medical Center, Dayton, Ohio, USA
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Kuczkowski A, Brinkkoetter PT. Metabolism and homeostasis in the kidney: metabolic regulation through insulin signaling in the kidney. Cell Tissue Res 2017; 369:199-210. [DOI: 10.1007/s00441-017-2619-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/22/2017] [Indexed: 02/07/2023]
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Affiliation(s)
- Jian Yang
- Department of Nutrition, Daping Hospital, The Third Military Medical University, Chongqing, China.,Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
| | - Pedro A Jose
- Division of Renal Disease & Hypertension, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, China
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Belani M, Shah P, Banker M, Gupta S. Dual effect of insulin resistance and cadmium on human granulosa cells - In vitro study. Toxicol Appl Pharmacol 2016; 313:119-130. [DOI: 10.1016/j.taap.2016.10.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 10/10/2016] [Accepted: 10/24/2016] [Indexed: 12/29/2022]
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Singh RS, Chaudhary DK, Mohan A, Kumar P, Chaturvedi CP, Ecelbarger CM, Godbole MM, Tiwari S. Greater efficacy of atorvastatin versus a non-statin lipid-lowering agent against renal injury: potential role as a histone deacetylase inhibitor. Sci Rep 2016; 6:38034. [PMID: 27901066 PMCID: PMC5128790 DOI: 10.1038/srep38034] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 11/01/2016] [Indexed: 12/21/2022] Open
Abstract
Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors have been shown to improve diabetic nephropathy. However, whether they provide protection via Histone deacetylases (HDAC) inhibition is not clear. We conducted a comparative evaluation of Atorvastatin (AT) versus the non-statin cholesterol-lowering drug, Ezetimibe (EZT) on severity of diabetic nephropathy. Streptozotocin-treated male Wistar rats were fed a cholesterol-supplemented diet and gavaged daily with vehicle, AT or EZT. Control rats received normal diet and gavaged vehicle (n = 8-9/group). Diabetes increased blood glucose, urine albumin-to-creatinine ratio (ACR), kidney pathology and HDAC activity, and reduced renal E-cadherin levels. Both AT and EZT reduced circulating cholesterol, attenuated renal pathology, and did not lower blood glucose. However, AT was significantly more effective than EZT at reducing kidney pathology and HDAC activity. Chromatin immunoprecipitation revealed a significantly higher association of acetylated H3 and H4 with the E-cadherin promoter in kidneys from AT-, relative to EZT- or vehicle-treated rats. Moreover, we demonstrated a direct effect of AT, but not EZT, on HDAC-inhibition and, H3 and H4- acetylation in primary glomerular mesangial cells. Overall, both AT and EZT attenuated diabetic nephropathy; however, AT exhibited greater efficacy despite a similar reduction in circulating cholesterol. HDAC-inhibition may underlie greater efficacy of statins in attenuating kidney injury.
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Affiliation(s)
- Ravi Shankar Singh
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Dharmendra Kumar Chaudhary
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Aradhana Mohan
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Praveen Kumar
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | | | | | - Madan M. Godbole
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Katsoulieris EN, Drossopoulou GI, Kotsopoulou ES, Vlahakos DV, Lianos EA, Tsilibary EC. High Glucose Impairs Insulin Signaling in the Glomerulus: An In Vitro and Ex Vivo Approach. PLoS One 2016; 11:e0158873. [PMID: 27434075 PMCID: PMC4951020 DOI: 10.1371/journal.pone.0158873] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 06/23/2016] [Indexed: 01/14/2023] Open
Abstract
Objective Chronic hyperglycaemia, as seen in type II diabetes, results in both morphological and functional impairments of podocytes in the kidney. We investigated the effects of high glucose (HG) on the insulin signaling pathway, focusing on cell survival and apoptotic markers, in immortalized human glomerular cells (HGEC; podocytes) and isolated glomeruli from healthy rats. Methods and Findings HGEC and isolated glomeruli were cultured for various time intervals under HG concentrations in the presence or absence of insulin. Our findings indicated that exposure of HGEC to HG led to downregulation of all insulin signaling markers tested (IR, p-IR, IRS-1, p-Akt, p-Fox01,03), as well as to increased sensitivity to apoptosis (as seen by increased PARP cleavage, Casp3 activation and DNA fragmentation). Short insulin pulse caused upregulation of insulin signaling markers (IR, p-IR, p-Akt, p-Fox01,03) in a greater extent in normoglycaemic cells compared to hyperglycaemic cells and for the case of p-Akt, in a PI3K-dependent manner. IRS-1 phosphorylation of HG-treated podocytes was negatively regulated, favoring serine versus tyrosine residues. Prolonged insulin treatment caused a significant decrease of IR levels, while alterations in glucose concentrations for various time intervals demonstrated changes of IR, p-IR and p-Akt levels, suggesting that the IR signaling pathway is regulated by glucose levels. Finally, HG exerted similar effects in isolated glomeruli. Conclusions These results suggest that HG compromises the insulin signaling pathway in the glomerulus, promoting a proapoptotic environment, with a possible critical step for this malfunction lying at the level of IRS-1 phosphorylation; thus we herein demonstrate glomerular insulin signaling as another target for investigation for the prevention and/ or treatment of diabetic nephropathy.
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Affiliation(s)
- Elias N. Katsoulieris
- Institute of Biosciences and Applications, National Center for Scientific Research ‘Demokritos’, Athens, Greece
| | - Garyfalia I. Drossopoulou
- Institute of Biosciences and Applications, National Center for Scientific Research ‘Demokritos’, Athens, Greece
- * E-mail: (GID); (ECT)
| | - Eleni S. Kotsopoulou
- Institute of Biosciences and Applications, National Center for Scientific Research ‘Demokritos’, Athens, Greece
| | - Dimitrios V. Vlahakos
- 2nd Department of Propaedeutic Medicine, Attikon University Hospital, Athens, Greece
| | - Elias A. Lianos
- Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Effie C. Tsilibary
- Institute of Biosciences and Applications, National Center for Scientific Research ‘Demokritos’, Athens, Greece
- * E-mail: (GID); (ECT)
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Pandey G, Shankar K, Makhija E, Gaikwad A, Ecelbarger C, Mandhani A, Srivastava A, Tiwari S. Reduced Insulin Receptor Expression Enhances Proximal Tubule Gluconeogenesis. J Cell Biochem 2016; 118:276-285. [PMID: 27322100 DOI: 10.1002/jcb.25632] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 06/16/2016] [Indexed: 12/18/2022]
Abstract
Reduced insulin receptor protein levels have been reported in the kidney cortex from diabetic humans and animals. We recently reported that, targeted deletion of insulin receptor (IR) from proximal tubules (PT) resulted in hyperglycemia in non-obese mice. To elucidate the mechanism, we examined human proximal tubule cells (hPTC) and C57BL/6 mice fed with high-fat diet (HFD, 60% fat for 20 weeks). Immunoblotting revealed a significantly lower protein level of IR in HFD compare to normal chow diet (NCD). Furthermore, a blunted rise in p-AKT308 levels in the kidney cortex of HFD mice was observed in response to acute insulin (0.75 IU/kg body weight, i.p) relative to NCD n = 8/group, P < 0.05). Moreover, we found significantly higher transcript levels of phosphoenolpyruvate carboxykinase (PEPCK, a key gluconeogenic enzyme) in the kidney cortex from HFD, relative to mice on NCD. The higher level of PEPCK in HFD was confirmed by immunoblotting. However, no significant differences were observed in cortical glucose-6-phosphatase (G6Pase) or fructose-1,6, bisphosphosphatase (FBPase) enzyme transcript levels. Furthermore, we demonstrated insulin inhibited glucose production in hPTC treated with cyclic AMP and dexamethasone (cAMP/DEXA) to stimulate gluconeogenesis. Transcript levels of the gluconeogenic enzyme PEPCK were significantly increased in cAMP/DEXA-stimulated hPTC cells (n = 3, P < 0.05), and insulin attenuated this upregulation Furthermore, the effect of insulin on cAMP/DEXA-induced gluconeogenesis and PEPCK induction was significantly attenuated in IR (siRNA) silenced hPTC (n = 3, P < 0.05). Overall the above data indicate a direct role for IR expression as a determinant of PT-gluconeogenesis. Thus reduced insulin signaling of the proximal tubule may contribute to hyperglycemia in the metabolic syndrome via elevated gluconeogenesis. J. Cell. Biochem. 118: 276-285, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Gaurav Pandey
- Department of Molecular Medicine and Biotechnology, SGPGIMS, Lucknow, 226014, India
| | | | - Ekta Makhija
- Department of Molecular Medicine and Biotechnology, SGPGIMS, Lucknow, 226014, India
| | | | - Carolyn Ecelbarger
- Department of Medicine, Georgetown University, Washington, District of Columbia
| | | | | | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, SGPGIMS, Lucknow, 226014, India.,Department of Medicine, Georgetown University, Washington, District of Columbia
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The Wnt11 Signaling Pathway in Potential Cellular EMT and Osteochondral Differentiation Progression in Nephrolithiasis Formation. Int J Mol Sci 2015; 16:16313-29. [PMID: 26193266 PMCID: PMC4519952 DOI: 10.3390/ijms160716313] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 06/22/2015] [Accepted: 07/07/2015] [Indexed: 11/17/2022] Open
Abstract
The molecular events leading to nephrolithiasis are extremely complex. Previous studies demonstrated that calcium and transforming growth factor-β1 (TGF-β1) may participate in the pathogenesis of stone formation, but the explicit mechanism has not been defined. Using a self-created genetic hypercalciuric stone-forming (GHS) rat model, we observed that the increased level of serous/uric TGF-β1 and elevated intracellular calcium in primary renal tubular epithelial cells (PRECs) was associated with nephrolithiasis progression in vivo. In the setting of high calcium plus high TGF-β1 in vitro, PRECs showed great potential epithelial to mesenchymal transition (EMT) progression and osteochondral differentiation properties, representing the multifarious increased mesenchymal and osteochondral phenotypes (Zeb1, Snail1, Col2A1, OPN, Sox9, Runx2) and decreased epithelial phenotypes (E-cadherin, CK19) bythe detection of mRNAs and corresponding proteins. Moreover, TGF-β-dependent Wnt11 knockdown and L-type Ca2+ channel blocker could greatly reverse EMT progression and osteochondral differentiation in PRECs. TGF-β1 alone could effectively promote EMT, but it had no effect on osteochondral differentiation in NRK cells (Rat kidney epithelial cell line). Stimulation with Ca2+ alone did not accelerate differentiation of NRK. Co-incubation of extracellular Ca2+ and TGF-β1 synergistically promotes EMT and osteochondral differentiation in NRK control cells. Our data supplied a novel view that the pathogenesis of calcium stone development may be associated with synergic effects of TGF-β1 and Ca2+, which promote EMT and osteochondral differentiation via Wnt11 and the L-type calcium channel.
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Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and β-Cell Dysfunction. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:181643. [PMID: 26257839 PMCID: PMC4516838 DOI: 10.1155/2015/181643] [Citation(s) in RCA: 247] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 06/10/2015] [Indexed: 02/06/2023]
Abstract
The prevalence of diabetes mellitus (DM) is increasing worldwide, a consequence of the alarming rise in obesity and metabolic syndrome (MetS). Oxidative stress and inflammation are key physiological and pathological events linking obesity, insulin resistance, and the progression of type 2 DM (T2DM). Unresolved inflammation alongside a “glucolipotoxic” environment of the pancreatic islets, in insulin resistant pathologies, enhances the infiltration of immune cells which through secretory activity cause dysfunction of insulin-secreting β-cells and ultimately cell death. Recent molecular investigations have revealed that mechanisms responsible for insulin resistance associated with T2DM are detected in conditions such as obesity and MetS, including impaired insulin receptor (IR) signalling in insulin responsive tissues, oxidative stress, and endoplasmic reticulum (ER) stress. The aim of the present review is to describe the evidence linking oxidative stress and inflammation with impairment of insulin secretion and action, which result in the progression of T2DM and other conditions associated with metabolic dysregulation.
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