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Li YQ, Zhang LY, Zhao YC, Xu F, Hu ZY, Wu QH, Li WH, Li YN. Vascular endothelial growth factor B improves impaired glucose tolerance through insulin-mediated inhibition of glucagon secretion. World J Diabetes 2023; 14:1643-1658. [DOI: 10.4239/wjd.v14.i11.1643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/11/2023] [Accepted: 09/06/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND Impaired glucose tolerance (IGT) is a homeostatic state between euglycemia and hyperglycemia and is considered an early high-risk state of diabetes. When IGT occurs, insulin sensitivity decreases, causing a reduction in insulin secretion and an increase in glucagon secretion. Recently, vascular endothelial growth factor B (VEGFB) has been demonstrated to play a positive role in improving glucose metabolism and insulin sensitivity. Therefore, we constructed a mouse model of IGT through high-fat diet feeding and speculated that VEGFB can regulate hyperglycemia in IGT by influencing insulin-mediated glucagon secretion, thus contributing to the prevention and cure of prediabetes.
AIM To explore the potential molecular mechanism and regulatory effects of VEGFB on insulin-mediated glucagon in mice with IGT.
METHODS We conducted in vivo experiments through systematic VEGFB knockout and pancreatic-specific VEGFB overexpression. Insulin and glucagon secretions were detected via enzyme-linked immunosorbent assay, and the protein expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) was determined using western blot. Further, mRNA expression of forkhead box protein O1, phosphoenolpyruvate carboxykinase, and glucose-6 phosphatase was detected via quantitative polymerase chain reaction, and the correlation between the expression of proteins was analyzed via bioinformatics.
RESULTS In mice with IGT and VEGFB knockout, glucagon secretion increased, and the protein expression of PI3K/AKT decreased dramatically. Further, in mice with VEGFB overexpression, glucagon levels declined, with the activation of the PI3K/AKT signaling pathway.
CONCLUSION VEGFB/vascular endothelial growth factor receptor 1 can promote insulin-mediated glucagon secretion by activating the PI3K/AKT signaling pathway to regulate glucose metabolism disorders in mice with IGT.
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Affiliation(s)
- Yu-Qi Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Lu-Yang Zhang
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Yu-Chi Zhao
- Department of Surgery, Yantaishan Hospital, Yantai 264000, Shandong Province, China
| | - Fang Xu
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Zhi-Yong Hu
- School of Public Health and Management, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Qi-Hao Wu
- The First School of Clinical Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Wen-Hao Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
| | - Ya-Nuo Li
- Department of Pathophysiology, School of Basic Medicine, Binzhou Medical University, Yantai 264000, Shandong Province, China
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Boyer CK, Bauchle CJ, Zhang J, Wang Y, Stephens SB. Synchronized proinsulin trafficking reveals delayed Golgi export accompanies β-cell secretory dysfunction in rodent models of hyperglycemia. Sci Rep 2023; 13:5218. [PMID: 36997560 PMCID: PMC10063606 DOI: 10.1038/s41598-023-32322-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/25/2023] [Indexed: 04/03/2023] Open
Abstract
The pancreatic islet β-cell's preference for release of newly synthesized insulin requires careful coordination of insulin exocytosis with sufficient insulin granule production to ensure that insulin stores exceed peripheral demands for glucose homeostasis. Thus, the cellular mechanisms regulating insulin granule production are critical to maintaining β-cell function. In this report, we utilized the synchronous protein trafficking system, RUSH, in primary β-cells to evaluate proinsulin transit through the secretory pathway leading to insulin granule formation. We demonstrate that the trafficking, processing, and secretion of the proinsulin RUSH reporter, proCpepRUSH, are consistent with current models of insulin maturation and release. Using both a rodent dietary and genetic model of hyperglycemia and β-cell dysfunction, we show that proinsulin trafficking is impeded at the Golgi and coincides with the decreased appearance of nascent insulin granules at the plasma membrane. Ultrastructural analysis of β-cells from diabetic leptin receptor deficient mice revealed gross morphological changes in Golgi structure, including shortened and swollen cisternae, and partial Golgi vesiculation, which are consistent with defects in secretory protein export. Collectively, this work highlights the utility of the proCpepRUSH reporter in studying proinsulin trafficking dynamics and suggests that altered Golgi export function contributes to β-cell secretory defects in the pathogenesis of Type 2 diabetes.
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Affiliation(s)
- Cierra K Boyer
- Department of Neuroscience and Pharmacology, University of Iowa, Iowa City, IA, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52246, USA
| | - Casey J Bauchle
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52246, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, USA
| | - Jianchao Zhang
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Yanzhuang Wang
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
- Department of Neurology, School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Samuel B Stephens
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA, 52246, USA.
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, USA.
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Nakamura Y, Haraguchi A, Horie I, Kawakami A, Abiru N. Pilot Trial on the Effect of 5-Aminolevulinic Acid on Glucose Tolerance in Patients with Maternally Inherited Diabetes and Deafness. Diabetes Ther 2023; 14:447-459. [PMID: 36418716 PMCID: PMC9943925 DOI: 10.1007/s13300-022-01335-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 10/31/2022] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION The amino acid 5-aminolevulinic acid (5-ALA) is the first heme biosynthetic precursor. The combination of 5-ALA with sodium ferrous citrate (SFC) enhances heme production, leading to increased adenosine triphosphate (ATP) production in mitochondria. We investigated whether administering 5-ALA/SFC improves glucose tolerance with an increase in insulin secretion in patients with maternally inherited diabetes and deafness (MIDD), which is characterized by an insulin secretory disorder due to impaired mitochondrial ATP production. METHODS This was a single-arm, open-label, interventional study. We prospectively administered the oral glucose tolerance test (OGTT) twice in five patients with MIDD who had received intensive insulin therapy: before and 24 weeks after an administration of 5-ALA/SFC (200/232 mg per day). We measured the concentrations of glucose, insulin, C-peptide, and proinsulin at fasting, and 30, 60, and 120 min after glucose load in each OGTT. The primary endpoint was the changes in the area under the curve (AUC) of serum insulin from 0 to 120 min during OGTT from baseline to 24 weeks. RESULTS The serum insulin AUC (µU/mL) during the 120-min OGTT tended to increase from baseline to 24 weeks but not significantly (17.1 ± 13.7 versus 22.3 ± 13.4, p = 0.077). The plasma glucose AUC (mg/dL) during the 120-min OGTT at 24 weeks was not significantly decreased; the late phase of glucose excursion from 60 to 120 min was significantly decreased compared with baseline (357 ± 42 versus 391 ± 50, p = 0.041). The mean level of glycated hemoglobin (HbA1c) decreased from 8.3 ± 1.2% at baseline to 7.9 ± 0.3% at 24 weeks (p = 0.36) without increasing the daily dose of insulin injections. CONCLUSION The 24-week administration of 5-ALA/SFC did not demonstrate a significant improvement in insulin secretion in patients with MIDD. Further investigations with a larger number of patients and a placebo control group are required to clarify the potential efficacy of 5-ALA/SFC for ameliorating mitochondrial dysfunctions in MIDD. TRIAL REGISTRATION UMIN-CTR000040581 and jRCT071200025.
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Affiliation(s)
- Yuta Nakamura
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Ai Haraguchi
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Ichiro Horie
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
| | - Atsushi Kawakami
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Norio Abiru
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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4
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Chen Z, Wen J. Elevated triglyceride-glucose (TyG) index predicts impaired islet β-cell function: A hospital-based cross-sectional study. Front Endocrinol (Lausanne) 2022; 13:973655. [PMID: 36246870 PMCID: PMC9563389 DOI: 10.3389/fendo.2022.973655] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE To explore the relationship between the TyG index and the insulin secretion function of pancreatic β-cells, and to determine the possibility of the TyG index in predicting β-cell dysfunction and the development of diabetes. METHODS A cross-sectional study was performed among 914 participants who took their annual health checkups at the Third Xiangya Hospital. The early- and late-phase pancreatic β-cell secretion was assessed based on the results of the oral glucose tolerance test (OGTT). In addition to anthropometric parameters and laboratory parameters, information about health-related habits and disease histories was obtained from the National Physical Examination Questionnaire. Partial correlation analysis was used to study the relationship between the TyG index and pancreatic β-cell function. The receiver operating characteristic (ROC) curve was used to calculate the cut-off points of the TyG index in predicting β-cell dysfunction. According to the OGTT results and medical history, the participants were categorized into three groups: the normal glucose tolerance group (NGT, n=276), the impaired glucose regulation group (IGT, n=323), and the diabetes group (DM, n=315). The correlation between the TyG index and β-cell function among the three groups and the association between the TyG index and glucose metabolic conditions were further explored. RESULTS The TyG index was negatively correlated with the indexes that reflect the early and late secretory function of β-cells, not only in the NGT group but also in the IGT and DM group. The minimum cut-off values for the TyG index to identify the risk of early- and late-phase β-cell dysfunction are 9.08 and 9.2 respectively. The TyG indexes of the IGT and DM group were higher than that of the NGT group, and with the growth of the TyG index, the risk of prediabetes and diabetes increased significantly. CONCLUSION Increased TyG index is associated with impaired β-cell function regardless of the glucose metabolic conditions. The TyG index is an alternative indicator for predicting β-cell dysfunction.
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Affiliation(s)
- Zi Chen
- Department of Health Management, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jie Wen
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Jie Wen,
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5
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Bril F, McPhaul MJ, Kalavalapalli S, Lomonaco R, Barb D, Gray ME, Shiffman D, Rowland CM, Cusi K. Intact Fasting Insulin Identifies Nonalcoholic Fatty Liver Disease in Patients Without Diabetes. J Clin Endocrinol Metab 2021; 106:e4360-e4371. [PMID: 34190318 DOI: 10.1210/clinem/dgab417] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Indexed: 01/08/2023]
Abstract
CONTEXT Patients with nonalcoholic fatty liver disease (NAFLD) are characterized by insulin resistance and hyperinsulinism. However, insulin resistance measurements have not been shown to be good diagnostic tools to predict NAFLD in prior studies. OBJECTIVE We aimed to assess a newly validated method to measure intact molecules of insulin by mass spectrometry to predict NAFLD. METHODS Patients underwent a 2-hour oral glucose tolerance test (OGTT), a liver magnetic resonance spectroscopy (1H-MRS), and a percutaneous liver biopsy if they had a diagnosis of NAFLD. Mass spectrometry was used to measure intact molecules of insulin and C-peptide. RESULTS A total of 180 patients were recruited (67% male; 52 ± 11 years of age; body mass index [BMI] 33.2 ± 5.7 kg/m2; 46% with diabetes and 65% with NAFLD). Intact fasting insulin was higher in patients with NAFLD, irrespective of diabetes status. Patients with NAFLD without diabetes showed ~4-fold increase in insulin secretion during the OGTT compared with all other subgroups (P = 0.008). Fasting intact insulin measurements predicted NAFLD in patients without diabetes (area under the receiver operating characteristic curve [AUC] of 0.90 [0.84-0.96]). This was significantly better than measuring insulin by radioimmunoassay (AUC 0.80 [0.71-0.89]; P = 0.007). Intact fasting insulin was better than other clinical variables (eg, aspartate transaminase, triglycerides, high-density lipoprotein, glucose, HbA1c, and BMI) to predict NAFLD. When combined with alanine transaminase (ALT) (intact insulin × ALT), it detected NAFLD with AUC 0.94 (0.89-0.99) and positive and negative predictive values of 93% and 88%, respectively. This newly described approach was significantly better than previously validated noninvasive scores such as NAFLD-LFS (P = 0.009), HSI (P < 0.001), and TyG index (P = 0.039). CONCLUSION In patients without diabetes, accurate measurement of fasting intact insulin levels by mass spectrometry constitutes an easy and noninvasive strategy to predict presence of NAFLD.
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Affiliation(s)
- Fernando Bril
- Internal Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL 32610, USA
| | - Michael J McPhaul
- Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675, USA
| | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL 32610, USA
| | - Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL 32610, USA
| | - Diana Barb
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL 32610, USA
| | - Meagan E Gray
- Division of Gastroenterology, Hepatology and Nutrition, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Dov Shiffman
- Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675, USA
| | - Charles M Rowland
- Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92675, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL 32610, USA
- Division of Endocrinology, Diabetes and Metabolism, Malcom Randall, VAMC, Gainesville, FL 32611, USA
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Shigeno R, Horie I, Miwa M, Ito A, Haraguchi A, Natsuda S, Akazawa S, Nagata A, Hasegawa Y, Miura S, Miura K, Kawakami A, Abiru N. Bihormonal dysregulation of insulin and glucagon contributes to glucose intolerance development at one year post-delivery in women with gestational diabetes: a prospective cohort study using an early postpartum 75-g glucose tolerance test. Endocr J 2021; 68:919-931. [PMID: 33827994 DOI: 10.1507/endocrj.ej20-0795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is known to be a significant risk factor for the future development of type 2 diabetes. Here, we investigated whether a precise evaluation of β- and α-cell functions helps to identify women at high risk of developing glucose intolerance after GDM. Fifty-six women with GDM underwent a 75-g oral glucose tolerance test (OGTT) at early (6-12 weeks) postpartum. We measured their concentrations of glucose, insulin, proinsulin and glucagon at fasting and 30, 60 and 120 min. At 1-year post-delivery, we classified the women into a normal glucose tolerance (NGT) group or an impaired glucose tolerance (IGT)/diabetes mellitus (DM) group. Forty-three of the 56 women completed the study. At 1-year post-delivery, 17 women had developed IGT/DM and 26 women showed NGT. In the early-postpartum OGTTs, the IGT/DM group showed a lower insulinogenic index, a less glucagon suppression evaluated by the change from fasting to 30 min (ΔGlucagon 30 min), and a higher glucagon-to-insulin ratio at 30 min compared to the NGT group. There were no significant between-group differences in proinsulin levels or proinsulin-to-insulin ratios. Insulinogenic index <0.6 and ΔGlucagon 30 min >0 pg/mL were identified as predictors for the development of IGT/DM after GDM, independent of age, body mass index, and lactation intensity. These results suggest that the bihormonal disorder of insulin and glucagon causes the postpartum development of glucose intolerance. The measurement of plasma insulin and glucagon during the initial OGTT at early postpartum period can help to make optimal decisions regarding the postpartum management of women with GDM.
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Affiliation(s)
- Riyoko Shigeno
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Ichiro Horie
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Masaki Miwa
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Ayako Ito
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Ai Haraguchi
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Shoko Natsuda
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Satoru Akazawa
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Ai Nagata
- Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki 852-8501, Japan
| | - Yuri Hasegawa
- Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki 852-8501, Japan
| | - Shoko Miura
- Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki 852-8501, Japan
| | - Kiyonori Miura
- Department of Obstetrics and Gynecology, Nagasaki University Hospital, Nagasaki 852-8501, Japan
| | - Atsushi Kawakami
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Norio Abiru
- Department of Endocrinology and Metabolism, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
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Germanos M, Gao A, Taper M, Yau B, Kebede MA. Inside the Insulin Secretory Granule. Metabolites 2021; 11:metabo11080515. [PMID: 34436456 PMCID: PMC8401130 DOI: 10.3390/metabo11080515] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/03/2021] [Accepted: 08/03/2021] [Indexed: 12/19/2022] Open
Abstract
The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.
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Ma C, Liu Y, He S, Zeng J, Li P, Ma C, Ping F, Zhang H, Xu L, Li W, Li Y. Association between glucose fluctuation during 2-hour oral glucose tolerance test, inflammation and oxidative stress markers, and β-cell function in a Chinese population with normal glucose tolerance. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:327. [PMID: 33708954 PMCID: PMC7944279 DOI: 10.21037/atm-20-6119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Backgrounds Glucose fluctuation (GF) may have detrimental effects in individuals with diabetes; however, clinical data on the association between short-term GF, inflammation/oxidative stress markers, and islet β-cell function based on a population with normal glucose tolerance (NGT) are insufficient. Therefore, we aimed to explore these associations in a Chinese population of 209 individuals with NGT in a cross-sectional analysis. Methods Individuals were categorized based on GF tertiles, calculated as the maximum-minimum glucose levels among four time points (0, 30, 60, 120 min) during 2-hour oral glucose tolerance test (OGTT). Plasma inflammation markers tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and oxidative stress markers superoxide dismutase (SOD), and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were measured. Islet β-cell function was estimated according to the disposition index (DI) at the early (30 min) and total (120 min) phase of the OGTT, adjusted for insulin sensitivity. Results Individuals in the middle and highest tertile of GF had reduced β-cell function, and increased plasma SOD and TNF-α levels compared with those in the lowest tertile of GF (P<0.05). Multiple linear regression analysis indicated that GF was positively associated with TNF-α, 8-oxo-dG and SOD levels, but negatively associated with β-cell function, whereas IL-6, TNF-α, 8-oxo-dG and SOD levels were negatively associated with β-cell function (P<0.05). Conclusions GF may increase inflammation and oxidative stress markers in individuals with NGT, which could contribute to reduced β-cell function. Thus, maintaining glucose stability after a meal may have beneficial effects on delaying β-cell dysfunction, suggesting that diet and exercise strategies to decrease diet related GF are warranted.
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Affiliation(s)
- Chifa Ma
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yiwen Liu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuli He
- Department of Nutrition, Peking Union Medical College Hospital, Beijing, China
| | - Jingbo Zeng
- Department of Endocrinology, Fuxing Hospital, the Eighth Clinical Medical College, Capital Medical University, Beijing, China
| | - Pingping Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
| | - Chunxiao Ma
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Murai N, Saito N, Kodama E, Iida T, Mikura K, Imai H, Kaji M, Hashizume M, Kigawa Y, Koizumi G, Tadokoro R, Sugisawa C, Endo K, Iizaka T, Saiki R, Otsuka F, Ishibashi S, Nagasaka S. Insulin and Proinsulin Dynamics Progressively Deteriorate From Within the Normal Range Toward Impaired Glucose Tolerance. J Endocr Soc 2020; 4:bvaa066. [PMID: 32617449 PMCID: PMC7316365 DOI: 10.1210/jendso/bvaa066] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 05/29/2020] [Indexed: 12/14/2022] Open
Abstract
Context Slight elevations in plasma glucose (PG) manifest in advance of diabetes onset, but abnormalities in immunoreactive insulin (IRI), proinsulin (Pro), and adiponectin dynamics during this stage remain poorly understood. Objective The objective of this work is to investigate whether IRI and Pro dynamics become abnormal as glucose tolerance deteriorates from within the normal range toward impaired glucose tolerance (IGT), as well as the relationship between PG, and these dynamics and serum adiponectin levels. Design A cross-sectional study was designed. Setting This study took place at Jichi Medical University in Japan. Participants and Measurements PG, IRI, and Pro levels were determined in 1311 young Japanese individuals (age < 40 years) with normal or IGT before and at 30, 60, and 120 minutes during a 75-g oral glucose tolerance test. Participants were assigned to 4 groups according to glucose tolerance, and then background factors, adiponectin levels, insulin sensitivity (SI), and insulin secretion (β) indexes were determined. Results PG levels as well as IRI and Pro levels 60 and 120 minutes after glucose-loading increased incrementally with deteriorating glucose tolerance. All measures of β and the SI measure index of insulin sensitivity (ISI)-Matsuda decreased incrementally. Serum adiponectin levels were not significantly different among the glucose tolerance groups, but were independently and negatively correlated with fasting glucose. Conclusions Early β decreased and postloading Pro levels became excessive in a progressive manner as glucose tolerance deteriorated from within the normal range toward IGT.
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Affiliation(s)
- Norimitsu Murai
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Naoko Saito
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Eriko Kodama
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Tatsuya Iida
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Kentaro Mikura
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Hideyuki Imai
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Mariko Kaji
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Mai Hashizume
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Yasuyoshi Kigawa
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Go Koizumi
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Rie Tadokoro
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Chiho Sugisawa
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Kei Endo
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Toru Iizaka
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Ryo Saiki
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Fumiko Otsuka
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
| | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Shoichiro Nagasaka
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan.,Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi, Japan
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Tong Y, Yang L, Shao F, Yan X, Li X, Huang G, Xiao Y, Zhou Z. Distinct secretion pattern of serum proinsulin in different types of diabetes. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:452. [PMID: 32395496 PMCID: PMC7210169 DOI: 10.21037/atm.2020.03.189] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Background Latent autoimmune diabetes in adults (LADA) is characterized by autoimmunity, late-onset and intermediate beta-cell deprivation rate between type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM). Herein, we investigated proinsulin (PI) secretion patterns and the endoplasmic reticulum (ER) dysfunction biomarker, PI-to-C-peptide (PI:CP) ratio, to elucidate beta-cell intrinsic pathogenesis mechanisms in different types of diabetes. Methods Total serum fasting PI (FPI) were measured in adult-onset and newly-diagnosed diabetes patients, including 60 T1DM, 60 LADA and 60 T2DM. Thirty of each type underwent mixed meal tolerance tests (MMTTs), and hence 120 min postprandial PI (PPI) were detected. PI:CP ratio = PI (pmol/L) ÷ CP (pmol/L) × 100%. PI-related measurements among types of diabetes were compared. Correlation between PI-related measurements and beta-cell autoimmunity were analyzed. The possibility of discriminating LADA from T1DM and T2DM with PI-related measurements were tested. Results FPI and PPI were significantly higher in LADA than T1DM (P<0.001 for both comparisons), but lower than those in T2DM (P<0.001 and P=0.026, respectively). Fasting PI:CP ratio was significantly higher in T1DM than both LADA and T2DM (median 3.25% vs. 2.13% and 2.32%, P=0.011 and P=0.017, respectively). In LADA, positive autoantibody numbers increased by both fasting and postprandial PI:CP ratio (P=0.007 and P=0.034, respectively). Areas under receiver operation characteristic curves (AUCROC) of FPI and PPI for discriminating LADA from adult-onset T1DM were 0.751 (P<0.001) and 0.838 (P<0.001), respectively. Between LADA and T2DM, AUCROC of FPI and PPI were 0.685 (P<0.001) and 0.741 (P=0.001), respectively. Conclusions In the development of autoimmune diabetes, interplays between ER stress and beta-cell autoimmunity are potentially responsible for severer beta-cell destruction. PI-related measurements could help in differentiating LADA from adult-onset T1DM and T2DM.
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Affiliation(s)
- Yue Tong
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.,National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.,Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
| | - Lin Yang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.,National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.,Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
| | - Feng Shao
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.,National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.,Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
| | - Xiang Yan
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.,National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.,Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.,National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.,Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.,National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.,Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
| | - Yang Xiao
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.,National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.,Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.,National Clinical Research Center for Metabolic Diseases, Changsha 410011, China.,Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha 410011, China
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