scholarly journals Exendin-4 Improves β-Cell Function in Autophagy-Deficient β-Cells

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4512-4524 ◽  
Author(s):  
Hiroko Abe ◽  
Toyoyoshi Uchida ◽  
Akemi Hara ◽  
Hiroki Mizukami ◽  
Koji Komiya ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Death ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Apoptotic Cell ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus. Treatment with exendin-4, a glucagon like peptide-1 receptor agonist, improved glucose tolerance in db/db mice without significant changes in p62 expression in β-cells. Also in β-cell-specific Atg7-deficient mice, exendin-4 efficiently improved blood glucose level and glucose tolerance mainly by enhanced insulin secretion. In addition, we found that exendin-4 reduced apoptotic cell death and increased proliferating cells in the Atg7-deficient islets, and that exendin-4 counteracted thapsigargin-induced cell death of isolated islets augmented by autophagy deficiency. Our results suggest the potential involvement of reduced autophagy in β-cell dysfunction in type 2 diabetes. Without altering the autophagic state in β-cells, exendin-4 improves glucose tolerance associated with autophagy deficiency in β-cells. This is mainly achieved through augmentation of insulin secretion. In addition, exendin-4 prevents apoptosis and increases the proliferation of β-cells associated with autophagy deficiency, also without altering the autophagic machinery in β-cells.

Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass

2015 ◽  
Vol 308 (6) ◽  
pp. E535-E544 ◽  
Author(s):  
Christoffer Martinussen ◽  
Kirstine N. Bojsen-Møller ◽  
Carsten Dirksen ◽  
Siv H. Jacobsen ◽  
Nils B. Jørgensen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Β Cell ◽  
Glucose Effectiveness ◽  
Β Cell Function ◽  
First Phase Insulin Secretion

Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic β-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose effectiveness with Bergman's minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and β-cell function by HOMA-β. Moreover, mixed-meal tests and oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-β already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic β-cell function per se, reflected in enhanced first-phase insulin secretion to iv glucose and increased HOMA-β. A major role for improved glucose effectiveness after RYGB was not supported by this study.

scholarly journals Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

2020 ◽  
Author(s):  
Rong Huang ◽  
Songping Yin ◽  
Yongxin Ye ◽  
Nixuan Chen ◽  
Shiyun Luo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Retinol Binding Protein ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Β Cell Function ◽  
Oral Minimal Model

<p>OBJECTIVE: The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS: Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). CONCLUSION: Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.</p>

BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner

2009 ◽  
Vol 296 (2) ◽  
pp. C346-C354 ◽  
Author(s):  
Fan Zhang ◽  
Deben Dey ◽  
Robert Bränström ◽  
Lars Forsberg ◽  
Ming Lu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
High Glucose ◽  
Cell Function ◽  
Dependent Manner ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function ◽  
Amp Activated Protein Kinase

BLX-1002 is a novel small thiazolidinedione with no apparent affinity to peroxisome proliferator-activated receptors (PPAR) that has been shown to reduce glycemia in type 2 diabetes without adipogenic effects. Its precise mechanisms of action, however, remain elusive, and no studies have been done with respect to possible effects of BLX-1002 on pancreatic β-cells. We have investigated the influence of the drug on β-cell function in mouse islets in vitro. BLX-1002 enhanced insulin secretion stimulated by high, but not low or intermediate, glucose concentrations. BLX-1002 also augmented cytoplasmic free Ca2+ concentration ([Ca2+]i) at high glucose, an effect that was abolished by pretreatment with the Ca2+-ATPase inhibitor thapsigargin. In contrast, BLX-1002 did not interfere with voltage-gated Ca2+ channel or ATP-sensitive K+ channel activities. In addition, cellular NAD(P)H stimulated by glucose was not affected by the drug. The stimulatory effect of BLX-1002 on insulin secretion at high glucose was completely abolished by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY-294002. Stimulation of the β-cells with BLX-1002 also induced activation of AMP-activated protein kinase (AMPK) at high glucose. Our study suggests that BLX-1002 potentiates insulin secretion only at high glucose in β-cells in a PI3K-dependent manner. This effect of BLX-1002 is associated with an increased [Ca2+]i mediated through Ca2+ mobilization, and an enhanced activation of AMPK. The glucose-sensitive stimulatory impact of BLX-1002 on β-cell function may translate into substantial clinical benefits of the drug in the management of type 2 diabetes, by avoidance of hypoglycemia.

scholarly journals Circulating LncRNAs Analysis in Patients with Type 2 Diabetes Reveals Novel Genes Influencing Glucose Metabolism and Islet β-Cell Function

2018 ◽  
Vol 46 (1) ◽  
pp. 335-350 ◽  
Author(s):  
Yuting Ruan ◽  
Nie Lin ◽  
Qiang Ma ◽  
Rongping Chen ◽  
Zhen Zhang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Diabetic Patients ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Min6 Cells ◽  
Β Cell Function

Background/Aims: The islet is an important endocrine organ to secrete insulin to regulate the metabolism of glucose and maintain the stability of blood glucose. Long noncoding RNAs (lncRNAs) are involved in a variety of biological functions and play key roles in many diseases, including type 2 diabetes (T2D). The aim of this study was to determine whether lncRNA-p3134 is associated with glucose metabolism and insulin signaling in pancreatic β cells. Methods: LncRNA microarray technology was used to identify the differentially expressed circulating lncRNAs in T2D patients. RT-PCR analyses were performed to determine the expression of lncRNA-p3134 in 30 pairs of diabetic and non-diabetic patients. The correlation of lncRNA-p3134 to clinical data from T2D patients was analyzed. LncRNA-p3134 was overexpressed in Min6 cells and db/db mice by adenovirus-mediated technology. CCK-8, TUNEL, Western blot, glucose-stimulated insulin secretion (GSIS), ELISAs and immunochemistry were performed to determine the effect of lncRNA-p3134 on proliferation, apoptosis and insulin secretion both in vitro and vivo. Results: The circulating level of lncRNA-p3134 was higher in diabetic patients than in non-diabetic controls and was correlated with fasting blood glucose and HOMA-β levels. The lncRNA-p3134 had risen by 4 times in serum exosomes but nearly unchanged in exosome-free samples. The secretion of lncRNA-p3134 was dynamically modulated by glucose in both Min6 cells and isolated mouse islet cells. LncRNA-p3134 positively regulate GSIS through promoting of key regulators (Pdx-1, MafA, GLUT2 and Tcf7l2) in β cells. In addition, the overexpression of lncRNA-p3134 resulted in a decreased apoptosis ratio and partially reversed the glucotoxicity effects on GSIS function in Min6 cells. The restoration of insulin synthesis and secretion the increase of the insulin positive cells areas by upregulation of lncRNA-p3134 in db/db mice confirmed the compensatory role of lncRNA-p3134 to preserve β-cell function. Furthermore, a protective effect of lncRNA-p3134 on GSIS by positive modulation of PI3K/Akt/mTOR signaling was also confirmed. After blocking the PI3K/AKT signals with their specific inhibitor, the effect of overexpressed lncRNA-p3134 on insulin secretion was obviously attenuated. Conclusion: Taken together, the results of this study provide new insights into lncRNA-p3134 regulation in pancreatic β cells and provide a better understanding of novel mechanism of glucose homeostasis.

scholarly journals Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

2020 ◽  
Author(s):  
Rong Huang ◽  
Songping Yin ◽  
Yongxin Ye ◽  
Nixuan Chen ◽  
Shiyun Luo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Retinol Binding Protein ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Β Cell Function ◽  
Oral Minimal Model

<p>OBJECTIVE: The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. RESULTS: Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). CONCLUSION: Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.</p>

scholarly journals Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

2020 ◽  
Author(s):  
Rong Huang ◽  
Songping Yin ◽  
Yongxin Ye ◽  
Nixuan Chen ◽  
Shiyun Luo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Retinol Binding Protein ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Β Cell Function ◽  
Oral Minimal Model

<p><b>OBJECTIVE:</b> The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. </p><p><b>RESEARCH DESIGN AND METHODS:</b> A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. </p><p><b>RESULTS:</b> Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). </p><p><b>CONCLUSION:</b> Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.</p>

scholarly journals Circulating Retinol Binding Protein 4 is Inversely Associated with Pancreatic β Cell Function across the Spectrum of Glycemia

2020 ◽  
Author(s):  
Rong Huang ◽  
Songping Yin ◽  
Yongxin Ye ◽  
Nixuan Chen ◽  
Shiyun Luo ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Retinol Binding Protein ◽  
Β Cell ◽  
Retinol Binding Protein 4 ◽  
Β Cell Function ◽  
Oral Minimal Model

<p><b>OBJECTIVE:</b> The aim of this study was to examine the association of circulating retinol binding protein 4 (RBP4) levels with β cell function across the spectrum of glucose tolerance from normal to overt type 2 diabetes. </p><p><b>RESEARCH DESIGN AND METHODS:</b> A total of 291 subjects aged 35-60 with normal glucose tolerance (NGT), newly diagnosed impaired fasting glucose or glucose tolerance (IFG/IGT) and type 2 diabetes were screened by standard 2-h oral glucose tolerance test (2-h OGTT) with the use of traditional measures to evaluate β cell function. 74 subjects from these participants were recruited in oral minimal model test and assessed β cell function with model-derived indices. Circulating RBP4 levels were measured by a commercially available ELISA kit. </p><p><b>RESULTS:</b> Circulating RBP4 levels were significantly and inversely correlated with β cell function indicated by the Stumvoll first-phase and second-phase insulin secretion indexes, but not with HOMA-β, calculated from the 2-h OGTT in 291 subjects across the spectrum of glycemia. The inverse association was also observed in subjects involved in the oral minimal model test with β cell function assessed by both direct measures and model-derived measures, after adjustment for potential confounders. Moreover, RBP4 emerged as an independent factor of the disposition index-total insulin secretion (DI-PhiT). </p><p><b>CONCLUSION:</b> Circulating RBP4 levels are inversely and independently correlated with β cell function across the spectrum of glycemia, providing another possible explanation of the linkage between RBP4 and the pathogenesis of type 2 diabetes.</p>

Let7b-5p is Upregulated in the Serum of Emirati Patients with Type 2 Diabetes and Regulates Insulin Secretion in INS-1 Cells

2020 ◽  
Author(s):  
Hayat Aljaibeji ◽  
Noha Mousaad Elemam ◽  
Abdul Khader Mohammed ◽  
Hind Hasswan ◽  
Mahammad Al Thahyabat ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Viability ◽  
Cell Function ◽  
Serum Levels ◽  
Insulin Content ◽  
Β Cell ◽  
Control Subjects ◽  
Β Cell Function

Abstract Let7b-5p is a member of the Let-7 miRNA family and one of the top expressed miRNAs in human islets that implicated in glucose homeostasis. The levels of Let7b-5p in type 2 diabetes (T2DM) patients or its role in β-cell function is still unclear. In the current study, we measured the serum levels of let7b-5p in Emirati patients with T2DM (with/without complications) and control subjects. Overexpression or silencing of let7b-5p in INS-1 (832/13) cells was performed to investigate the impact on insulin secretion, content, cell viability, apoptosis, and key functional genes. We found that serum levels of let7b-5p are significantly (p<0.05) higher in T2DM-patients or T2DM with complications compared to control subjects. Overexpression of let7b-5p increased insulin content and decreased glucose-stimulated insulin secretion, whereas silencing of let7b-5p reduced insulin content and secretion. Modulation of the expression levels of let7b-5p did not influence cell viability nor apoptosis. Analysis of mRNA and protein expression of hallmark genes in let7b-5p transfected cells revealed a marked dysregulation of Insulin, Pancreatic And Duodenal Homeobox 1 (PDX1), glucokinase (GCK), glucose transporter 2 (GLUT2), and INSR. In conclusion, an appropriate level of let7b-5p is essential to maintain β-cell function and may be regarded as a biomarker for T2DM.

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