scholarly journals The Role of Endogenous Incretin Secretion as Amplifier of Glucose-Stimulated Insulin Secretion in Healthy Subjects and Patients With Type 2 Diabetes

Diabetes ◽  
2012 ◽  
Vol 61 (9) ◽  
pp. 2349-2358 ◽  
Author(s):  
H. J. Woerle ◽  
L. Carneiro ◽  
A. Derani ◽  
B. Goke ◽  
J. Schirra
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Healthy Subjects ◽  
Incretin Secretion ◽  
Glucose Stimulated Insulin Secretion

scholarly journals In vivo phosphoproteomics reveals pathogenic signaling changes in diabetic islets

2018 ◽  
Author(s):  
Francesca Sacco ◽  
Anett Seelig ◽  
Sean J. Humphrey ◽  
Natalie Krahmer ◽  
Francesco Volta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Drug Targets ◽  
High Sensitivity ◽  
Glucose Stimulated Insulin Secretion

SUMMARYProgressive decline of pancreatic beta cells function is key to the pathogenesis of type 2 diabetes. Protein phosphorylation is the central mechanism controlling glucose-stimulated insulin secretion in beta cells. However, if and how signaling networks are remodeled in diabetic isletsin vivoremain unknowns. Here we applied high-sensitivity mass spectrometry-based proteomics and quantified the levels of about 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls. This highlighted drastic remodeling of key kinase hubs and signaling pathways. We integrated our phosphoproteomic dataset with a literature-derived signaling network, which revealed a crucial and conserved role of GSK3 kinase in the control of the beta cells-specific transcription factor PDX1 and insulin secretion, which we functionally verified. Our resource will enable the community to investigate potential mechanisms and drug targets in type 2 diabetes.

scholarly journals Metabolic cycling in control of glucose-stimulated insulin secretion

2008 ◽  
Vol 295 (6) ◽  
pp. E1287-E1297 ◽  
Author(s):  
Mette V. Jensen ◽  
Jamie W. Joseph ◽  
Sarah M. Ronnebaum ◽  
Shawn C. Burgess ◽  
A. Dean Sherry ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pyruvate Metabolism ◽  
Coupling Factors ◽  
Stimulus Secretion Coupling ◽  
Channel Dependent ◽  
Glucose Stimulated Insulin Secretion ◽  
Dependent Mechanism

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of β-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in β-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K+ (KATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. Whereas this KATP channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet β-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and α-ketoglutarate, in control of GSIS.

scholarly journals Plasma FGF-21 and Sclerostin Levels, Glycemia, Adiposity and Insulin Sensitivity in Normoglycemic Black and White Adults

2021 ◽  
Author(s):  
Nkiru Umekwe ◽  
Ibiye Owei ◽  
Frankie Stentz ◽  
Sam Dagogo-Jack
Keyword(s):  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Healthy Subjects ◽  
Fibroblast Growth ◽  
Black And White ◽  
Fasting Plasma ◽  
White Adults

Abstract Increased circulating fibroblast growth factor (FGF)-21 and sclerostin levels have been reported in patients with type 2 diabetes (T2D). We assessed the association of FGF-21 and sclerostin with adiposity, glycemia and glucoregulatory measures in healthy subjects. We studied 20 normoglycemic Black and White offspring of parents with T2D. Assessments included OGTT, insulin sensitivity (Si-clamp), insulin secretion (HOMA-B), and body fat (DXA). Fasting plasma FGF-21 and sclerostin levels were measured with ELISAs. The participants' mean (+SD) age was 50.4 ± 5.97 yr; BMI 32.5 ± 5.86 kg/m2; fasting plasma glucose (FPG) 96.1 ± 5.21 mg/dl, and 2-hr post-load glucose (2hPG) 116 ± 5.45 mg/dl. FGF-21 levels were similar in Blacks vs. Whites (0.36 ± 0.15 ng/ml vs. 0.39 ± 0.25 ng/ml), men vs. women (0.45 ± 0.14 vs. 0.44 ± 0.07ng/ml), correlated positively with body mass index (BMI) (r=0.23, P=0.05) and waist circumference (r=0.27, P=0.04), and inversely with FPG (r= -0.26, P=0.05). Sclerostin levels also were similar in Blacks (33.5 ± 17.1 pmol/l) vs. Whites (34.2 ± 6.41 pmol/l), men vs. women (35.3 ± 9.01 pmol/l vs. 32.3 ± 15.8 pmol/l), and correlated inversely with FPG (r= - 0.11-0.44) but not adiposity measures. The correlation coefficient between Si-clamp values and FGF-21 levels was -0.31 (P=0.09) compared with 0.04 (P=0.89) for sclerostin levels. FGF-21 and sclerostin levels were not correlated with each other or HOMA-B. Among healthy Black and White subjects, plasma FGF-21 and sclerostin showed differential associations with adiposity but concordant association with FPG levels.

scholarly journals Two decades since the fetal insulin hypothesis: what have we learned from genetics?

Diabetologia ◽  
2021 ◽  
Author(s):  
Alice E. Hughes ◽  
Andrew T. Hattersley ◽  
Sarah E. Flanagan ◽  
Rachel M. Freathy
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Later Life ◽  
Fat Distribution ◽  
Ample Evidence ◽  
Lower Birthweight

AbstractIn 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease. Graphical abstract

scholarly journals Differential gene expression between Zucker Fatty rats and Zucker Diabetic Fatty rats: a potential role for the immediate-early gene Egr-1 in regulation of beta cell proliferation

2005 ◽  
Vol 35 (1) ◽  
pp. 13-25 ◽  
Author(s):  
Kay E Garnett ◽  
Philip Chapman ◽  
Julie A Chambers ◽  
Ian D Waddell ◽  
David S W Boam
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Cell Proliferation ◽  
Transcription Factors ◽  
Insulin Secretion ◽  
Early Gene ◽  
Β Cell ◽  
Zucker Diabetic Fatty Rats ◽  
Glucose Stimulated Insulin Secretion

The β-cell failure that characterises type 2 diabetes is likely to involve altered expression of many genes. We aimed to identify global changes in gene expression underlying β-cell dysfunction in pre-diabetic Zucker Diabetic Fatty rat islets, followed by functional studies to verify our findings. Gene expression profiles in islets from 6-week-old Zucker Diabetic Fatty rats and Zucker Fatty rat controls were analysed using Affymetrix microarrays. Totally 977 genes were found to be differentially regulated, comprising large groups of membrane and structural proteins, kinases, channels, receptors, transporters, growth factors and transcription factors. We are particularly interested in transcription factors, which can have profound effects on cellular function. Thus a subset of those with no role yet defined in the β-cell was selected for further study namely the immediate-early gene Egr-1, PAG608, rCGR19 and mSin3b. Tissue specificity of these factors varied but interestingly Egr-1 expression was highly enriched in the pancreatic islet. To determine a possible role of Egr-1 in the β-cell, Egr-1 expression in INS-1 cells was silenced using RNA interference (RNAi). Glucose-stimulated insulin secretion in these cells was then measured using ELISA and cell proliferation was measured by [3H]thymidine incorporation. Small interfering RNA (siRNA)-mediated silencing of the Egr-1 gene inhibited its induction by glucose but had no observable effect on glucose-stimulated insulin secretion. However, Egr-1 gene silencing did inhibit proliferation of INS-1 cells in a glucose-independent manner. Our studies have revealed a role for Egr-1 and suggest that reduced Egr-1 gene expression may contribute to decreased β-cell proliferation and the consequent β-cell failure observed in the later stages of type 2 diabetes.

Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes

Metabolism ◽  
2019 ◽  
Vol 97 ◽  
pp. 87-91 ◽  
Author(s):  
Min Joo Kim ◽  
Mi Na Kim ◽  
Se Hee Min ◽  
Dong-Sik Ham ◽  
Ji-Won Kim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Mouse Model ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Decreased expression of genes involved in oxidative phosphorylation in human pancreatic islets from patients with type 2 diabetes

2011 ◽  
Vol 165 (4) ◽  
pp. 589-595 ◽  
Author(s):  
Anders H Olsson ◽  
Beatrice T Yang ◽  
Elin Hall ◽  
Jalal Taneera ◽  
Albert Salehi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Insulin Secretion ◽  
Oxidative Phosphorylation ◽  
Pancreatic Islets ◽  
Human Pancreatic Islets ◽  
Qrt Pcr ◽  
Glucose Stimulated Insulin Secretion

ObjectiveGene expression alterations, especially in target tissues of insulin, have been associated with type 2 diabetes (T2D). In this study, we examined if genes involved in oxidative phosphorylation (OXPHOS) show differential gene expression and DNA methylation in pancreatic islets from patients with T2D compared with non-diabetic donors.Design and methodsGene expression was analyzed in human pancreatic islets from 55 non-diabetic donors and nine T2D donors using microarray.ResultsWhile the expected number of OXPHOS genes with reduced gene expression is 7.21, we identified 21 downregulated OXPHOS genes in pancreatic islets from patients with T2D using microarray analysis. This gives a ratio of observed over expected OXPHOS genes of 26.37 by aχ2-test withP=2.81×10−7. The microarray data was validated by qRT-PCR for four selected OXPHOS genes:NDUFA5, NDUFA10, COX11, andATP6V1H. All four OXPHOS genes were significantly downregulated in islets from patients with T2D compared with non-diabetic donors using qRT-PCR (P≤0.01). Furthermore, HbAlc levels correlated negatively with gene expression ofNDUFA5, COX11, andATP6V1H(P<0.05). Gene expression ofNDUFA5, NDUFA10, COX11, andATP6V1Hcorrelated positively with glucose-stimulated insulin secretion (P<0.03). Finally, DNA methylation was analyzed upstream of the transcription start forNDUFA5, COX11, andATP6V1H. However, none of the analyzed CpG sites in the three genes showed differences in DNA methylation in islets from donors with T2D compared with non-diabetic donors.ConclusionPancreatic islets from patients with T2D show decreased expression of a set of OXPHOS genes, which may lead to impaired insulin secretion.

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