scholarly journals Tumor‐like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin‐induced insulin secretion in obese diabetes: A study of Zucker fatty diabetes mellitus rat

2020 ◽  
Vol 11 (6) ◽  
pp. 1434-1447
Author(s):  
Tomohide Hayami ◽  
Norihide Yokoi ◽  
Takuro Yamaguchi ◽  
Kohei Honda ◽  
Naoya Murao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Metabolic Profiles

Nitric oxide donor SIN-1 inhibits insulin release

1996 ◽  
Vol 271 (4) ◽  
pp. C1098-C1102 ◽  
Author(s):  
A. Sjoholm
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Kinase C ◽  
Stimulus Secretion Coupling

Preceding the onset of insulin-dependent diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1 beta, which exerts cytotoxic and inhibitory actions on islet beta-cell insulin secretion through induction of nitric oxide (NO) synthesis. The influence of the NO donor 3-morpholinosydnonimine (SIN-1) on insulin secretion from isolated pancreatic islets in response to various secretagogues was investigated. Stimulation of insulin release evoked by glucose, phospholipase C activation with carbachol, and protein kinase C activation with phorbol ester were obtained by SIN-1, whereas the response to adenylyl cyclase activation or K(+)-induced depolarization was not affected. It is concluded that enzymes involved in glucose catabolism, phospholipase C or protein kinase C, may be targeted by NO. Reversal of SIN-1 inhibition of glucose-stimulated insulin release by dithiothreitol suggests that NO may inhibit insulin secretion partly by S-nitrosylation of thiol residues in key proteins in the stimulus-secretion coupling. These adverse effects of NO on the beta-cell stimulus-secretion coupling may be of importance for the development of the impaired insulin secretion characterizing diabetes mellitus.

Abstract 63: ACE2 Deficiency Reduces Insulin Content of Isolated Pancreatic Islets and Plasma Insulin Concentrations Post-Glucose Challenge in Obese C57BL/6 Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Robin C Shoemaker ◽  
Lisa A Cassis
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Plasma Insulin ◽  
Insulin Content ◽  
Isolated Pancreatic Islets ◽  
Diet Induced Obesity ◽  
Glucose Challenge ◽  
Ace2 Gene ◽  
Deficient Mice

Objective: Diet-induced obesity promotes type 2 diabetes (T2D). Drugs that inhibit the renin-angiotensin system (RAS) have been demonstrated in clinical trials to decrease the onset of T2D. Angiotensin converting enzyme 2 (ACE2) negatively regulates the RAS by catabolizing angiotensin II (AngII). Preliminary data indicate that ACE2 deficient mice display impairments in glucose homeostasis at 8 weeks of age. We tested the hypothesis that ACE2 deficiency promotes the development of glucose intolerance and β-cell dysfunction in mice with diet-induced obesity. Methods and Results: Male Ace2 +/y or -/y mice were fed a low fat (LF, 10% kcal as fat) or high fat (HF, 60% kcal as fat) diet for 5 or 17 weeks. After 5 weeks, plasma insulin concentrations (0, 30 min) following a glucose challenge were significantly greater in HF versus ( vs) LF-fed mice. However, glucose-stimulated increases in plasma insulin concentrations were decreased in HF-fed ACE2 deficient mice compared to controls (2.96 ± 0.18 vs 4.44 ± 0.40 ng/ul, respectively; P<0.01). Surprisingly, isolated pancreatic islets from HF-fed mice of either genotype released similar concentrations of insulin in response to glucose. However, mRNA abundance of insulin was significantly reduced in islets from HF-fed Ace2 -/y compared to +/y mice (1.76 ± 0.17 vs 2.54 ± 0.18 insulin/18S ratio; P<0.05). After 17 weeks, the plasma insulin response to glucose was further reduced in the HF-fed ACE2 deficient mice compared to controls (8.07 ± 0.98 vs 13.90 ± 1.10 ng/ul; P<0.01). Further, LF-fed ACE2 deficient mice also displayed reductions in plasma glucose-stimulated insulin concentrations (1.92 ± 0.98 vs 3.09 ± 0.98 ng/ul; P<0.01). Islets from HF-fed wild type mice displayed reduced ACE2 gene expression compared to LF (0.069 ± 0.009 vs 0.169 ± 0.01, ACE2/18S ratio; P<0.001) and AngII totally suppressed islet glucose-stimulated insulin secretion compared to vehicle (-0.16 ± 0.18 vs 0.9 ± 0.26, fold change over basal; P<0.05). Conclusions: These results demonstrate that ACE2 deficiency promotes the development of T2D by regulating islet insulin content. Moreover, diet-induced obesity reduces islet ACE2 gene expression with augmented AngII-induced impairment of insulin secretion.

scholarly journals Islet Gene View - a tool to facilitate islet research

2018 ◽  
Author(s):  
Olof Asplund ◽  
Petter Storm ◽  
Vikash Chandra ◽  
Emilia Ottosson-Laakso ◽  
Gad Hatem ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Genetic Variants ◽  
Scientific Community ◽  
Regulation Of Gene Expression ◽  
Web Resource ◽  
Islet Hormones

AbstractChanges in the hormone-producing pancreatic islets are central culprits in type 2 diabetes (T2D) pathogenesis. Characterization of gene expression in islets how it is altered in T2D are therefore vital in understanding islet function and T2D pathogenesis. We leveraged RNA-sequencing and genome-wide genotyping in islets from 188 donors to create the Islet Gene View (IGW) platform to make this information easily accessible to the scientific community. The IGW combines expression data for a given gene with phenotypical data such as T2D status, BMI, HbA1c, insulin secretion, purity of islets, etc.), regulation of gene expression by genetic variants e.g., expression quantitative trait loci (eQTLs) and relationship with expression of islet hormones. In IGW, 285 differentially expressed genes (DEGs) were identified in T2D donors islets compared to controls. Forty percent of the DEGs showed cell-type enrichment and a large proportion of them were significantly co-expressed with islet hormone-encoding genes like glucagon (GCG, 56%), amylin (IAPP, 52%), insulin (INS, 44%) and somatostatin (SST, 24%). Inhibition of two DEGs, UNC5D and SERPINE2 impaired glucose-stimulated insulin secretion and impacted cell survival in a human beta-cell model.Significance StatementWe present Islet Gene View (IGW), a web resource facilitating information on gene expression in human pancreatic islets from organ donors easily accessible to the scientific community. In IGW, we explored RNA expression from 188 donor-islets and examined their relationship with islet phenotypes including insulin secretion and expression of genes encoding islet hormones. GWAS have shown 403 genetic variants associated with risk of type 2 diabetes (T2D) risk, however, the target genes and function of these variants in islets are largely unknown. By linking T2D risk variants to expression in islets from T2D and non-diabetic donors as well as islet phenotypes, use of IGW provided new insight into mechanisms by which variants in these loci may increase risk of T2D.

scholarly journals Leptin Suppression of Insulin Secretion and Gene Expression in Human Pancreatic Islets: Implications for the Development of Adipogenic Diabetes Mellitus1

1999 ◽  
Vol 84 (2) ◽  
pp. 670-676 ◽  
Author(s):  
Jochen Seufert ◽  
Timothy J. Kieffer ◽  
Colin A. Leech ◽  
George G. Holz ◽  
Wolfgang Moritz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Ribonucleic Acid ◽  
Leptin Receptor ◽  
Human Islets ◽  
Β Cells ◽  
Messenger Ribonucleic Acid ◽  
Fluorescence Confocal Microscopy ◽  
Glucagon Like Peptide 1

Previously we demonstrated the expression of the long form of the leptin receptor in rodent pancreatic β-cells and an inhibition of insulin secretion by leptin via activation of ATP-sensitive potassium channels. Here we examine pancreatic islets isolated from pancreata of human donors for their responses to leptin. The presence of leptin receptors on islet β-cells was demonstrated by double fluorescence confocal microscopy after binding of a fluorescent derivative of human leptin (Cy3-leptin). Leptin (6.25 nm) suppressed insulin secretion of normal islets by 20% at 5.6 mm glucose. Intracellular calcium responses to 16.7 mm glucose were rapidly reduced by leptin. Proinsulin messenger ribonucleic acid expression in islets was inhibited by leptin at 11.1 mm, but not at 5.6 mm glucose. Leptin also reduced proinsulin messenger ribonucleic acid levels that were increased in islets by treatment with 10 nm glucagon-like peptide-1 in the presence of either 5.6 or 11.1 mm glucose. These findings demonstrate direct suppressive effects of leptin on insulin-producingβ -cells in human islets at the levels of both stimulus-secretion coupling and gene expression. The findings also further indicate the existence of an adipoinsular axis in humans in which insulin stimulates leptin production in adipocytes and leptin inhibits the production of insulin in β-cells. We suggest that dysregulation of the adipoinsular axis in obese individuals due to defective leptin reception byβ -cells may result in chronic hyperinsulinemia and may contribute to the pathogenesis of adipogenic diabetes.

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.

scholarly journals Effect of Retinoic Acid on Glucokinase Activity and Gene Expression and on Insulin Secretion in Primary Cultures of Pancreatic Islets*

Endocrinology ◽  
1999 ◽  
Vol 140 (7) ◽  
pp. 3091-3096 ◽  
Author(s):  
Gabriela Cabrera-Valladares ◽  
Michael S. German ◽  
Franz M. Matschinsky ◽  
Juehu Wang ◽  
Cristina Fernandez-Mejia
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Retinoic Acid ◽  
Pancreatic Islets ◽  
Primary Cultures

scholarly journals Downregulation of Type II Diabetes Mellitus and Maturity Onset Diabetes of Young Pathways in Human Pancreatic Islets from Hyperglycemic Donors

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Jalal Taneera ◽  
Petter Storm ◽  
Leif Groop
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Pancreatic Islets ◽  
Type Ii Diabetes ◽  
Enrichment Analysis ◽  
Type Ii Diabetes Mellitus ◽  
Type Ii ◽  
Maturity Onset Diabetes ◽  
Human Pancreatic Islets ◽  
Onset Diabetes

Although several molecular pathways have been linked to type 2 diabetes (T2D) pathogenesis, it is uncertain which pathway has the most implication on the disease. Changes in the expression of an entire pathway might be more important for disease pathogenesis than changes in the expression of individual genes. To identify the molecular alterations in T2D, DNA microarrays of human pancreatic islets from donors with hyperglycemian=20and normoglycemian=58were subjected to Gene Set Enrichment Analysis (GSEA). About 178 KEGG pathways were investigated for gene expression changes between hyperglycemic donors compared to normoglycemic. Pathway enrichment analysis showed that type II diabetes mellitus (T2DM) and maturity onset diabetes of the young (MODY) pathways are downregulated in hyperglycemic donors, while proteasome and spliceosome pathways are upregulated. The mean centroid of gene expression of T2DM and MODY pathways was shown to be associated positively with insulin secretion and negatively with HbA1c level. To conclude, downregulation of T2DM and MODY pathways is involved in islet function and might be involved in T2D. Also, the study demonstrates that gene expression profiles from pancreatic islets can reveal some of the biological processes related to regulation of glucose hemostats and diabetes pathogenesis.

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