Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects

2003 ◽  
Vol 284 (1) ◽  
pp. E129-E137 ◽  
Author(s):  
Elisabeth Qvigstad ◽  
Ingrid L. Mostad ◽  
Kristian S. Bjerve ◽  
Valdemar E. Grill
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Insulin Secretion ◽  
Dietary Intervention ◽  
Insulin Response ◽  
Low Fat Diet ◽  
Hyperglycemic Clamp ◽  
Glucose Stimulated Insulin Secretion ◽  
Secretion Rates

We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60–120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60–120 in the 50% having the lowest levels of hemoglobin A1c (379 ± 34 vs. 326 ± 30 pmol · kg−1 · min−1without Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects.

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

2007 ◽  
Vol 292 (6) ◽  
pp. E1775-E1781 ◽  
Author(s):  
Kenneth Cusi ◽  
Sangeeta Kashyap ◽  
Amalia Gastaldelli ◽  
Mandeep Bajaj ◽  
Eugenio Cersosimo
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Family History ◽  
Second Phase ◽  
Β Cell ◽  
C Peptide ◽  
Hyperglycemic Clamp ◽  
History Of ◽  
Plasma Ffa

Elevated plasma FFA cause β-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% ( P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or ΔC-peptide/Δglucose AUC (+177%, P = 0.02), an index of improved β-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 ± 5% ( P < 0.04). First- (+19 ± 6%, P = 0.1) and second-phase (+31 ± 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 ± 7 ( P < 0.05) and 41 ± 8% ( P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR ( r2 = 0.31, P < 0.02) and acute (2–4 min) glucose-induced insulin release after acipimox ( r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

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.

Fimasartan increases glucose‐stimulated insulin secretion in patients with type 2 diabetes and hypertension compared with amlodipine

2018 ◽  
Vol 20 (7) ◽  
pp. 1670-1677 ◽  
Author(s):  
Ye Seul Yang ◽  
Min Hyuk Lim ◽  
Seong Ok Lee ◽  
Eun Roh ◽  
Chang Ho Ahn ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Angiotensin(1–7) activates MAS-1 and upregulates CFTR to promote insulin secretion in pancreatic β-cells: the association with type 2 diabetes

2021 ◽  
Author(s):  
Xue-Lian Zhang ◽  
Xinyi Zhao ◽  
Yong Wu ◽  
Wen-qing Huang ◽  
Jun-jiang Chen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Human Blood ◽  
Human Subjects ◽  
Blood Levels ◽  
Intracellular Camp ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Objective: The beneficial effect of angiotensin(1–7), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how angiotensin(1–7) or MAS-1 affects insulin secretion remains elusive and whether endogenous level of angiotensin(1–7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of CFTR, a cAMP-activated Cl- channel, in regulation of insulin secretion. Here, we tested possible involvement of CFTR in mediating angiotensin(1–7)’s effect on insulin secretion and measured the level of angiotensin(1–7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes. Methods: Angiotensin(1–7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, western blotting as well as insulin ELISA in a pancreatic β cell line, RINm5F. Human blood samples were collected from 333 individuals with (n=197) and without (n=136) type 2 diabetes. Angiotensin(1–7), MAS-1 and CFTR level in the human blood were determined by ELISA. Results: In RINm5F cells, angiotensin(1–7) induced intracellular cAMP increase, CREB activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not angiotensin(1–7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2-diabetic but not non-diabetic subjects. Conclusion: These results suggested MAS-1 and CFTR as key players in mediating angiotensin(1–7)-promoted insulin secretion in pancreatic β cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

1833-P: PERK Inhibitors Enhanced Glucose-Stimulated Insulin Secretion in a Mouse Model of Type 2 Diabetes

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1833-P
Author(s):  
YE SEUL YANG ◽  
MIN JOO KIM ◽  
MI NA KIM ◽  
JIWON KIM ◽  
KUN-HO YOON ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Mouse Model ◽  
Glucose Stimulated Insulin Secretion
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