Fatty Acid Signaling in the β-Cell and Insulin Secretion

Nolan, Christopher; Madiraju, Murthy S.R.; Delghingaro-Augusto, Viviane; Peyot, Marie‐Line; Prentki, Marc

doi:10.2337/db06-s003

Cited by 363 publications

(350 citation statements)

References 110 publications

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“…After fat ingestion, insulin levels were increased, with a peak during the first 30 -60 min. This was a larger increase in insulin than in previous studies (15,19) and would perhaps be explained by lipids, which both directly and indirectly stimulate insulin secretion (28,32). However, there was no increase in circulating FFA after fat ingestion, and triglyceride levels increased after 60 min, which was a later time point than the rapid insulin release.…”

Section: Ajp-endocrinol Metabcontrasting

confidence: 47%

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

Carr

Larsen²,

Winzell

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

167

129

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and glucose-dependent insulinotropic polypeptide (GIP) regulate islet function after carbohydrate ingestion. Whether incretin hormones are of importance for islet function after ingestion of noncarbohydrate macronutrients is not known. This study therefore examined integrated incretin and islet hormone responses to ingestion of pure fat (oleic acid; 0.88 g/kg) or protein (milk and egg protein; 2 g/kg) over 5 h in healthy men, aged 20 -25 yr (n ϭ 12); plain water ingestion served as control. Both intact (active) and total GLP-1 and GIP levels were determined as was plasma activity of dipeptidyl peptidase-4 (DPP-4). Following water ingestion, glucose, insulin, glucagon, GLP-1, and GIP levels and DPP-4 activity were stable during the 5-h study period. Both fat and protein ingestion increased insulin, glucagon, GIP, and GLP-1 levels without affecting glucose levels or DPP-4 activity. The GLP-1 responses were similar after protein and fat, whereas the early (30 min) GIP response was higher after protein than after fat ingestion (P Ͻ 0.001). This was associated with sevenfold higher insulin and glucagon responses compared with fat ingestion (both P Ͻ 0.001). After protein, the early GIP, but not GLP-1, responses correlated to insulin (r 2 ϭ 0.86; P ϭ 0.0001) but not glucagon responses. In contrast, after fat ingestion, GLP-1 and GIP did not correlate to islet hormones. We conclude that, whereas protein and fat release both incretin and islet hormones, the early GIP secretion after protein ingestion may be of primary importance to islet hormone secretion.insulin; glucagon; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; incretins; man THE INTEGRATED ENDOCRINE RESPONSES TO FOOD INGESTION are dependent on both the size and the composition of a meal and include the postprandial release of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and the islet hormones insulin and glucagon (3,5,21,32). Most studies have focused on responses to an oral glucose tolerance test, after which levels of GIP, GLP-1, and insulin rise, whereas glucagon levels are suppressed (4,18,20, 24). It is also known that fat and protein ingestion stimulate GLP-1 and GIP secretion (10,14,20,27). Less is known, however, regarding relationships between the incretin responses and changes in insulin and glucagon levels after meal or noncarbohydrate macronutrient ingestions.GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which cleaves the two NH 2 -terminal amino acids of the peptides, making them largely inactive (9). Accurate estimation of the relationship between incretin hormone secretion and islet hormones therefore requires measurement of both the total and the active intact forms of the two incretins. How this is related to macronutrient ingestion is not known. Indeed, we recently showed in mice that protein ingestion increased intact incretin hormone levels compared with carbohydrate ingestion, and this was associated with reduced intestinal DPP-4...

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Section: Ajp-endocrinol Metabcontrasting

confidence: 47%

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

Carr

Larsen²,

Winzell

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

167

129

View full text Add to dashboard Cite

show abstract

“…Thus, it was of interest to determine whether defects in islet lipid metabolism, short of causing steatosis, could be involved in beta cell failure in ZF-Px rats. Interestingly, 60% Px in ZL and ZF rats was associated with an increase in lipolysis, suggesting that increased GL/FA cycling may be a process involved not only in the compensatory response to obesityassociated insulin resistance [39], but also in beta cell Fig. 8 Model illustrating the natural history of type 2 diabetes in the ZF-Px rat model.…”

Section: Discussionmentioning

confidence: 99%

“…The beta cell mass at 3 weeks is almost normalised, consistent with the compensation phase being associated with enhanced beta cell growth and neogenesis. Furthermore, accelerated GL/FA cycling may be involved in the compensation [39] as well as allowing fuel excess detoxification and lipoadaptation [42,43]. Circulating glucose, triacylglycerol (TAG) and NEFA levels rise after 1 week post-Px, such that beta cells are in a glucolipotoxic environment.…”

Section: Discussionmentioning

confidence: 99%

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Delghingaro-Augusto¹,

Nolan

Gupta

et al. 2009

Diabetologia

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Aims/hypothesis The Zucker fatty (ZF) rat subjected to 60% pancreatectomy (Px) develops moderate diabetes by 3 weeks. We determined whether a progressive fall in beta cell mass and/or beta cell dysfunction contribute to beta cell failure in this type 2 diabetes model. Methods Partial (60%) or sham Px was performed in ZF and Zucker lean (ZL) rats. At 3 weeks post-surgery, beta cell mass and proliferation, proinsulin biosynthesis, pancreatic insulin content, insulin secretion, and islet glucose and lipid metabolism were measured. Results ZL-Px rats maintained normal glycaemia and glucose-stimulated insulin secretion (GSIS) despite incomplete recovery of beta cell mass possibly due to compensatory enhanced islet glucose metabolism and lipolysis. ZF-Px rats developed moderate hyperglycaemia (14 mmol/l), hypertriacylglycerolaemia and relative hypoinsulinaemia. Despite beta cell mass recovery and normal arginine-induced insulin secretion, GSIS and pancreatic insulin content were profoundly lowered in ZF-Px rats. Proinsulin biosynthesis was not reduced. Compensatory increases in islet glucose metabolism above those observed in ZF-Sham rats were not seen in ZF-Px rats. Triacylglycerol content was not increased in ZF-Px islets, possibly due to lipodetoxification by enhanced lipolysis and fatty acid oxidation. Fatty acid accumulation into monoacylglycerol and diacylglycerol was increased in ZF-Px islets together with a 4.5-fold elevation in stearoyl-CoA desaturase mRNA expression. Conclusions/interpretation Falling beta cell mass, reduced proinsulin biosynthesis and islet steatosis are not implicated in early beta cell failure and glucolipotoxicity in ZF-Px rats. Rather, severe beta cell dysfunction with a specific reduction in GSIS and marked depletion of beta cell insulin stores with altered lipid partitioning underlie beta cell failure in this animal model of type 2 diabetes.

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“…Glucose oxidation is then favored and FAs are excluded from the mitochondrion, rendering glucose the main fuel in ␤-cell metabolism. The resulting increase in the cytosolic long chain acyl-CoA pool has been implicated as an amplifying process in GSIS (15). Conversely, acetyl-CoA, derived from FA oxidation, inhibits pyruvate dehydrogenase, and citrate inhibits phosphofructokinase.…”

Section: Type 2 Diabetes (T2d)mentioning

confidence: 99%

Coordinate Changes in Histone Modifications, mRNA Levels, and Metabolite Profiles in Clonal INS-1 832/13 β-Cells Accompany Functional Adaptations to Lipotoxicity

Malmgren

Sartipy

Danielsson

et al. 2013

Journal of Biological Chemistry

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Background: Epigenetic regulation may mediate lipotoxic effects on ␤-cells in type 2 diabetes. Results: Lipotoxicity impairs insulin secretion, and alters metabolism, gene expression, and histone marks in INS-1 832/13 ␤-cells. Conclusion: Perturbed insulin secretion results from epigenetic, genetic, and metabolic adaptations to increased fatty acid metabolism in ␤-cells. Significance: Elucidation of the link between lipotoxicity and insulin secretion is crucial for understanding the pathogenesis of type 2 diabetes.

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Fatty Acid Signaling in the β-Cell and Insulin Secretion

Cited by 363 publications

References 110 publications

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

Incretin and islet hormonal responses to fat and protein ingestion in healthy men

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

Coordinate Changes in Histone Modifications, mRNA Levels, and Metabolite Profiles in Clonal INS-1 832/13 β-Cells Accompany Functional Adaptations to Lipotoxicity

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