Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects

Paolisso, Giuseppe; Gambardella, A.; Amato, Luca; Tortoriello, R.; D’Amore, Alberto; Varricchio, Maria Teresa; D’Onofrio, Francesca

doi:10.1007/s001250050426

Cited by 18 publications

(16 citation statements)

References 16 publications

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“…In situations, such as in type 2 diabetes, in which ␤-cell function is defective and cannot fully compensate for the decline in S I , there is a decline in DI but not necessarily in absolute insulin secretion. In contrast to the above findings, Paolisso et al (357) reported that a 6-h elevation of plasma FFAs results in an absolute increase in GSIS, as assessed by the first phase insulin response to an iv glucose tolerance test, but that prolonged FFA elevation for 24 h results in an absolute reduction in the acute insulin response to glucose. The FFA effect on insulin clearance (345) should also be taken into account, as this is expected to decrease, in part, the need for insulin secretion.…”

Section: Effect Of Chronically Elevated Ffas On Insulin Secretion mentioning

confidence: 81%

Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes

et al. 2002

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The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.

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Section: Effect Of Chronically Elevated Ffas On Insulin Secretion mentioning

confidence: 81%

Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes

et al. 2002

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“…In the present study, ingestion of any of the fats decreased insulin clearance, which explains the elevated plasma insulin concentrations in the fat ingestion studies. Although the present study does not answer the question of whether beta cell function is truly impaired by fat ingestion or is simply resting in response to a reduction in insulin clearance, we favour the view that fat ingestion primarily impairs insulin secretion because of the large body of in vitro work from various groups supporting the concept of reduced GSIS in beta cells exposed in a prolonged fashion to high NEFA concentrations [9] and because of other in vivo studies showing absolute reductions in glucose-stimulated insulin levels after prolonged NEFA elevation [8,30,47]. The mechanism for this apparently coordinated reduction in insulin clearance when the action or secretion of insulin is reduced is not known at present.…”

Section: Discussionmentioning

confidence: 94%

Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans

et al. 2006

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“…Prolonged exposure of beta cells to fatty acids in vitro inhibits glucose-stimulated insulin secretion [9–12], a phenomenon also observed in vivo in rats [61] and humans [62]. In recent years, several potential mechanisms have been investigated, including upregulation of uncoupling protein 2 (UCP2), activation of the novel isoform of protein kinase C PKCε, and late exocytotic events.…”

Section: Cellular and Molecular Mechanisms Of Glucolipotoxicity Imentioning

confidence: 99%

Glucolipotoxicity of the pancreatic beta cell

Poitout

Amyot

Semache

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

338

290

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SummaryThe concept of glucolipotoxicity refers to the combined, deleterious effects of elevated glucose and fatty acid levels on pancreatic beta-cell function and survival. Significant progress has been made in recent years towards a better understanding of the cellular and molecular basis of glucolipotoxicity in the beta cell. The permissive effect of elevated glucose on the detrimental actions of fatty acids stems from the influence of glucose on intracellular fatty-acid metabolism, promoting the synthesis of cellular lipids. The combination of excessive levels of fatty acids and glucose therefore leads to decreased insulin secretion, impaired insulin gene expression, and beta-cell death by apoptosis, all of which probably have distinct underlying mechanisms. Recent studies from our laboratory have identified several pathways implicated in fatty-acid inhibition of insulin gene expression, including the extracellular-regulated kinase (ERK1/2) pathway; the metabolic sensor Per-Arnt-Sim kinase (PASK); and the ATF6 branch of the unfolded protein response. We have also confirmed in vivo in rats that the decrease in insulin gene expression is an early defect which precedes any detectable abnormality in insulin secretion. While the role of glucolipotoxicity in humans is still debated, the inhibitory effects of chronically elevated fatty acid levels has been clearly demonstrated in several studies, at least in individuals genetically predisposed to developing type 2 diabetes. It is therefore likely that glucolipotoxicity contributes to beta-cell failure in type 2 diabetes as well as to the decline in beta-cell function observed after the onset of the disease.

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Opposite effects of short- and long-term fatty acid infusion on insulin secretion in healthy subjects

Cited by 18 publications

References 16 publications

Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes

Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes

Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans

Glucolipotoxicity of the pancreatic beta cell

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