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, Anna; Varricchio, M; D'Onofrio, F

doi:10.1007/bf00401761

Cited by 199 publications

(131 citation statements)

References 19 publications

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“…The prior increase of plasma NEFA concentrations resulted in higher plasma insulin concentrations during basal glucose and during glucose stimulation, with the first and second phase being exaggerated. Other studies also showed enhanced insulin secretion when plasma NEFA concentrations were increased for 20 min, 90 min or 5 h, by Intralipid and heparin in healthy volunteers [12,13,15]. A short-term (9-h) plasma NEFA increase induced insulin secretion in humans and this was sufficient to prevent an increase in plasma glucose concentrations [28].…”

Section: Discussionmentioning

confidence: 90%

“…A short-term (9-h) plasma NEFA increase induced insulin secretion in humans and this was sufficient to prevent an increase in plasma glucose concentrations [28]. However, no hyperinsulinaemic response has been reported when plasma NEFA concentrations were increased for 5 h to 10 h [29,30] and this turned into an inhibitory effect after a very long-term increase (>24 h) [13,15]. In these studies, a wide range of plasma NEFA concentrations were reported, which may partly explain the divergence in insulin response.…”

Section: Discussionmentioning

confidence: 99%

“…Contrary findings have been observed after a long-term increase of plasma NEFA concentrations. Studies showed that a prolonged (24-48 h) increase of NEFA concentrations either impaired [15] or increased [14] glucose-stimulated insulin secretion in healthy volunteers.…”

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Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

et al. 2002

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Aims/hypothesis. Fatty acids affect insulin secretion in vivo, but little is known about the effects of specific fatty acids. Our aim was to investigate differential effects of acutely increased plasma monounsaturated, polyunsaturated and saturated fatty acids on glucosestimulated insulin secretion in healthy humans. Methods. A new experimental protocol was used to increase plasma monounsaturated (MUFA test), polyunsaturated (PUFA test) or saturated (SFA test) nonesterified fatty acids for 2 h by repeated oral fat feeding and continuous intravenous heparin infusion. This was followed by a hyperglycaemic clamp (10 mmol/l) to test insulin secretion in response to a prior plasma NEFA increase. Results. Total plasma NEFA concentrations were increased during the fat tests compared to the control visit (1.7-fold increase for MUFA and SFA tests and 1.4-fold increase for PUFA test; p<0.001). Exaggerated responses in plasma insulin, C-peptide and proinsulin concentrations were seen during the hyperglycaemic clamp after increasing plasma NEFA concentrations compared with the control (p<0.01). The effects were greatest for the MUFA test followed by the PUFA test and SFA test (p<0.01). Plasma GLP-1 concentrations increased during fat feeding, with a higher response during the MUFA test compared to PUFA and SFA tests (p<0.01). Conclusion/interpretation. Increasing plasma NEFA concentrations by oral fat feeding with heparin infusion augments glucose-stimulated insulin secretion with the greatest effect for monounsaturated fatty acids and the lowest effect for saturated fatty acids. Monounsaturated fatty acids also increase GLP-1 more than saturated fatty acids. Therefore, the exaggerated insulin concentrations could be due to both NEFA and GLP-1. [Diabetologia (2002[Diabetologia ( ) 45:1533[Diabetologia ( -1541 Keywords Monounsaturated fatty acids, polyunsaturated fatty acids, saturated fatty acids, insulin secretion, GLP-1. High fat diets lead to obesity, which in turn is one of the main causes of the development of Type II (noninsulin-dependent) diabetes mellitus. Both obesity and Type II diabetes are characterized by increased plasma non-esterified fatty acid concentrations [1] and raised fasting plasma NEFA concentrations are a risk marker for the development of Type II diabetes in Caucasian subjects [2] and in Pima Indians [3]. Increased plasma NEFA concentrations can have adverse effects on various tissues. Excess plasma NEFA concentrations can lead to a reduced skeletal muscle glucose uptake and oxidation [4,5,6], increased hepatic glucose output [7] and a decrease in hepatic insulin clearance [8,9]. These mechanisms could lead to glucose intolerance and insulin resistance leading to Type II diabetes.Inappropriately high concentrations of plasma NEFA have also been shown to alter glucose-stimulat-

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

et al. 2002

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“…Also, circulating fatty acids, both observationally and experimentally, seem closely involved in the pathogenesis of type 2 diabetes [31,33]. Depending on chain length, fatty acids also stimulate insulin secretion [34,35], which may further aggravate hepatic insulin resistance [36]. The fall in NEFA after glucose challenge between the sites (Fig.…”

Section: Discussionmentioning

confidence: 99%

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India

et al. 2005

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Aims/hypotheses: We previously reported independent links between the IGF system and the development of impaired glucose tolerance and cardiovascular risk. This study tests the hypothesis that the lifestyle change which accompanies population migration, with attendant increases in cardiovascular risk, is reflected by changes in the IGF system. Materials and methods: We compared a specific Gujarati community in Sandwell, UK (n=205), with people still resident in the same villages of origin near Navsari, India (n=246). We performed anthropometry and measured fasting plasma insulin, IGF-I, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3. Results: Daily calorie intake, BMI and WHR were significantly higher in UK Gujaratis than in Indian Gujaratis. IGFBP-1 was significantly lower in UK migrants (mean 29.5 [95% CI 25.9-33.0] vs 56.5 [50.6-62.5]μg/l; F=48.4, p<0.001). Conversely, fasting insulin, IGFBP-3 and IGF-I were all higher in UK Gujaratis (mean IGF-I 145.9 [138.1-153.6]ng/ml in UK Gujaratis and 100.9 [94.6-107.3] ng/ml in Navsari Gujaratis; F=76.6, p<0.001). These differences were still apparent when adjustment was made for BMI by location for IGF-I (F=57.4, p<0.001) and IGFBP-3 (F=5.7, p=0.02), but were no longer apparent for IGFBP-1 and insulin. At the population level, the decrease in IGFBP-1 for a given increase in insulin was significantly smaller in UK Gujaratis, suggesting greater hepatic insulin resistance in this group. Conclusions/interpretation: Environmental factors have profound effects on circulating IGF system components and on the relationship between IGFBP-1, IGF-I and related metabolic variables. This may have long-term implications for the development of worsening glucose tolerance and cardiovascular disease.

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“…4,5 Administration of intralipid and heparin to raise plasma FFA results in an increased GSIS. 6,7 Experiments performed on perfused pancreas indicate that the insulinotropic action of FFA increases with their chain length and degree of saturation. 8 In contrast, long-term exposure to FFA increases basal and blunts GSIS.…”

Section: Short-term Effects Of Fatty Acids On Insulin Secretionmentioning

confidence: 99%

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Assimacopoulos-Jeannet

2004

Int J Obes

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Obesity is associated with increased storage of lipids in nonadipose tissues like skeletal muscle, liver, and pancreatic b cells. These lipids constitute a continuous source of long-chain fatty acyl CoA (LC-CoA) and derived metabolites like diacylglycerol and ceramide, acting as signalling molecules on protein kinases activities (in particular, the family of PKCs), ion channel, gene expression, and protein acylation. In skeletal muscle, the increase in LC-CoA and diacylglycerol translocates and activates specific protein kinase C (PKC) isoforms, which will phosphorylate IRS-1 on serine, preventing its phosphorylation on tyrosine and association with PI3 kinase. This interrupts the insulin signalling pathway leading to the stimulation of glucose transport. In pancreatic b cells, short-term excess of fatty acids or LC-CoA activates PKC and also directly stimulates insulin exocytosis. Longterm exposure to free fatty acids (FFA) leads to an increased basal and blunted glucose-stimulated insulin secretion by affecting gene expression, increase in K ATP channel activity, and uncoupling of the mitochondria. In addition, the saturated FFA palmitate increases cell death by apoptosis via increase in ceramide synthesis.

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

Cited by 199 publications

References 19 publications

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

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