NEFA elevation during a hyperglycaemic clamp enhances insulin secretion

Chalkley, Simon; Kraegen, Edward W.; Furler, Stuart M.; Campbell, Lesley V.; Chisholm, Donald J.

doi:10.1002/(sici)1096-9136(199804)15:4<327::aid-dia574>3.0.co;2-u

Cited by 15 publications

(4 citation statements)

References 35 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: 85%

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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: 85%

“…Short-term in vitro incubation of islets with longchain fatty acids increased insulin release during glucose stimulation [10,11]. This was also seen in healthy volunteers after a short-term increase of plasma NEFA concentrations by Intralipid and heparin [12,13,14]. Contrary findings have been observed after a long-term increase of plasma NEFA concentrations.…”

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confidence: 81%

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

et al. 2002

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“…In that study, the shape of the C-peptide responses were virtually superimposable, suggesting that first and second phase were equally potentiated. An HGC study performed with and without preingestion of oral fat also concluded that firstand second-phase insulin release were equally potentiated (ϳ2-fold) (14), although a similar clamp study, in which the FFA level was elevated with an intravenous infusion of intralipid/heparin, showed that only the second phase was potentiated (17-25%) (27). Finally, a study comparing meal-induced insulin secretion with and without a concomitant intravenous glucagon-like peptide-1 infusion concluded that insulin secretion is augmented by glucagonlike peptide-1 in the absence of potentiation of the rateof-change component (K D ) (28).…”

Section: Discussionmentioning

confidence: 98%

Evaluation of Insulin Sensitivity and β-Cell Function Indexes Obtained From Minimal Model Analysis of a Meal Tolerance Test

et al. 2004

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Modeling analysis of glucose, insulin, and C-peptide following a meal has been proposed as a means to estimate insulin sensitivity (S i ) and ␤-cell function from a single test. We compared the model-derived meal indexes with analogous indexes obtained from an intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp (HGC) in 17 nondiabetic subjects (14 men, 3 women, aged 50 ؎ 2 years [mean ؎ SE], BMI 25.0 ؎ 0.7 kg/m 2 ). S i estimated from the meal was correlated with S i estimated from the IVGTT and the HGC (r ‫؍‬ 0.59 and 0.76, respectively; P < 0.01 for both) but was ϳ2.3 and 1.4 times higher (P < 0.05 for both). The meal-derived estimate of the ␤-cell's response to a steady-state change in glucose (static secretion index) was correlated with the HGC second-phase insulin response (r ‫؍‬ 0.69; P ‫؍‬ 0.002), but the estimated rate-of-change component (dynamic secretion index) was not correlated with first-phase insulin release from either the HGC or IVGTT. Indexes of ␤-cell function obtained from the meal were significantly higher than those obtained from the HGC. In conclusion, insulin sensitivity and ␤-cell indexes derived from a meal are not analogous to those from the clamp or IVGTT. Further work is needed before these indexes can be routinely used in clinical and epidemiological studies. Diabetes 53:1201-1207, 2004 E stablishing a single test that assesses insulin secretion and insulin sensitivity under normal physiologic conditions is potentially of great value for both epidemiological and clinical studies. To this end, a minimal model estimate of insulin sensitivity based on a meal tolerance test has recently been developed by Caumo et al. (1), and several groups (2-10) have proposed model-based methods for assessing ␤-cell function from arbitrary glucose excursions. The meal-derived estimate of insulin sensitivity [S i(MEAL) ] has been shown to correlate with that obtained from an intravenous glucose tolerance test (IVGTT) [S i(IVGTT) ] (1), but none of the model-based indexes of ␤-cell function have been rigorously compared with estimates of first-and second-phase insulin release obtained from standard tests such as the IVGTT (11-13) or hyperglycemic clamp (HGC) (14 -16).To more fully assess whether indexes of insulin sensitivity and ␤-cell function can both be obtained from a meal test, we measured plasma glucose, insulin, and C-peptide concentrations over a 24-h period. On separate days, an IVGTT and HGC were performed. The IVGTT was used to assess insulin sensitivity [S i(IVGTT) ] and first-phase insulin release [⌽ 1(IVGTT) ]. The HGC was used to assess first-[⌽ 1(HGC) ] and second-phase insulin release [⌽ 2(HGC) ] and to obtain an additional estimate of insulin sensitivity [S i(HGC) ]. These estimates were then compared with analogous estimates of S i and ␤-cell function obtained from the breakfast meal. The role of potentiation in enhancing ␤-cell secretion throughout the day was evaluated by comparing the secretion indexes obtained from breakfast with those obtained from lunch and di...

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“…Of the nutrient modulators, fatty acids are particularly important as, at one extreme, islet fatty acid deprivation essentially abolishes glucose-induced insulin secretion (GIIS) (4 -7), whereas at the other extreme, acutely elevated fatty acid levels augment GIIS (6,8,9). Elevated circulating free fatty acids (FFAs) most probably contribute to islet ␤-cell compensation in insulin-resistant states (10 -13) but if chronically elevated, particularly in association with high glucose (14), cause ␤-cell failure via diverse mechanisms including induction of ␤-cell apoptosis, reduced GIIS, and insulin biosynthesis resulting in type 2 diabetes (10 -16).…”

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confidence: 99%

A Role for the Malonyl-CoA/Long-Chain Acyl-CoA Pathway of Lipid Signaling in the Regulation of Insulin Secretion in Response to Both Fuel and Nonfuel Stimuli

Roduit

Nolan²,

Alarcón³

et al. 2004

Diabetes

167

148

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The malonyl-CoA/long-chain acyl-CoA (LC-CoA) model of glucose-induced insulin secretion (GIIS) predicts that malonyl-CoA derived from glucose metabolism inhibits fatty acid oxidation, thereby increasing the availability of LC-CoA for lipid signaling to cellular processes involved in exocytosis. For directly testing the model, INSr3 cell clones overexpressing malonylCoA decarboxylase in the cytosol (MCDc) in a tetracycline regulatable manner were generated, and INS(832/ 13) and rat islets were infected with MCDc-expressing adenoviruses. MCD activity was increased more than fivefold, and the malonyl-CoA content was markedly diminished. This was associated with enhanced fat oxidation at high glucose, a suppression of the glucoseinduced increase in cellular free fatty acid (FFA) content, and reduced partitioning at elevated glucose of exogenous palmitate into lipid esterification products. MCDc overexpression, in the presence of exogenous FFAs but not in their absence, reduced GIIS in all ␤-cell lines and in rat islets. It also markedly curtailed the stimulation of insulin secretion by other fuel and nonfuel secretagogues. In the absence of MCDc overexpression, the secretory responses to all types of secretagogues were amplified by the provision of exogenous fatty acids. In the presence of exogenous FFAs, the fatty acyl-CoA synthetase inhibitor triacsin C reduced secretion in response to glucose and nonfuel stimuli. The data show the existence of important links between the metabolic coupling factor malonyl-CoA, the partitioning of fatty acids, and the stimulation of insulin secretion to both fuel and nonfuel stimuli. Diabetes 53:

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NEFA elevation during a hyperglycaemic clamp enhances insulin secretion

Cited by 15 publications

References 35 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

Evaluation of Insulin Sensitivity and β-Cell Function Indexes Obtained From Minimal Model Analysis of a Meal Tolerance Test

A Role for the Malonyl-CoA/Long-Chain Acyl-CoA Pathway of Lipid Signaling in the Regulation of Insulin Secretion in Response to Both Fuel and Nonfuel Stimuli

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