Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes.

Abstract

Our recent in vivo observations in healthy nonobese humans have demonstrated that prolonged elevation of plasma free fatty acids (FFAs) results in diminished glucose-stimulated insulin secretion (GSIS) when the F FA-mediated decrease in insulin sensitivity is taken into account. In the present study, we investigated whether obese individuals and patients with type 2 diabetes are more sensitive than healthy control subjects to the inhibitory effect of prolonged elevation of plasma FFAs on GSIS. In seven patients with type 2 diabetes and seven healthy nondiabetic obese individuals, we assessed GSIS with a programmed graded intravenous glucose infusion on two occasions, 6-8 weeks apart, with and without a prior 48-h infusion of heparin and Intralipid, which was designed to raise plasma FFA concentration approximately twofold over basal. The nondiabetic obese subjects had a significant 21% decrease in GSIS (P = 0.0008) with the heparin and Intralipid infusion, associated with a decrease in whole body insulin clearance. The impairment in GSIS was evident at low (<11 mmol/l) but not at higher plasma glucose concentrations. In contrast, the patients with t y p e 2 diabetes had a slight increase in GSIS (P = 0.027) and no change in insulin clearance, although there was marked interindividual variability in response. Plasma proinsulin concentrations measured in a subset of subjects were not altered in either group by the infusion of heparin and Intralipid. In summary, 1) obese nondiabetic individuals are susceptible to a desensitization of GSIS with heparin and Intralipid infusion, and 2) patients with type 2 diabetes do not demonstrate such susceptibility when FFAs are elevated approximately twofold above basal with heparin and Intralipid. Our results suggest that FFAs could play an important role in the development of -cell failure in obese individuals who are at risk for developing t y p e 2 diabetes. They do not, however, seem to further deteriorate the -cell function of patients who already have established type 2 diabetes and may even result in a slight increase in GSIS in this latter group. D i a b e t e s 4 9 :3 9 9-408, 2000 I t is well accepted that type 2 diabetes is characterized by defects in both insulin action and insulin secretion (1,2), with a specific defect in glucose-stimulated insulin secretion (GSIS) early in the evolution of this disease (3,4). Over the past decade, several investigators have focused their attention on the possible role of free fatty acids (FFAs), which are often elevated in states of insulin resistance, in selectively desensitizing the -cell to glucose (5-9). The concept of FFA-induced -cell desensitization has received support from prospective epidemiological studies, which show that elevated plasma FFA levels are a risk marker for the long-term development of glucose intolerance and progression toward type 2 diabetes both in Caucasians (10) and in Pima Indians (11).The acute stimulating effect of FFAs on GSIS has been well described both in vitro (12,13) and in vivo (14-16), and...

Effect of increased plasma non-esterified fatty acids (NEFAs) on arginine-stimulated insulin secretion in obese humans

“…These observations contrast with our previous finding of a reduction of GSIS after a prolonged increase of plasma NEFA in a similar population [11]. Our present findings also contrast with previous findings of others whom have shown blunting of the acute insulin response to glucose after a 24-h increase of plasma NEFAs in healthy non-obese subjects [12].…”

“…First, we did not show an absolute NEFA-mediated reduction in insulin secretion in acute response to arginine, as we have previously shown for GSIS [11]. Because arginine is believed to stimulate insulin secretion distal in the insulin secretion cascade of events, primarily by inducing depolarisation of the beta-cell membrane (22,23,40), the absence of a significant effect at normoglycaemia, combined with our previous observation of a NEFA-induced reduction of GSIS, would suggest that prolonged NEFA exposure could alter glucose-mediated insulin secretion and glucose potentiation of arginine-stimulated insulin secretion primarily by interfering with the metabolism of glucose, leaving the exocytotic machinery relatively intact.…”

“…The subjects who participated in the present as well as in our previous study [11] were heterogeneous with regards to glucose tolerance, although none had definite Type II diabetes. The small number of subjects in our present study does not allow us to compare the effect of prolonged increases of plasma NEFA on arginine-stimulated insulin secretion between the obese subjects with and without glucose intolerance and therefore we could not determine if the glucose tolerance status modulates this response in this population.…”

“…Recently, we reported that obese non-diabetic subjects but not obese subjects with Type II (non-insulin-dependent) diabetes mellitus showed an absolute reduction in GSIS after a 48 h increase in plasma NEFAs and triglycerides [11]. Our results supported the findings which have shown a decrease in first phase insulin response to glucose with a prolonged increase in plasma NEFAs in healthy subjects [12] and improvement of first phase insulin response with 1-week lowering of plasma NEFAs with acipimox in normoglycaemic relatives of patients with Type II diabetes [13].…”

“…To that aim, we measured the acute incremental insulin, C-peptide and insulin secretion response as well as the total incremental area under the respective curves of these parameters after arginine stimulation at both fasting and at about 11 mmol of plasma glucose. We chose to study obese non-diabetic humans since we had previously shown that these subjects are particularly sensitive to the impairing effect of chronically increased NEFAs on beta-cell function [11]. Arginine is thought to stimulate insulin secretion mainly by inducing pancreatic beta-cell membrane depolarization by directly entering the cell through cationic amino acid transporters [20±23], and therefore, arginine-induced insulin secretion bypasses the K + -ATP channels, which mediate a large part of the glucose-stimulated insulin secretion.…”