Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects

Abstract

Qvigstad, Elisabeth, Ingrid L. Mostad, Kristian S. Bjerve, and Valdemar E. Grill. Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects. Am J Physiol Endocrinol Metab 284: E129-E137, 2003; 10.1152/ajpendo.00114.2002.-We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol Ͼ2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60-120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60-120 in the 50% having the lowest levels of hemoglobin A 1c (379 Ϯ 34 vs. 326 Ϯ 30 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 without Acipimox, P Ͻ 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects. insulin sensitivity; hypertriglyceridemia; lipotoxicity; Acipimox; low-fat diet AN ELEVATED PLASMA LEVEL of fatty acids (FA) is a risk factor for type 2 diabetes (8, 24). The risk has been ascribed to an insulin resistance-inducing effect of FA in skeletal muscle and in liver (3). Randle and colleagues proposed many years ago that resistance may be due to a glucose-fatty acid cycle, i.e., a reciprocal relationship between the metabolism of FA and glucose in which abundance of FA decreases the uptake and metabolism of glucose (reviewed in Refs. 27, 28). The pyruvate dehydrogenase (PDH) complex played a key role in this concept. It was demonstrated in liver, heart, and skeletal muscle that FA decreased PDH activity through activation of PDH kinase (27, 28). Evidence was presented that an ambient effect of FA on PDH kinase activity was supplemented by a timedependent one. Many data support the operation of the glucose-fatty acid cycle (27), although alternative concepts have also been put forward (17, 37).More recent evidence indicates that elevated FA can exert negative effects on pancreatic ␤-cells and that such effects add to the diabetogenicity of elevated FA. In the obese and diabetic Zucker rat, triacylglycerols accumulate in ␤-cells in conjunction with elevated plasma FA (for review see Ref. 19). Such accumulation has been associated with ␤-cell damage, with proposed implications i...

Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration on Intramuscular Long-Chain Fatty Acyl-CoAs and Insulin Action in Type 2 Diabetic Patients

“…However, in the present study, the enhanced insulin sensitivity of type 2 diabetic patients after acipimox treatment strongly correlated with decreases in plasma FFA and intramyocellular LCFA-CoA concentrations, suggesting that the reduction in plasma FFA levels is the predominant mechanism for the acipimox-induced improvement in insulin sensitivity. Consistent with the results of the present study, Qvigstad et al (52) recently demonstrated that the acipimox-induced enhancement in insulin sensitivity was reversed with the infusion of intralipid/heparin in type 2 diabetic patients.…”

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

“…Intralipid-induced ␤-cell dysfunction was not evident, however, in subjects with established type 2 diabetes (15), presumably because of the preexisting profound ␤-cell impairment. Consistent with these results, other authors have found that lowering of fatty acids improved GSIS only in diabetic patients having the lowest levels of Hb A 1c (72). In our study (15), those with established diabetes actually showed an increase in absolute GSIS vs. controls, which is similar to our finding in prediabetic ZDF rats with mild hyperglycemia (33).…”

Effects of prolonged fasting and sustained lipolysis on insulin secretion and insulin sensitivity in normal subjects

“…Hyperglycemic clamp-derived measures of insulin secretion were unchanged after acipimox was administered (45). However, with the use of nicotinic acid and lipid/heparin infusions, two other studies showed that decreases in plasma FFA levels were associated with reductions in basal and glucose-stimulated insulin secretion (7,13).…”

“…Our aim was to explore whether a prolonged fast would increase plasma FFA levels sufficiently to study the effect of elevated levels on the glucose-stimulated acute insulin response (AIR) and S I and whether any potential effects could be reversed by lowering FFA levels with the antilipolytic drug acipimox (7,13,45). We studied 14 healthy volunteers without a family history of diabetes to test the hypothesis that increased plasma FFA levels are directly linked to changes in AIR and S I .…”