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...
