Insulin Secretion After Short- and Long-Term Low-Grade Free Fatty Acid Infusion in Men With Increased Risk of Developing Type 2 Diabetes Heidi Storgaard, Christine B. Jensen, Allan A. Vaag, Aage Vølund, and Sten Madsbad We studied the effect of a low-grade short- and long-term 20% Intralipid infusion (0.4 mL 1  kg 1  h 1 ) on insulin secretion and insulin action in 15 elderly obese men; 7 glucose intolerant first-degree relatives of type 2 diabetic patients (impaired glucose tolerance [IGT] relatives) and 8 healthy controls of similar age and body mass index (BMI). Intravenous glucose tolerance test (IVGTT) and a graded glucose infusion (dose-response test [DORE]) were performed to determine first phase insulin response and to explore the dose response relationship between glucose concentration and insulin secretion rates (ISR). ISR were calculated by deconvolution of plasma C-peptide concentrations. Insulin action was determined by performing a 120-minute hyperinsulinemic euglycemic clamp. All tests were performed 3 times, preceded by 0, 2, or 24 hours Intralipid infusion. Disposition indices (DI) were calculated for the IVGTT. Insulin action was reduced 25% after 2 and 24 hours Intralipid infusion in both groups. In IGT relatives, the -cell responsiveness to glucose (measured during DORE) decreased after 2 and 24 hours Intralipid infusion (P  .02), whereas first phase insulin response (measured during IVGTT) decreased after 24 hours Intralipid infusion. Insulin secretion measured during DORE and IVGTT was not affected by Intralipid infusion in controls. DI decreased after 2 and 24 hours Intralipid infusion in the total study population. In conclusion, insulin resistance induced by low-grade short- and long-term Intralipid infusion is not balanced by an adequate compensatory increase in insulin secretion in IGT relatives or in matched controls. IGT relatives appear to be more sensitive to the deleterious effects of low-grade fat infusion on insulin secretion than normal glucose tolerant control subjects. © 2003 Elsevier Inc. All rights reserved. P ATIENTS WITH TYPE 2 diabetes are characterized by elevated fasting and postprandial plasma free fatty acid (FFA) and triglyceride concentrations, 1-4 and changes in lipid metabolism are considered to play an important role in the development of type 2 diabetes. Defects in both insulin secre- tion and insulin action are known to be present in individuals predisposed to type 2 diabetes already in the prediabetic stage, 5-8 and it is well established that elevated plasma FFA deteri- orates insulin action in both healthy subjects 9-12 and in type 2 diabetic patients. 13,14 Most previous studies investigating the effects of elevated plasma FFA on insulin secretion and action were performed applying supraphysiologic amounts of FFA inducing a 2- to 3-fold increase in fasting plasma FFA. 10-18 The effect of elevated plasma FFA on insulin secretion is controversial. Both in vitro 19,20 and in vivo 16,21 studies have shown that acutely elevated plasma FFA levels had a stimula- tory effect on glucose-stimulated insulin secretion (GSIS), whereas prolonged exposure of rat 22,23 and human islets 24 to FFA decreased GSIS. Prolonged (24 to 48 hours) elevation of FFA in vivo decreased GSIS in rats 25 and in humans, 16,21 although one study reported increased GSIS in healthy subjects after prolonged FFA exposure. 26 Carpentier et al 17 showed that 48-hour fat infusion decreased GSIS during graded glucose infusion in obese 50-year-old subjects, whereas no effect on insulin secretion was found in patients with type 2 diabetes, 17 indicating that no further deterioration of insulin secretion can be induced by FFA in patients with overt type 2 diabetes. Insulin secretion is inversely related to insulin action in subjects with normal glucose tolerance (NGT) in a hyperbolic manner. 27,28 Thus, individuals with NGT exhibit a high insulin response to glucose when insulin sensitivity is low and vice versa. This means that insulin secretion must be related to the concomitant insulin sensitivity to obtain a correct estimate of the -cell function. The present study was designed to establish whether a phys- iologic elevation of plasma FFA causes changes in -cell function in potentially prediabetic elderly obese men without or with impaired glucose tolerance (IGT) combined with a family history of type 2 diabetes when insulin action is taken into account. In particular, we wanted to study whether IGT rela- tives were more sensitive to the lipotoxic effects of elevated plasma FFA than control subjects. -cell function was evalu- ated by performing 2 different glucose challenge tests address- ing different aspects of the -cell function: first phase respon- siveness (IVGTT) and dose-response relationship between plasma glucose concentration and insulin secretion rate (ISR) during a prolonged graded intravenous glucose infusion. The first reflects the acute response and the second the ability of the  cell to detect and respond appropriately to gradually in- creased plasma glucose concentrations. In vivo insulin action was also measured in each subject using the hyperinsulinemic euglycemic clamp technique before and after both short- (2-hour) and long-term (24-hour) low- grade Intralipid infusion. SUBJECTS AND METHODS Subjects Seventy-one Caucasian men recruited through local newspaper ad- vertisements underwent an oral glucose (75 g) tolerance test (OGTT). From the Hvidovre Hospital, University of Copenhagen, Hvidovre; Steno Diabetes Center, Gentofte; and Novo Nordisk, Bagsværd, Den- mark. Submitted September 20, 2002; accepted February 19, 2003. Supported by grants from the Novo-Nordisk Foundation, Danish Research Council, Danish Diabetes Association, Association of Danish Female Doctors, Grosserer C.P. Frederiksens Foundation, Beckett Foundation, Direktør E. Danielsen and Wife’s Foundation, Eli Lilly’s Diabetes Research Foundation, Handelsgartner Ove V. B. Olsen’s and Edith B. Olsen’s Foundation, Ebba Celinders Foundation, and Chris- tian the 3rd Foundation. Address reprint requests to Heidi Storgaard, MD, Department of Endocrinology, Hvidovre Hospital, DK-2650, Hvidovre, Denmark. © 2003 Elsevier Inc. All rights reserved. 0026-0495/03/5207-0014$30.00/0 doi:10.1016/S0026-0495(03)00102-1 885 Metabolism, Vol 52, No 7 (July), 2003: pp 885-894