A Sustained Increase in Plasma Free Fatty Acids Impairs Insulin Secretion in Nondiabetic Subjects Genetically Predisposed to Develop Type 2 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 10; pp. 2461 - 2474
• Main Authors: KASHYAP, Sangeeta, BELFORT, Renata, GASTALDELLI, Amalia, PRATIPANAWATR, Thongchai, BERRIA, Rachele, PRATIPANAWATR, Wilailak, BOJOJ, Mandeep, MANDARINO, Lawrence, DEFRONZO, Ralph, CUSI, Kenneth
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2003
• Subjects: Adult; Associated diseases and complications; Biological and medical sciences; Blood Glucose - analysis; Development and progression; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Disease susceptibility; Drug Administration Schedule; Emulsions; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fat Emulsions, Intravenous - administration & dosage; Fatty acid metabolism; Fatty Acids, Nonesterified - blood; Female; Genetic aspects; Genetic Predisposition to Disease; Glucose Clamp Technique; Glucose Tolerance Test; Hormones - blood; Humans; Hyperglycemia - blood; Infusions, Intravenous; Insulin - blood; Insulin - metabolism; Insulin Secretion; Male; Medical sciences; Osmolar Concentration; Phospholipids; Physiological aspects; Reference Values; Soybean Oil; Time Factors; Type 2 diabetes; United States; Type 2 diabetes; Endocrinopathy; Human; Pancreatic hormone; Lipids; Free fatty acid; Insulin; Endocrine secretion
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.10.2461

A Sustained Increase in Plasma Free Fatty Acids Impairs Insulin Secretion in Nondiabetic Subjects Genetically Predisposed to Develop Type 2 Diabetes Sangeeta Kashyap 1 , Renata Belfort 1 , Amalia Gastaldelli 1 , Thongchai Pratipanawatr , Rachele Berria 1 , Wilailak Pratipanawatr 1 , Mandeep Bajaj 1 , Lawrence Mandarino 1 , Ralph DeFronzo 1 2 and Kenneth Cusi 1 2 1 Diabetes Division, Department of Medicine, the University of Texas Health Science Center at San Antonio, San Antonio, Texas 2 Audie L. Murphy Veterans Administration Medical Center, San Antonio, Texas Address correspondence and reprint requests to Kenneth Cusi, University of Texas H.S.C. at San Antonio, Diabetes Division, Room 3.380S, 7703 Floyd Curl Dr., San Antonio, TX 78284-3900. E-mail: cusi{at}uthscsa.edu Abstract Acute elevations in free fatty acids (FFAs) stimulate insulin secretion, but prolonged lipid exposure impairs β-cell function in both in vitro studies and in vivo animal studies. In humans data are limited to short-term (≤48 h) lipid infusion studies and have led to conflicting results. We examined insulin secretion and action during a 4-day lipid infusion in healthy normal glucose tolerant subjects with (FH+ group, n = 13) and without (control subjects, n = 8) a family history of type 2 diabetes. Volunteers were admitted twice to the clinical research center and received, in random order, a lipid or saline infusion. On days 1 and 2, insulin and C-peptide concentration were measured as part of a metabolic profile after standardized mixed meals. Insulin secretion in response to glucose was assessed with a +125 mg/dl hyperglycemic clamp on day 3. On day 4, glucose turnover was measured with a euglycemic insulin clamp with [3- 3 H]glucose. Day-long plasma FFA concentrations with lipid infusion were increased within the physiological range, to levels seen in type 2 diabetes (∼500–800 μmol/l). Lipid infusion had strikingly opposite effects on insulin secretion in the two groups. After mixed meals, day-long plasma C-peptide levels increased with lipid infusion in control subjects but decreased in the FH+ group (+28 vs. −30%, respectively, P < 0.01). During the hyperglycemic clamp, lipid infusion enhanced the insulin secretion rate (ISR) in control subjects but decreased it in the FH+ group (first phase: +75 vs. −60%, P < 0.001; second phase: +25 vs. −35%, P < 0.04). When the ISR was adjusted for insulin resistance (ISR Rd = ISR ÷ [1/ R d ], where R d is the rate of insulin-stimulated glucose disposal), the inadequate β-cell response in the FH+ group was even more evident. Although ISR Rd was not different between the two groups before lipid infusion, in the FH+ group, lipid infusion reduced first- and second-phase ISR Rd to 25 and 42% of that in control subjects, respectively (both P < 0.001 vs. control subjects). Lipid infusion in the FH+ group (but not in control subjects) also caused severe hepatic insulin resistance with an increase in basal endogenous glucose production (EGP), despite an elevation in fasting insulin levels, and impaired suppression of EGP to insulin. In summary, in individuals who are genetically predisposed to type 2 diabetes, a sustained physiological increase in plasma FFA impairs insulin secretion in response to mixed meals and to intravenous glucose, suggesting that in subjects at high risk of developing type 2 diabetes, β-cell lipotoxicity may play an important role in the progression from normal glucose tolerance to overt hyperglycemia. EGP, endogenous glucose production FFA, free fatty acid FPG, fasting plasma glucose FPI, fasting plasma insulin IGT, impaired glucose tolerance ISR, insulin secretion rate LBM, lean body mass PCOS, polycystic ovary syndrome Rd, glucose disposal rate Footnotes Accepted July 9, 2003. Received November 27, 2002. DIABETES