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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 296; no. 3; pp. E454 - E461
• Main Authors: Salgin, B, Marcovecchio, M. L, Humphreys, S. M, Hill, N, Chassin, L. J, Lunn, D. J, Hovorka, R, Dunger, D. B
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2009
• Subjects: Adult; Diabetes; Endocrinology; Fasting - physiology; Fatty acids; Fatty Acids, Nonesterified - blood; Female; Genetics; Glucose; Glucose Tolerance Test; Growth hormones; Human Growth Hormone - blood; Humans; Hypolipidemic Agents - administration & dosage; Insulin; Insulin - blood; Insulin - metabolism; Insulin Resistance - physiology; Insulin Secretion; Lipolysis - drug effects; Lipolysis - physiology; Male; Pyrazines - administration & dosage; Young Adult; Young adults
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.90613.2008

1 University Department of Paediatrics, Institute of Metabolic Science, University of Cambridge; 2 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford; and 3 Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom Submitted 21 July 2008 ; accepted in final form 15 December 2008 Normal β-cells adjust their function to compensate for any decrease in insulin sensitivity. Our aim was to explore whether a prolonged fast would allow a study of the effects of changes in circulating free fatty acid (FFA) levels on insulin secretion and insulin sensitivity and whether any potential effects could be reversed by the antilipolytic agent acipimox. Fourteen (8 female, 6 male) healthy young adults (aged 22.8–26.9 yr) without a family history of diabetes and a body mass index of 22.6 ± 3.2 kg/m 2 were studied on three occasions in random order. Growth hormone and FFA levels were regularly measured overnight (2200-0759), and subjects underwent an intravenous glucose tolerance test in the morning (0800-1100) on each visit. Treatment A was an overnight fast, treatment B was a 24-h fast with regular administrations of a placebo, and treatment C was a 24-h fast with regular ingestions of 250 mg of acipimox. The 24-h fast increased overnight FFA levels (as measured by the area under the curve) 2.8-fold [51.3 (45.6–56.9) vs. 18.4 (14.4–22.5) *10 4 µmol/l*min, P < 0.0001], and it led to decreases in insulin sensitivity [5.7 (3.6–8.9) vs. 2.6 (1.3–4.7) *10 –4 min –1 per mU/l, P < 0.0001] and the acute insulin response [16.3 (10.9–21.6) vs. 12.7 (8.7–16.6) *10 2 pmol/l*min, P = 0.02], and therefore a reduction in the disposition index [93.1 (64.8–121.4) vs. 35.5 (21.6–49.4) *10 2 pmol/mU, P < 0.0001]. Administration of acipimox during the 24-h fast lowered FFA levels by an average of 20% (range: –62 to +49%; P = 0.03), resulting in a mean increase in the disposition index of 31% ( P = 0.03). In conclusion, the 24-h fast was accompanied by substantial increases in fasting FFA levels and induced reductions in the acute glucose-simulated insulin response and insulin sensitivity. The use of acipimox during the prolonged fast increased the disposition index, suggesting a partial reversal of the effects of fasting on the acute insulin response and insulin sensitivity. free fatty acid; growth hormone; first phase insulin secretion; disposition index; lipotoxicity Address for reprint requests and other correspondence: B. Salgin, Univ. Dept. of Paediatrics, Addenbrooke's Hospital, Level 8, Box 116, Cambridge CB2 0QQ, UK (e-mail: burak{at}cantab.net )