title: Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes.
abstract: Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or DeltaC-peptide/Deltaglucose AUC (+177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 +/- 5% (P < 0.04). First- (+19 +/- 6%, P = 0.1) and second-phase (+31 +/- 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 +/- 7 (P < 0.05) and 41 +/- 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r2 = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.
authors.affiliation: Diabetes Division, Department of Medicine, The University of Texas Health Science Center at San Antonio, TX 78284-3900, USA. cusi@uthscsa.edu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cusi
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Kashyap
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.forename: Mandeep
authors.initials: M
authors.lastname: Bajaj
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cersosimo
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D002940:Circadian Rhythm; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005230:Fatty Acids, Nonesterified / Q000037:antagonists & inhibitors* / Q000097:blood*; D005260:Female; D020022:Genetic Predisposition to Disease; D015309:Glucose Clamp Technique; D006728:Hormones / Q000097:blood; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism / Q000502:physiology*; D000078790:Insulin Secretion; D008297:Male; D009994:Osmolar Concentration; D011719:Pyrazines / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D006728:Hormones; D000960:Hypolipidemic Agents; D007328:Insulin; D011719:Pyrazines; C027696:acipimox