title: The effect of insulin on net lipid oxidation predicts worsening of insulin resistance and development of type 2 diabetes mellitus.
abstract: Suppression of lipid oxidation (L(ox)) by insulin is impaired in obesity and type 2 diabetes mellitus (T2DM). Here we tested whether high L(ox) represents a primary or acquired characteristic in the pathogenesis of T2DM. Hood-indirect calorimetry was performed under postabsorptive conditions and during a two-step hyperinsulinemic euglycemic clamp (insulin infusion rates in mU.m(-2).min(-1): 40 low and 400 high) in 465 Pima Indians: 317 with normal glucose tolerance (NGT), 117 with impaired glucose tolerance (IGT), and 31 with T2DM. The predictive effect of net lipid oxidation (L(ox)) on development of T2DM was assessed in 296 subjects (51 of whom developed T2DM), whereas the predictive effect of L(ox) on followup changes in insulin-mediated glucose disposal (M) and acute insulin response (AIR) was studied in 190 subjects with NGT at baseline. Cross-sectionally, after adjustment for age, sex, body fat (BF), and M low, L(ox) low was increased in T2DM compared with NGT and IGT subjects (P < 0.05). Prospectively, after adjustment for followup duration, age, sex, BF, M, and AIR, increased clamp L(ox) predicted T2DM [hazard rate ratios (95% CI): L(ox) low, 1.5 (1.1, 2.0), P < 0.01; L(ox) high, 1.3 (1.0, 1.8), P = 0.05]. High L(ox) low at baseline was also associated with subsequent worsening of M low (P = 0.04). These data indicate that the inability of insulin to suppress L(ox) may represent an early risk marker for insulin resistance and T2DM that is independent of adiposity, acute insulin secretion, and insulin action on glucose uptake.
authors.affiliation: Obesity and Diabetes Clinical Research Section, NIDDK/NIH/DHHS, 4212 N. 16th St., Rm. 5-35, Phoenix, AZ 85016, USA. jkoska@mail.nih.gov
authors.forename: Juraj
authors.initials: J
authors.lastname: Koska
authors.forename: Emilio
authors.initials: E
authors.lastname: Ortega
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krakoff
authors.forename: Joy C
authors.initials: JC
authors.lastname: Bunt
mesh_terms: D000328:Adult; D001823:Body Composition; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008137:Longitudinal Studies; D008297:Male; D010084:Oxidation-Reduction; D011379:Prognosis; D011446:Prospective Studies
chemical_list: D007328:Insulin