2011 ADA Posters 1261-2041.indd - Diabetes

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INTEGRATED PHYSIOLOGY—MACRONUTRIENT CATEGORY METABOLISM AND FOOD INTAKE & 1703-P Meal-Induced Insulin Secretion Is Associated with Postprandial Triglyceride Clearance in Subjects Consuming Glucose, Fructose or High Fructose Corn Syrup-Sweetened Beverages ROEL G. VINK, KIMBER L. STANHOPE, ANDREW A. BREMER, VALENTINA MEDICI, GUOXIA CHEN, TAK HOU FONG, VIVIEN LEE, ROSE MENORCA, NANCY L. KEIM, PETER J. HAVEL, Davis, CA, Nashville, TN It has been proposed that the adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased meal-induced glucose and insulin excursions, i.e. dietary glycemic index. Our objective was to investigate the role of post-meal insulin peaks, which activate lipoprotein lipase (LPL), in postprandial triglyceride (TG) clearance in 48 adults (age: 18-40 years, BMI: 18-35 kg/m²) consuming glucose, fructose or high fructose corn syrup (HFCS) sweetened beverages. For 12 days subjects resided at home and consumed their usual ad libitum diet along with glucose, fructose or HFCS (16/group) sweetened beverages at 25% of total energy requirements. Subsequently, fasting ApoC3 and 23-h insulin and TG levels were measured at the clinical research center while the subjects consumed the sweetened beverages with meals with an energy balanced diet (25% sugar-sweetened beverage, 30% complex carbohydrate, 30% fat, 15% protein). Net TG clearance was calculated as the decrease of TG 2 hours after the post-dinner TG peak. Consumption of glucose-sweetened beverages resulted in the largest glucose and insulin peaks and 23-h AUC. These levels were lowest in subjects consuming fructose and intermediate in subjects consuming HFCS (effect of sugar P
Integrated Physiology/ Obesity POSTERS For author disclosure information, see page 785. INTEGRATED PHYSIOLOGY—MACRONUTRIENT CATEGORY METABOLISM AND FOOD INTAKE & 1707-P Inhibition of Delta-6 Desaturase Increases Phospholipid Linoleate Content, Improves Cardiac Mitochondrial Function and Restores Glucose Tolerance in ob Mice MELISSA A. ROUTH, CHRISTOPHER M. MULLIGAN, CATHERINE H. LE, JULIANO SILVEIRA, GERRIT T. BOUMA, GENEVIEVE C. SPARAGNA, SIMONA ZARINI, ROBERT C. MURPHY, <strong>ADA</strong>M J. CHICCO, Fort Collins, CO, Boulder, CO, Aurora, CO Epidemiological studies have linked a lower proportion of linoleic acid (LA, 18:2n6) in serum phospholipids (PLs) to insulin resistance and cardiovascular mortality in humans, but the mechanism and pathophysiological basis of this phenomenon are unclear. A selective loss of LA also occurs in PLs from multiple tissues in obese/insulin-resistant (ob) vs. lean (C57Bl/6) mice, which is paralleled by increases in long-chain PUFAs and an accumulation of their eicosanoid derivatives. We hypothesized that this PL remodeling results from increased activity of delta-6 desaturase (D6D), the rate limiting enzyme in long-chain PUFA biosynthesis that utilizes LA as a substrate, and explored potential pathophysiological consequences of this phenomenon in ob mice. qRT-PCR revealed a 1-2 fold induction of D6D mRNA in ob vs. lean mice that paralleled increases in PL PUFA molar% ratios indicative of greater D6D activity in heart, liver, serum and muscle (P < 0.01). Treatment of 4 mo old male ob mice with the selective D6D inhibitor SC-26196 (SC, 100 mg/kg/d for 4 wks) reversed D6D indices and increased the molar% of LA in tissue PLs, and ameliorated 2 to 20-fold elevations in several pro-infl ammatory eicosanoid species present in the serum and hearts of untreated ob mice. SC treatment completely normalized the fatty acid composition of cardiolipin in cardiac mitochondria, which was associated with improvements in the rate (state 3) and effi ciency (ADP/O ratio) of mitochondrial respiration (P < 0.05). Interestingly, D6D inhibition also improved response to an acute glucose challenge in ob mice (1 mg/g BW i.p.), indicated by lower peak (146% vs. 219% of fasting) and fi nal (85 vs. 180% fasting 2 hrs-post challenge) blood glucose levels vs. untreated ob mice (P < 0.01). These studies indicate that D6D plays a pivotal role in PL remodeling and eicosanoid production in ob mice, and highlight the need for further investigation of PUFA metabolism in the development of glucose intolerance and cardiac mitochondrial dysfunction associated with obesity/insulin resistance. Supported by: AHA Grant & 1708-P Improving Mitochondrial Fat Oxidation by Restoring Tissue Glutathione Concentrations Increases Insulin Sensitivity, and Lowers Hepatic Fat, Triglycerides and Body Weight in Aged Mice RAJAGOPAL V. SEKHAR, DAN NGUYEN, SUSAN L. SAMSON, VASUMATHI T. REDDY, Houston, TX Introduction: We tested the hypotheses that glutathione defi ciency underlies impaired mitochondrial fat oxidation in aging, and contributes to insulin resistance, elevated hepatic fat and obesity, and whether improving tissue glutathione concentrations with dietary precursors would restore these defects. Methods: 8 young (18w) and 16 old (76w) male C57BL/6 mice were studied. The old mice were matched for age, sex, weight, glucose tolerance and fat oxidation: one group (‘treated’) was pair fed to the other (‘untreated’) control group using an isocaloric-isonitrogenous diet for 6w (both groups ate identical daily calories and protein nitrogen - diet of the treated group had higher content of glycine and cysteine (as n-acetylcysteine), precursor amino-acids for glutathione). Outcome measures were liver and muscle glutathione, body weights and composition, fat oxidation, glucose and insulin tolerance, plasma triglycerides, liver and renal profi les, and hepatic fat content. Results: Compared to young mice, untreated old mice had30-35% lower glutathione levels in the liver and muscle, 20% lower mitochondrial fattyacid oxidation, and signifi cantly higher hepatic fat, body weight, total body fat, and plasma triglycerides. Compared to the untreated old control mice, the treated mice showed signifi cantly improved liver and muscle glutathione concentrations by 20- 36%, and mitochondrial fatty acid oxidation by 22%, completely restored liver fat content, and improved body weight by 16%, triglycerides by 36%, and insulin sensitivity by 66%, and no changes in expression of glutamylcystinyl ligase, an enzyme regulating glutathione synthesis. Conclusions: Glutathione defi ciency contributes to impaired mitochondrial fattyacid oxidation in aging, and predisposes to elevated hepatic fat, insulin resistance, dyslipidemia and obesity. Restoring glutathione concentrations reverses these defects. Using simple, safe and inexpensive amino-acid supplementation to boost glutathione levels may be developed as a novel nutritional approach to treat fatty liver disease, obesity and insulin resistance in aging. Supported by: Baylor Seed Fund A464 1709-P Amino Acid Metabolites and Insulin Resistance in Human BRIAN A. IRVING, AUDREY J. WEYMILLER, HUSNAIN SYED, HELEN KARAKELIDES, MATTIAS SOOP, RICKEY E. CARTER, K. SREEKUMARAN NAIR, Rochester, MN Elevations in amino acids (AA), particularly branched chain AA (BCAA), have been reported to contribute to the development of insulin-resistance. We sought to determine the additive effects of AA, AA metabolites, and body composition on insulin sensitivity (SI). 24 non-diabetic lean (49+5 y, 22.8+0.4 kg/m2 ), 27 non-diabetic obese (49+4 y, 30.4+0.4 kg/m2 ), and 12 type 2 diabetic obese (57+4 y, 30.2+1.0 kg/m2 ) adults were studied. SI was assessed using the steady-state glucose infusion rate (GIR, umol/ kgFFM/min) obtained during a standardized hyperinsulinemic (1.5 mU/ kgFFM/min) euglycemic clamp. Body composition was determined using DEXA. Ultra-performance LC-MS/MS was used to quantify fasting AA and AA metabolites. Compared to the non-diabetic lean GIR (53+3) was progressively lower in both non-diabetic obese (40+3, p
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