Jensen, Michael D.

Abstract The sections in this article are: Pathogenesis of Type I Diabetes Effect of Type I Diabetes on Carbohydrate Metabolism Insulin Secretion and Action Postabsorptive and Postprandial Carbohydrate Metabolism Effects of Type I Diabetes and Its Treatment on Fatty Acid Metabolism Adipose Tissue Postabsorptive FFA Metabolism Postprandial FFA Availability Effects of Exercise on Adipose Tissue Lipolysis Regulation of Lipolysis During Hypoglycemia Effects Of Type I Diabetes on Protein Metabolism Regulation of Body Protein Mass, Amino Acid Levels and Nitrogen Balance Effect of Insulin on Protein Balance and Interaction of Insulin with Other Hormones and Substrates Effects of Insulin on Whole‐Body Protein Dynamics Effect of Insulin on Amino Acid Transamination Effect of Insulin on Regional Protein Dynamics Effect of Insulin on the Synthesis Rates of Specific Proteins Impact of Type I Diabetes on Protein Metabolism

Background Increases in circulating free‐fatty acids (FFAs) contribute to obesity‐associated cardiometabolic pathology and may be considered a surrogate marker for adipose tissue dysfunction. However, alterations in FFA metabolism resulting from modest weight gain have not been previously evaluated. Objective Examine the changes in FFAs during modest weight gain in healthy individuals and to investigate the relationship between regional fat depots. Study Design We evaluated the effects of overfeeding in 8 healthy, non‐obese participants (4 men; age 29 ± 5.7 years; BMI: 25.1 ± 2.1 kg/m2). FFA concentrations were measured using liquid chromatography/mass spectrometry under fasting conditions and during oral‐glucose tolerance test (OGTT) at baseline and after 8 weeks of weight gain. Prior to the baseline and weight gain visits, subjects consumed isocaloric macro‐nutrient stable diet for three days (50% carbohydrate, 35% fat and 15% protein). Body composition and regional fat depots were assessed using dual‐energy X‐ray absorptiometry and abdominal computed tomography scans. Results Overfeeding was accompanied by 3.9 ± 1.6 kg weight gain (p=0.01) resulting from 2.9 ± 0.9 kg (p=0.01) increase in fat mass and 1.0 ± 0.9 kg (p=0.04) increase in fat‐free mass. Compared to baseline, fasting FFA (439 ± 162 μM vs. 368 ± 123 μM, p=0.55) and area under the curve (AUC) for FFA during OGTT (23319 ± 11686 μM. min−1 vs. 20495 ± 4847 μM.min−1, p=0.55) did not change with weight gain. However, at 120 min. of the OGTT FFA were significantly greater after weight gain (60 ± 18 μM vs. 77 ± 34 μM, p=0.04). We found a negative relationship between relative changes in visceral fat area and FFA at 120 min of glucose challenge (rho=−0.76, p=0.03). Furthermore, relative changes in fasting FFA and AUC for FFA during OGTT with weight gain were associated with baseline total fat mass (fasting FFA: rho=0.76, p=0.03; AUC FFA: rho=0.81; p=0.02) and baseline abdominal fat area (fasting FFA: rho=0.76, p=0.03; AUC FFA: rho=0.79; p=0.02). Conclusions Modest weight gain does not alter fasting FFA or overall FFA response to oral glucose challenge. However, our data suggest development of early stages of adipose tissue insulin resistance which is apparent via lesser suppression of FFA at 120 min. of OGTT. Furthermore, the relationships between fasting FFA, AUC‐FFA, and baseline fat mass suggest that individuals with high baseline adiposity may be more susceptible to develop adipose tissue insulin resistance with weight gain. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Omega‐3 polyunsaturated fatty acids (n‐3 PUFAs) protect insulin sensitivity and glucose homeostasis in rodent models of insulin resistance. These effects of n‐3 PUFAs are linked with anti‐inflammatory properties, but emerging data suggests that mechanisms may also converge on mitochondria. We evaluated the influence of dietary n‐3 PUFAs on mitochondrial physiology in the context of high‐fat diet (HFD) in mice. We hypothesized that the insulin‐sensitizing effects of n‐3 PUFAs would be accompanied by enhanced mitochondrial function in skeletal muscle, leading to attenuated levels of lipid metabolites known to interfere with insulin signaling. We fed mice HFD with or without fish oil for 10 weeks. HFD decreased glucose tolerance, but not in the presence of fish oil. Skeletal muscle long chain acyl coenzyme‐As and ceramides were significantly elevated with HFD, but attenuated in the presence of fish oil. Mitochondrial oxidative capacity was similarly increased in mice fed HFD with and without fish oil. These results indicate that n‐3 PUFAs protect insulin sensitivity, in part, by preventing the accumulation of lipid intermediated that interfere with insulin action. Furthermore, the respiratory function of skeletal muscle mitochondria does not appear to be a major factor in ectopic lipid accumulation, diet‐induced insulin resistance, or the protective effects of n‐3 PUFAs on insulin sensitivity.

The accuracy of non-steady-state equations for measuring changes in free fatty acid rate of appearance (Ra) is unknown. In the present study, endogenous lipolysis (traced with [14C]-linoleate) was pharmacologically suppressed in six conscious mongrel dogs. A computer-responsive infusion pump was then used to deliver an intravenous oleic acid emulsion in both constant and linear gradient infusion modes. Both non-steady-state equations with various effective volumes of distribution (V) and steady-state equations were used to measure oleate Ra [( 14C]oleate). Endogenous lipolysis did not change during the experiment. When oleate Ra increased in a linear gradient fashion, only non-steady-state equations with a large (150 ml/kg) V resulted in erroneous values (9% overestimate, P less than 0.05). In contrast, when oleate Ra decreased in a similar fashion, steady-state and standard non-steady-state equations (V = plasma volume = 50 ml/kg) overestimated total oleate Ra (18 and 7%, P less than 0.001 and P less than 0.05, respectively). Overall, non-steady-state equations with an effective V of 90 ml/kg (1.8 x plasma volume) allowed the most accurate estimates of oleate Ra.