Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects.

Insulin resistance plays an important role in the pathogenesis of type 2 diabetes; however, the multiple mechanisms causing insulin resistance are not yet fully understood. The aim of this study was to explore the possible contribution of intramyocellular lipid content in the pathogenesis of skeletal muscle insulin resistance. We compared insulin-resistant and insulin-sensitive subjects. To meet stringent matching criteria for other known confounders of insulin resistance, these individuals were selected from an extensively metabolically characterized group of 280 first-degree relatives of type 2 diabetic subjects. Some 13 lean insulin-resistant and 13 lean insulin-sensitive subjects were matched for sex, age, BMI, percent body fat, physical fitness, and waist-to-hip ratio. Insulin sensitivity was determined by the hyperinsulinemic-euglycemic clamp method (for insulin-resistant subjects, glucose metabolic clearance rate [MCR] was 5.77+/-0.28 ml x kg(-1) x min(-1) [mean +/- SE]; for insulin-sensitive subjects, MCR was 10.15+/-0.7 ml x kg(-1) x min(-1); P<0.002). Proton magnetic resonance spectroscopy (MRS) was used to measure intramyocellular lipid content (IMCL) in both groups. MRS studies demonstrated that in soleus muscle, IMCL was increased by 84% (11.8+/-1.6 vs. 6.4+/-0.59 arbitrary units; P = 0.008 ), and in tibialis anterior muscle, IMCL was increased by 57% (3.26+/-0.36 vs. 2.08+/-0.3 arbitrary units; P = 0.017) in the insulin-resistant offspring, whereas the extramyocellular lipid content and total muscle lipid content were not statistically different between the two groups. These data demonstrate that in these well-matched groups of lean subjects, IMCL is increased in insulin-resistant offspring of type 2 diabetic subjects when compared with an insulin-sensitive group matched for age, BMI, body fat distribution, percent body fat, and degree of physical fitness. These results indicate that increased IMCL represents an early abnormality in the pathogenesis of insulin resistance and suggest that increased IMCL may contribute to the defective glucose uptake in skeletal muscle in insulin-resistant subjects.

[1]  C. Burant,et al.  Troglitazone action is independent of adipose tissue. , 1997, The Journal of clinical investigation.

[2]  Isabel R Schlaepfer,et al.  Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle lipoprotein lipase. , 1997, The American journal of physiology.

[3]  S. Lillioja,et al.  Skeletal Muscle Triglyceride Levels Are Inversely Related to Insulin Action , 1997, Diabetes.

[4]  B. Fielding,et al.  Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects. , 1996, Metabolism: clinical and experimental.

[5]  S. Jacob,et al.  Differential effect of chronic treatment with two beta‐blocking agents on insulin sensitivity: the carvedilol‐metoprolol study , 1996, Journal of hypertension.

[6]  M. Taskinen,et al.  The insulin resistance syndrome in smokers is related to smoking habits. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[7]  N. Ruderman,et al.  Lipid abnormalities in tissues of the KKAy mouse: effects of pioglitazone on malonyl-CoA and diacylglycerol. , 1994, The American journal of physiology.

[8]  R. DeFronzo,et al.  Pathogenesis of NIDDM: A Balanced Overview , 1992, Diabetes Care.

[9]  K. Osei,et al.  Insulin Sensitivity, Glucose Effectiveness, and Body Fat Distribution Pattern in Nondiabetic Offspring of Patients With NIDDM , 1991, Diabetes Care.

[10]  L. Groop,et al.  The role of free fatty acid metabolism in the pathogenesis of insulin resistance in obesity and noninsulin-dependent diabetes mellitus. , 1991, The Journal of clinical endocrinology and metabolism.

[11]  A. Krolewski,et al.  Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. , 1990, Annals of internal medicine.

[12]  L. Groop,et al.  Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. , 1989, The New England journal of medicine.

[13]  H. Mortensen,et al.  Carbohydrate and Lipid Metabolism of Skeletal Muscle in Type 2 Diabetic Patients , 1988, Diabetic medicine : a journal of the British Diabetic Association.

[14]  R. DeFronzo,et al.  Role of Lipid Oxidation in Pathogenesis of Insulin Resistance of Obesity and Type II Diabetes , 1987, Diabetes.

[15]  E. Newsholme,et al.  The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. , 1963, Lancet.