A. D. Kriketos

In animal studies, increased amounts of triglyceride associated with skeletal muscle (mTG) correlate with reduced skeletal muscle and whole body insulin action. The aim of this study was to test this relationship in humans. Subjects were 38 nondiabetic male Pima Indians (mean age 28 +/- 1 years). Insulin sensitivity at physiological (M) and supraphysiological (MZ) insulin levels was assessed by the euglycemic clamp. Lipid and carbohydrate oxidation were determined by indirect calorimetry before and during insulin administration. mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy. Percentage of body fat (mean 29 +/- 1%, range 14-44%) was measured by underwater weighing. In simple regressions, negative relationships were found between mTG (mean 5.4 +/- 0.3 micromol/g, range 1.3-1.9 micromol/g) and log10M (r = -0.53, P < or = 0.001), MZ (r = -0.44, P = 0.006), and nonoxidative glucose disposal (r = -0.48 and -0.47 at physiological and supraphysiological insulin levels, respectively, both P = 0.005) but not glucose or lipid oxidation. mTG was not related to any measure of adiposity. In multiple regressions, measures of insulin resistance (log10M, MZ, log10[fasting insulin]) were significantly related to mTG independent of all measures of obesity (percentage of body fat, BMI, waist-to-thigh ratio). In turn, all measures of obesity were related to the insulin resistance measures independent of mTG. The obesity measures and mTG accounted for similar proportions of the variance in insulin resistance in these relationships. The results suggest that in this human population, as in animal models, skeletal muscle insulin sensitivity is strongly influenced by local supplies of triglycerides, as well as by remote depots and circulating lipids. The mechanism(s) underlying the relationship between mTG and insulin action on skeletal muscle glycogen synthesis may be central to an understanding of insulin resistance.

The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high-dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= -0.369, P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= 0.451, P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= -0.610, P < 0.0001). Indices of elongase activity (r= -0.467, P < 0.001), and delta9 desaturase activity (r= 0.332, P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance."

In animal studies, increased amounts of triglyceride associated with skeletal muscle (mTG) correlate with reduced skeletal muscle and whole body insulin action.The aim of this study was to test this relationship in humans.Subjects were 38 nondiabetic male Pima Indians (mean age 28 ± 1 years).Insulin sensitivity at physiological (M) and supraphysiological (MZ) insulin levels was assessed by the euglycemic clamp.Lipid and carbohydrate oxidation were determined by indirect calorimetry before and during insulin administration.mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy.Percentage of body fat (mean 29 ± 1%, range 14-44%) was measured by underwater weighing.In simple regressions, negative relationships were found between mTG (mean 5.4 ± 0.3 μmol/g, range 1.3-1.9μmol/g) and log 10 M (r = -0.53,P ≤ 0.001), MZ (r = -0.44,P = 0.006), and nonoxidative glucose disposal (r = -0.48 and -0.47 at physiological and supraphysiological insulin levels, respectively, both P = 0.005) but not glucose or lipid oxidation.mTG was not related to any measure of adiposity.In multiple regressions, measures of insulin resistance (log 10 M, MZ, log 10 [fasting insulin]) were significantly related to mTG independent of all measures of obesity (percentage of body fat, BMI, waist-to-thigh ratio).In turn, all measures of obesity were related to the insulin resistance measures independent of mTG.The obesity measures and mTG accounted for similar proportions of the variance in insulin resistance in these relationships.The results suggest that in this human population, as in animal models, skeletal muscle insulin sensitivity is strongly influenced by local supplies of triglycerides, as well as by remote depots and circulating lipids.The mechanism(s) underlying the relationship between mTG and insulin action on skeletal muscle glycogen synthesis may be central to an understanding of insulin resistance.