Decreased Susceptibility to Fatty Acid–Induced Peripheral Tissue Insulin Resistance in Women

Abstract

Elevation of plasma nonesterified fatty acid (NEFA) levels has been shown in various studies to induce peripheral tissue insulin resistance and impair the suppression of endogenous glucose production (EGP). These studies have been conducted predominantly in men. We compared the effects of elevated plasma NEFA levels on basal and insulin-stimulated glucose metabolism in 8 normal women (age 42 ؎ 8 years [mean ؎ SD], BMI 25 ؎ 3 kg/m 2 ) and 10 normal men (35 ؎ 6 years, 24 ؎ 3 kg/m 2 ). Each subject underwent two 5-h 80 mU ⅐ m -2 ⅐ min -1 hyperinsulinemic-euglycemic clamps with measurement of glucose kinetics (intravenous [3-3 H]glucose) and substrate oxidation. Plasma NEFA levels were elevated in one study for 3 h before and during the clamp (ϳ1 mmol/l in both groups) by infusion of 20% Intralipid (60 ml/h) and heparin (900 U/h). In the control studies, the men and women had similar insulin-stimulated glucose disposal rates (R d ) and substrate oxidation rates. In the men, elevated NEFA levels decreased insulinstimulated glucose R d during the final 40 min of the clamp by 23% (P < 0.001). By contrast, no significant change in glucose R d was found in the women (control 10.4 ؎ 1.1, lipid study 9.9 ؎ 1.3 mg ⅐ kg -1 ⅐ min -1). Glucose R d was also unchanged in six women studied at a lower insulin dose (40 mU ⅐ m -2 ⅐ min -1 ). During the last 40 min of the high-insulin dose clamps with elevated NEFA, glucose oxidation was decreased by 33% in the men (P < 0.001) and by 23% in the women (P < 0.02). Nonoxidative glucose R d at this time was decreased by 15% in the men (P ‫؍‬ 0.02) but was not significantly affected in women. Basal EGP was unaffected by elevation of plasma NEFA levels in both groups. Suppression of EGP during the glucose clamps, however, was impaired. At the insulin infusion rate used, the magnitude of this defect was comparable in men and women. In summary, our findings suggest that although the effects on EGP appear comparable, the inhibitory effects of NEFA on peripheral tissue insulin sensitivity are observed in men but cannot be demonstrated in women. I ncreased plasma nonesterified fatty acid (NEFA) levels have been implicated in the pathogenesis of insulin resistance (1-3). Whole-body insulin sensitivity has been found to be inversely related to fasting plasma NEFA levels in healthy nondiabetic subjects (4) and also in the lean normoglucose-tolerant offspring of type 2 diabetic parents (5). In nondiabetic Pima Indians, fasting plasma NEFA levels were found to predict the subsequent development of type 2 diabetes (6).Fatty acids affect both hepatic and peripheral tissue glucose metabolism (3). In the liver, they facilitate gluconeogenesis. Indeed, the inhibitory effect of insulin on hepatic glucose output may be in part indirect and mediated by suppression of adipose tissue lipolysis and plasma NEFA levels (7-11). In cardiac muscle and skeletal muscles with a predominance of red oxidative fibers, fatty acids compete with glucose for oxidative metabolism (1). During fasting, these effects of fatty ac...

Increased Efficiency of Fatty Acid Uptake Contributes to Lipid Accumulation in Skeletal Muscle of High Fat-Fed Insulin-Resistant Rats

“…However, the present study is the first report linking changes in CD36 mRNA and ACS activity to in vivo measures of FA uptake in the same tissue. It should be noted that the results from the present study were obtained from male rats and may not apply to female rats, as there is recent evidence that some aspects of fat-induced insulin resistance may be sex specific (34,35).…”

Female Rats Do Not Exhibit Free Fatty Acid–Induced Insulin Resistance

“…Here, we show that there are strong sex differences in the expression of this phenomenon. In addition, we have recently provided information showing that fatty acid infusions do not lead to insulin resistance in women, although they do in men (34). Further studies of this sex difference could lead to new insights into the mechanisms of fat-induced insulin resistance in males and the reasons for protection against this phenomenon in estrogen-replete females.…”

Structure-Function Studies of the Adipocyte-secreted Hormone Acrp30/Adiponectin

“…Consequently, male and female mice have comparable levels of Acrp30 protein in the hexamer form, but females have a vast excess of the higher order structure complex. It is an intriguing hypothesis that the sexually dimorphic absolute Acrp30 levels and differential distribution between the forms may be partly responsible for the increased insulin sensitivity of females compared with males and the reduced susceptibility of females to the deleterious actions of free fatty acids (30,31). Furthermore, it leads to the hypothesis that the hexamer is the "necessary" form of Acrp30, required for basal activity of this protein; despite the tremendous difference in absolute levels of circulating Acrp30 between the genders, male and female animals have similar levels of the hexamer.…”