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

Abstract

It is well described that excessive lipid metabolism can cause insulin resistance in both animals and humans, and this has been implicated as a causative factor in the development of insulin resistance and type 2 diabetes in humans. Recently, we have shown that intravenous lipid emulsion (liposyn) infusion during a 120-min euglycemichyperinsulinemic clamp led to significant reductions in insulin action and fatty acid translocase (FAT/CD36) skeletal muscle protein expression. After reviewing the literature, it became evident that essentially all past studies, including our own, were conducted in male animals. Therefore, to determine whether there were sex determinants of fat-induced insulin resistance, we assessed the impact of free fatty acid (FFA) elevation on insulin action in female rats. Here, we report that a fourfold elevation in plasma FFA concentration induced a 40% reduction in the insulin-stimulated glucose disposal rate, a 30% decline in insulin-stimulated skeletal muscle insulin substrate receptor-1 (IRS-1) phosphorylation, a 48% decrease in IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and a 50% reduction in muscle FAT/CD36 protein expression in male rats. In striking contrast, we found no effect of FFA elevation to cause insulin resistance, changes in IRS-1/PI 3-kinase, or FAT/CD36 protein levels in female animals. Our findings indicate that female animals are protected from lipid-induced reductions in insulin action. Diabetes 51: [1907][1908][1909][1910][1911][1912] 2002 I t is widely held that excessive lipid metabolism, achieved either by high-fat feeding or intravenous infusion of lipid emulsion to raise circulating free fatty acid (FFA) levels, leads to decreased insulinstimulated glucose uptake (1-10). This lipid-induced decrease in insulin-stimulated glucose disposal is associated with a decline in insulin substrate receptor-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle, and these in vivo and in vitro findings have been reported in several articles (1,6,9,10) and are well supported. Interestingly, after reviewing the literature, it became apparent that essentially all studies reporting fat-induced insulin resistance in humans or rodents have been conducted in men or male animals. Because the prevailing concept is that fat-induced impairment of glucose disposal is a major risk factor for the development of insulin resistance and type 2 diabetes, and because type 2 diabetes is equally prevalent in men and women, it is important to determine whether the deleterious effects of increased fat metabolism are the same for males and females.Although women have a lower skeletal muscle mass than men, a review of the literature points to improved glucose tolerance and heightened skeletal muscle insulin sensitivity in normal women compared with men (11-13). Thus, Fernandez-Real et al. (14) have shown that premenopausal women are more insulin sensitive than men when the groups are matched for body fat, and Yki-Jarvinen (13) has shown enhanced insuli...

Resistance to high-fat diet in the female progeny of obese mice fed a control diet during the periconceptual, gestation, and lactation periods

“…Some studies have reported such differences to be specific to developmental time windows (28) or to specific traits, such as plasma glucose and adiponectin levels, blood pressure, endothelial function, and visceral and subcutaneous fat deposits (1,20,22). As previously suggested for rats (10,16,19,28), female sex hormones may protect against the development of insulin resistance and associated disorders. In our experiments, the differences in adaptive programming between the two sexes apply to glucose and insulin, but not to lipids.…”

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.…”

Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control

“…Human 1,2 as well as animal studies [3][4][5][6][7] demonstrate less severe obesity-related metabolic disorders including peripheral tissue insulin resistance and dyslipidemia (i.e., the components of metabolic syndrome), and/or later onset of these adverse phenotypes in female than in male subjects. However, mechanisms underlying a relatively low susceptibility of females to metabolic syndrome remain largely unknown.…”