BACKGROUND-Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown.

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes in the elderly. To investigate how insulin resistance arises, we studied healthy, lean, elderly and young participants matched for lean body mass and fat mass. Elderly study participants were markedly insulinresistant as compared with young controls, and this resistance was attributable to reduced insulinstimulated muscle glucose metabolism. These changes were associated with increased fat accumulation in muscle and liver tissue assessed by 1 H nuclear magnetic resonance (NMR) spectroscopy, and with a ∼40% reduction in mitochondrial oxidative and phosphorylation activity, as assessed by in vivo 13 C/ 31 P NMR spectroscopy. These data support the hypothesis that an ageassociated decline in mitochondrial function contributes to insulin resistance in the elderly.Type 2 diabetes is the most common chronic metabolic disease in the elderly, affecting ∼30 million individuals 65 years of age or older in developed countries (1). The estimated economic burden of diabetes in the United States is ∼$100 billion per year, of which a substantial proportion can be attributed to persons with type 2 diabetes in the elderly age group (2). Epidemiological studies have shown that the transition from the normal state to overt type 2 diabetes in aging is typically characterized by a deterioration in glucose * To whom correspondence should be addressed. gerald.shulman@yale.edu. [11][12][13]. Increases in the intracellular concentration of fatty acid metabolites have been postulated to activate a serine kinase cascade leading to defects in insulin signaling in muscle (14-17) and the liver (18), which results in reduced insulinstimulated muscle glucose transport activity (14), reduced glycogen synthesis in muscle (19,20), and impaired suppression of glucose production by insulin in the liver (11-13).To examine whether insulin resistance in the elderly is associated with similar increases in intramyocellular and/or liver triglyceride content, we studied healthy elderly and young people that we matched for lean body mass (LBM) and fat mass. All study participants were non-smoking, sedentary, lean [body mass index (BMI) < 25 m 2 /kg], and taking no medications. Sixteen elderly volunteers (ages 61 to 84 years, 8 male and 8 female) were screened with a 3-hour oral glucose (75 g) tolerance test and underwent dual-energy x-ray absorptiometry to assess LBM and fat mass (21). One elderly man was excluded from the study because of an abnormal glucose profile. Thirteen young volunteers (ages 18 to 39 years, 6 male and 7 female), who had no family history of diabetes or hypertension, were matched to the older participants for BMI and habitual physical activity, which was assessed by means of an activity index questionnaire (22). All participants underwent a complete medical history and physical examination, as well as blood tests to confirm that they were in excellent health (23).Young and elderly participants had similar fat mass, percent fat mass, and LBM (Table 1...

To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13 C and 31 P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 Ϯ 0.02 mM [mean Ϯ SEM]; control) or high (1.93 Ϯ 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic ( ‫ف‬ 5.2 mM) hyperinsulinemic ( ‫ف‬ 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be ‫ف‬ 46% of control values after 6 h ( P Ͻ 0.00001). Augmented lipid oxidation was accompanied by a ‫ف‬ 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion ( P Ͻ 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to ‫ف‬ 50% of control values (4.0 Ϯ 1.0 vs. 9.3 Ϯ 1.6 mol/[kg и min], P Ͻ 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at ‫ف‬ 1.5 h (195 Ϯ 25 vs. control: 237 Ϯ 26 M; P Ͻ 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an ‫ف‬ 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation. ( J. Clin. Invest. 1996. 97:2859-2865.) Key words: free fatty acids • muscle glycogen • glucose transport • nuclear magnetic resonance spectroscopy • glucose-6-phosphate

Increased plasma free fatty acid (FFA) concentrations are typically associated with many insulin-resistant states including obesity and type 2 diabetes mellitus (1-3). Furthermore, raising plasma FFA levels in healthy humans, by triglyceride/heparin infusions, can also acutely induce insulin resistance (4-11). Over thirty years ago, Randle et al. (12,13) demonstrated that FFAs compete with glucose for oxidation in isolated rat heart and diaphragmatic muscle preparations, and they speculated that increased fat oxidation may cause the insulin resistance associated with diabetes and obesity. They proposed that increased FFA oxidation leads to an increase in the intramitochondrial acetyl-coenzyme A (acetyl-CoA) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD + ) ratios, resulting in inactivation of pyruvate dehydrogenase activity. The consequent increase in intracellular citrate concentration causes inhibition of phosphofructokinase resulting in an increase in glucose-6-phosphate levels. The elevated glucose-6-phosphate levels would inhibit hexokinase II activity and then lead to decreased glucose uptake. However, recent studies by our group (14) and others (15,16) have called this mechanism into question. Boden and coworkers have shown that a reduction in carbohydrate oxidation was responsible for only one-third of the fatty acid-dependent decrease in glucose uptake, while impaired non-oxidative glucose metabolism accounted for the remainder (16). These workers suggested that two different defects might contribute to the impairment in nonoxidative glucose metabolism. At FFA concentrations of ∼0.75 mM, they found an increase in glucose-6-phosphate concentrations in muscle biopsies, suggesting an inhibitory effect of FFA on glycogen synthase activity, whereas at lower FFA concentrations (∼0.50 mM) they observed no difference in intramuscular glucose-6-phosphate concentration. In contrast, using carbon-13/phosphorous-31 nuclear magnetic resonance (NMR) spectroscopy under increased plasma FFA concentrations (∼1.8 mM), we observed a decrease in intramuscular glucose-6-phosphate concentration associated with a 50% reduction in insulin-stimulated muscle glycogen synthesis (14). These data suggest that acute elevations in plasma FFA levels in humans cause insulin resistance by initial inhibition of glucose transport and/or phosphorylation activity that is concurrently followed by a reduction in the rate of both muscle glycogen synthesis and glucose oxidation. Because glucose-6-phosphate (and not intracellular glucose) concentration was measured, it was not possible to distinguish between To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. I...

Insulin resistance has long been associated with obesity. More than 40 years ago, Randle and colleagues postulated that lipids impaired insulin-stimulated glucose use by muscles through inhibition of glycolysis at key points. However, work over the past two decades has shown that lipid-induced insulin resistance in skeletal muscle stems from defects in insulin-stimulated glucose transport activity. The steatotic liver is also resistant to insulin in terms of inhibition of hepatic glucose production and stimulation of glycogen synthesis. In muscle and liver, the intracellular accumulation of lipids-namely, diacylglycerol-triggers activation of novel protein kinases C with subsequent impairments in insulin signalling. This unifying hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, lipodystrophy, and ageing; and the insulin-sensitising effects of thiazolidinediones.