Age, Obesity, and Sex Effects on Insulin Sensitivity and Skeletal Muscle Mitochondrial Function

OBJECTIVE

Reductions in insulin sensitivity in conjunction with muscle mitochondrial dysfunction have been reported to occur in many conditions including aging. The objective was to determine whether insulin resistance and mitochondrial dysfunction are directly related to chronological age or are related to age-related changes in body composition.

RESEARCH DESIGN AND METHODS

Twelve young lean, 12 young obese, 12 elderly lean, and 12 elderly obese sedentary adults were studied. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial ATP production rates (MAPRs) were measured in freshly isolated mitochondria obtained from vastus lateralis biopsy samples using the luciferase reaction.

RESULTS

Obese participants, independent of age, had reduced insulin sensitivity based on lower rates of glucose infusion during a hyperinsulinemic-euglycemic clamp. In contrast, age had no independent effect on insulin sensitivity. However, the elderly participants had lower muscle MAPRs than the young participants, independent of obesity. Elderly participants also had higher levels inflammatory cytokines and total adiponectin. In addition, higher muscle MAPRs were also noted in men than in women, whereas glucose infusion rates were higher in women.

CONCLUSIONS

The results demonstrate that age-related reductions in insulin sensitivity are likely due to an age-related increase in adiposity rather than a consequence of advanced chronological age. The results also indicate that an age-related decrease in muscle mitochondrial function is neither related to adiposity nor insulin sensitivity. Of interest, a higher mitochondrial ATP production capacity was noted in the men, whereas the women were more insulin sensitive, demonstrating further dissociation between insulin sensitivity and muscle mitochondrial function.As the population ages, the prevalence of several chronic health problems such as obesity, type 2 diabetes, and cardiovascular disease has risen. Insulin resistance is recognized as a key factor contributing to the development of both type 2 diabetes and its related cardiometabolic disorders (1,2). Insulin resistance and impaired glucose tolerance are commonly observed phenomena among elderly adults. For example, the glucose excursion postprandially is substantially greater and remains elevated longer in nondiabetic elderly adults than in nondiabetic younger adults, which is indicative of age-related declines in insulin sensitivity and glucose tolerance (3). Aging is associated with detrimental changes in body composition, which persists even when elderly adults are matched to younger adults for BMI (4). Adiposity, in particular abdominal adiposity, is well accepted as a determinant of insulin resistance and therefore may be a key mediator for the development of age-related insulin resistance. Despite an inverse relationship between age and insulin sensitivity (4,5), it remains contentious whether chronological age is a primary determinant of insulin resistance or whether age-related elevations in adiposity and/or physical inactivity are the primary causes of age-related insulin resistance (6,7).Aging is also associated with reductions in skeletal muscle mitochondrial function. In particular, skeletal muscle mitochondrial ATP production rates (MAPRs) in elderly people are reduced in vivo in the resting state (8) as well as in vitro in the maximally stimulated state (3). These age-related reductions in MAPRs have also been associated with concomitant reductions in skeletal muscle mitochondrial enzyme activities (9), protein synthesis and expression (3,10), and mtDNA abundance in humans (3,11) and rodents (12). Of interest, insulin resistance is closely associated with skeletal muscle mitochondrial dysfunction in some (3,5,13,14) but not in all conditions (15,16). This close association between muscle mitochondrial dysfunction and insulin resistance has led to the hypothesis that mitochondrial dysfunction could be the basis of insulin resistance (5). Another equally plausible hypothesis is that insulin resistance causes muscle mitochondrial dysfunction (16,17). In support of the later hypothesis is the demonstration that, in type 2 diabetic people, muscle MAPR fails to increase in response to physiologically high insulin levels, unlike in nondiabetic people (18). However, it should be recognized that the association between insulin resistance and mitochondrial dysfunction are not consistent. For example, we recently reported that Asian Indians in comparison with Northern European Americans matched for age, sex, and BMI are severely insulin resistant, while having higher muscle MAPR and mitochondrial DNA copy numbers (19). Furthermore, a recent report also indicated that while a low-calorie diet substantially enhanced insulin sensitivity (e.g., ∼30% increase in insulin-stimulated glucose disposal), it failed to increase skeletal muscle mitochondrial function in the absence of exercise (19). In contrast, in rats, a high-fat diet caused insulin resistance while enhancing mitochondrial biogenesis (15). Together, the results from the above studies indicate that the close association between insulin sensitivity and muscle mitochondrial function can be uncoupled, arguing against the hypothesis that insulin resistance causes muscle mitochondrial dysfunction or vice versa.Age is not only associated with insulin resistance and muscle mitochondrial dysfunction but is also associated with changes in body composition, which likely contribute to the development of age-related insulin resistance (20). We therefore sought to determine whether the changes in insulin sensitivity and muscle mitochondrial function are secondary to age-related changes in body composition rather than being directly related to chronological age. We studied 48 lean and obese, young and elderly men and women. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp and skeletal muscle mitochondrial function by measuring MAPRs from freshly prepared mitochondria obtained from muscle biopsy samples. The studies demonstrated the impact of not only age and body weight, but also sex on insulin sensitivity and muscle mitochondrial function in humans.