Skeletal Muscle Protein Anabolic Response to Increased Energy and Insulin Is Preserved in Poorly Controlled Type 2 Diabetes

Individuals with type 2 diabetes (T2DM)4 are characterized by hyperinsulinemia and insulin resistance leading to fasting and postprandial hyperglycemia and abnormal fatty acid metabolism (1,2). In addition, T2DM is associated with metabolic abnormalities in glucose utilization, including impaired glucose tolerance and insulin resistance (3,4) that might also extend to muscle protein metabolism if insulin signaling is compromised (5). Although insulin is a potent stimulator of skeletal muscle protein anabolism, the specific mechanism by which insulin exerts its effects in human skeletal muscle is controversial. For example, several studies have reported insulin to have an inhibitory effect on muscle protein breakdown (6–10), whereas others have shown insulin to have a direct stimulatory effect on muscle protein synthesis (11–14). The importance of insulin in regulating muscle protein turnover is highlighted by the estimated contribution of skeletal muscle (30–50%) to whole body protein breakdown (6,15). Furthermore, muscle protein turnover is an energy-requiring process, and several studies have shown that when additional energy is supplied in the form of either glucose or lipids, the rate of protein breakdown is also subsequently reduced (16–20). However, the interaction between an increase in insulin and nutritional energy on muscle protein turnover in T2DM has not been well described. Few studies have addressed skeletal muscle amino acid kinetics in T2DM. Most have reported that whole body protein turnover in insulin resistant obese individuals and individuals with T2DM is not impaired (21–25). However, it has also been shown that whole-body proteolysis is significantly elevated in obesity and T2DM (26,27). There have been even fewer studies that have looked at the effect of T2DM on protein utilization in human skeletal muscle. Using an arteriovenous two-pool model to calculate labeled phenylalanine kinetics across the leg, one study found that, even though whole body proteolysis was elevated in T2DM, the rate of phenylalanine release across the leg (an index of leg muscle proteolysis) was reduced (15). In addition, a recent study reports no differences in muscle fractional synthetic rates between the T2DM group and healthy controls (24). The traditional arteriovenous two-pool model, which is often used to calculate amino acid kinetics across the leg, actually measures the net kinetics of plasma amino acids across the leg while not offering any insight into the intracellular amino acid kinetics. Therefore, it remains unclear whether differences in muscle intracellular amino acid kinetics are present in the insulin resistant state of T2DM. The first aim of this study was to determine if poorly controlled T2DM (i.e., hemoglobin A1c > 7%) affects postabsorptive muscle protein anabolism. Our second aim was to determine if hyperinsulinemia, in combination with high nutritional energy availability, stimulates muscle protein anabolism to the same extent as healthy controls. To address our aims we studied whole body and regional phenylalanine kinetics following an overnight fast and during a hyperinsulinemic-isoenergetic nutritional energy clamp in controls and in subjects with poorly controlled T2DM.