Insulin resistance in skeletal muscle. With special reference to interstitial insulin and glycerol

Abstract

Insulin resistance is a central feature of type 2 diabetes and obesity and is associated with cardiovascular disease. In insulin-resistant muscle, the insulin-mediated glucose uptake is decreased.The delivery of insulin to the interstitial fluid of human skeletal muscle has previously not been investigated. The aim in this thesis was to determine the interstitial muscle insulin, glucose, and lactate concentrations in healthy subjects as well as in type 2 diabetes patients during stable hyperinsulinemia. Furthermore, the effect of insulin has a slow onset in insulin-resistant states and, therefore, the time kinetics of insulin delivery and action were investigated in obese subjects.Insulin resistance is also associated with enlarged triglyceride stores and increased lipid oxidation rates in skeletal muscle. The regulation of glycerol in the interstitial fluid of muscle was studied in healthy, obese, and type 2 diabetic subjects. The methods applied included muscle microdialysis for sampling of the interstitial fluid, the forearm technique for arterio-venous balance studies of metabolism, and the euglycemic hyperinsulinemic clamp to assess insulin sensitivity.Interstitial muscle insulin levels equaled half of the insulin concentration in plasma at steady-state hyperinsulinemia in both healthy and type 2 diabetic subjects. Insulin and glucose levels in the muscle interstitial fluid were similar in type 2 diabetes patients and their controls, but lactate in plasma and the muscle interstitial fluid was lower and the blood flow rate was decreased in these patients. In obese subjects, a delay in the delivery of interstitial insulin was demonstrated and a slow onset of the effect of insulin was confirmed. The muscle glycerol level was 2-3 times higher than plasma glycerol, while the arterio-venous glycerol concentration difference over the forearm was insignificant. The interstitial-arterial concentration difference of glycerol in muscle was not affected during insulin stimulation. In obese subjects, both interstitial and I-A concentration differences of glycerol were higher than in lean subjects, whereas type 2 diabetic subjects did not have significantly different interstitial glycerol or I-A glycerol levels than weight-matched controls. In conclusion, the capillary wall is rate limiting for insulin transport at high plasma insulin levels. It is suggested that cellular defects, rather than an insufficient delivery of insulin and glucose to the muscle interstitial fluid, are responsible for the insulin resistance in type 2 diabetes at steady-state hyperinsulinemia.The delay in insulin delivery and effect of insulin, shown in obese subjects, may contribute to insulin resistance in muscle. It is hypothesized that the decreased lactate production rates in response to insulin may contribute to the decreased blood flow rate and slow rate of insulin delivery in insulin-resistant muscle. Muscle glycerol appears to be a poor marker for muscle lipolysis since local uptake of glycerol occurs. Insulin does not seem to regulate muscle glycerol. Obesity has more impact on the interstitial muscle glycerol than the type 2 diabetes state per se.