The regulation of muscle interstitial insulin, nutrients and blood flow in insulin resistant models. An investigation using the euglycemic insulin clamp and microdialysis techniques

Abstract

Insulin resistance, mainly located to the skeletal muscle tissue, is one prominent feature in thedevelopment of non insulin-dependent diabetes mellitus (NIDDM) and further, associated withcardiovascular diseases. In this context the importance of blood flow for insulin sensitivity has beensuggested by regulating the delivery of insulin and nutrients to the target cells. By the presence ofsignificant arterial-interstitial concentration differences, the endothelial barrier has been shown to playan integrative role in the trans-capillary transport of insulin and the distribution of nutrients betweenthe compartments of plasma and interstitial fluid. To further explore the interaction of blood flow,insulin sensitivity and glucose and lactate metabolism in muscle we utilized the euglycemichyperinsulinemic clamp method in combination with the microdialysis technique. Three differentmodels of insulin resistance in the rat (induced by glucosamine, epinephrine or oophorectomy +testosterone treatment) and one group of NIDDM subjects (during forearm ischemia) were studied.In the rat, glucosamine infusion induced a significant reduction of the glucose infusion rate (GIR)compared to controls during clamp whereas neither plasma, nor interstitial muscle insulin or glucoseconcentrations were changed. Plasma lactate concentration was significantly reduced, as was theinterstitial lactate concentration. Muscle blood flow was reduced by 24 %. ß-adrenergic stimulation byepinephrine infusion caused a marked inhibition of GIR during clamp whereas plasma insulin, but notinterstitial muscle insulin, concentration was significantly increased. During epinephrine-infusioninterstitial muscle glucose and lactate concentrations, as well as blood flow, were significantlyelevated. All the effects induced by epinephrine were totally abolished by the ß-adrenergic blockerpropranolol. Rats treated with oophorectomy (OVX) + testosterone (T) showed a significantly delayedonset of glucose uptake at start of clamp compared to controls. In addition, OVX+T treated ratsdemonstrated a significantly slower raise in interstitial muscle insulin concentration after start ofclamp, whereas plasma insulin concentration changed normally. Peripheral blood flow wassignificantly decreased, as was the insulin binding to the vascular surface area after OVX+T treatment.Physical exercise totally normalized the time before onset of insulin action, although no effects on thedistribution of insulin between the compartments of plasma and interstitial fluid could be detected.In human muscle during ischemia, applied by stopping the blood flow, the interstitial glucoseconcentrations decreased and the interstitial lactate increased significantly compared to basal in bothNIDDM subjects and in controls. The arterial-interstitial (a-i) muscle glucose and lactate concentrationdifferences were significantly enhanced in both groups during ischemia. The a-i glucose concentrationdifference was even significantly higher in the NIDDM group compared to controls during ischemia.The data confirm the existence of arterial-interstitial concentration differences of glucose (positive)and lactate (negative) in muscle. However, in the different models of insulin resistance explored,interstitial glucose concentration was not further decreased even when blood flow was diminished.This may indicate that the insulin resistance in the muscle cell, in these models, decreases theelimination rate of glucose to an extent where the delivery rate of plasma insulin and glucose is notrate-limiting for glucose metabolism. However, muscle blood flow and vasodilation seem to be ofimportance for the time of onset of insulin action. Interestingly, data suggest that blood flow may bedependent on the insulin effect on the muscle cells and regulated by non-oxidative metabolism. Theresults obtained under ischemia further emphasize the importance of the putative non insulin-dependentpathway for activation of glucose transport in NIDDM subjects.