Studies on the Mechanism of Insulin Resistance in the Liver from Humans with Noninsulin-dependent Diabetes Insulin Action and Binding in Isolated Hepatocytes, Insulin Receptor Structure, and Kinase Activity

We have developed a method to isolate insulin-responsive human hepatocytes from an intraoperative liver biopsy to study insulin action and resistance in man. Hepatocytes from obese patients with noninsulin-dependent diabetes were resistant to maximal insulin concentration, and those from obese controls to submax-imal insulin concentration in comparison to nonobese controls. Insulin binding per cell number was similar in all groups. How-ever, insulin binding per surface area was decreased in the two obese groups because their hepatocytes were larger. In addition, the pool of detergent-extractable receptor was further decreased in diabetics. Insulin receptors in all groups were unaltered as determined by affinity-labeling methods. However, insulin-stim-ulated insulin receptor kinase activity was decreased in diabetics. Thus, in obesity, decreased surface binding could explain re-sistance to submaximal insulin concentrations. In diabetes, di-minished insulin-stimulated protein kinase activity and decreased intracellular pool of receptors could provide an explanation for postinsulin-binding defect(s) of insulin action in human liver