The intracellular mechanism of insulin resistance in pancreatic cancer patients

The diabetes that frequently occurs in pancreatic cancer patients is charac terized by profound peripheral insulin resistance. The intracellular mechan ism of this insulin resistance was investigated in skeletal muscle biopsies from pancreatic cancer patients with or without diabetes and control subje cts. Insulin receptor (IR) binding, tyrosine kinase activity, IR messenger RNA ( mRNA), IR substrate-1 content, GLUT-4, and GLUT-4 mRNA content were all nor mal in pancreatic cancer patients. In contrast, multiple defects in glycoge n synthesis were found in pancreatic cancer patients, especially in those w ith diabetes. Glycogen synthase I activity, total activity, and mRNA levels were significantly decreased in pancreatic cancer patients compared with c ontrols. The fractional velocity of glycogen synthase was decreased only in the diabetic pancreatic cancer group, Glycogen phosphorylase a and b activ ities were increased in diabetic pancreatic cancer patients, but glycogen p hosphorylase mRNA levels were not significantly different. The insulin resi stance associated with pancreatic cancer is associated with a post-IR defec t, which impairs skeletal muscle glycogen synthesis and glycogen storage.