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The Intracellular Mechanism of Insulin Resistance in Pancreatic Cancer Patients¹

Department of Biomedical Sciences, Creighton University School of Medicine (J.Li., J.A.K., T.E.A.), Omaha, Nebraska 68178; and Department of Surgery, Karolinska Institute at the Huddinge Hospital (L.S., J.P., J.La.), Stockholm S14186, Sweden

Address correspondence and requests for reprints to: Thomas E. Adrian, Ph.D., F.R.C.Path., Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68178. E-mail: tadrian{at}creighton.edu

The diabetes that frequently occurs in pancreatic cancer patients is characterized by profound peripheral insulin resistance. The intracellular mechanism of this insulin resistance was investigated in skeletal muscle biopsies from pancreatic cancer patients with or without diabetes and control subjects.

Insulin receptor (IR) binding, tyrosine kinase activity, IR messenger RNA (mRNA), IR substrate-1 content, GLUT-4, and GLUT-4 mRNA content were all normal in pancreatic cancer patients. In contrast, multiple defects in glycogen synthesis were found in pancreatic cancer patients, especially in those with diabetes. Glycogen synthase I activity, total activity, and mRNA levels were significantly decreased in pancreatic cancer patients compared with controls. The fractional velocity of glycogen synthase was decreased only in the diabetic pancreatic cancer group. Glycogen phosphorylase a and b activities were increased in diabetic pancreatic cancer patients, but glycogen phosphorylase mRNA levels were not significantly different. The insulin resistance associated with pancreatic cancer is associated with a post-IR defect, which impairs skeletal muscle glycogen synthesis and glycogen storage.

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