The intracellular mechanism of insulin resistance in pancreatic cancer patients.
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.
Liu
J
J
Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Knezetic
J A
JA
Strömmer
L
L
Permert
J
J
Larsson
J
J
Adrian
T E
TE
D015153:Blotting, Western; D003920:Diabetes Mellitus / Q000378:metabolism; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006005:Phosphorylases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins
D005656:Fungal Proteins; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; C065725:IRA1 protein, S cerevisiae; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C495692:SLC2A4 protein, human; D029701:Saccharomyces cerevisiae Proteins; D006005:Phosphorylases; D006006:Glycogen Synthase; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin