Palmitate action to inhibit glycogen synthase and stimulate protein phosphatase 2A increases with risk factors for type 2 diabetes.
Recent studies have suggested that abnormal regulation of protein phosphatase 2A (PP2A) is associated with Type 2 diabetes in rodent and human tissues. Results with cultured mouse myotubes support a mechanism for palmitate activation of PP2A, leading to activation of glycogen synthase kinase 3. Phosphorylation and inactivation of glycogen synthase by glycogen synthase kinase 3 could be the mechanism for long-chain fatty acid inhibition of insulin-mediated carbohydrate storage in insulin-resistant subjects. Here, we test the effects of palmitic acid on cultured muscle glycogen synthase and PP2A activities. Palmitate inhibition of glycogen synthase fractional activity is increased in subjects with high body mass index compared with subjects with lower body mass index (r = -0.43, P = 0.03). Palmitate action on PP2A varies from inhibition in subjects with decreased 2-h plasma glucose concentration to activation in subjects with increased 2-h plasma glucose concentration (r = 0.45, P < 0.03) during oral glucose tolerance tests. The results do not show an association between palmitate effects on PP2A and glycogen synthase fractional activity. We conclude that subjects at risk for Type 2 diabetes have intrinsic differences in palmitate regulation of at least two enzymes (PP2A and glycogen synthase), contributing to abnormal insulin regulation of glucose metabolism.
Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases/NIH, 4212 N 16th Street, Phoenix, AZ 85016, USA. dmott@mail.nih.gov
David M
DM
Mott
Karen
K
Stone
Mary C
MC
Gessel
Joy C
JC
Bunt
Clifton
C
Bogardus
D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005951:Glucose Tolerance Test; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors*; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D032446:Myoblasts / Q000187:drug effects; D019308:Palmitic Acid / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D012307:Risk Factors
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D019308:Palmitic Acid; D006006:Glycogen Synthase; D054648:Protein Phosphatase 2