Insulin decreases skeletal muscle cAMP-dependent protein kinase (PKA) activity in normal monkeys and increases PKA activity in insulin-resistant rhesus monkeys.
Insulin activation of skeletal muscle glycogen synthase and glucose disposal is defective in both prediabetic and diabetic primates. Reduction in the activation of glycogen synthase by insulin could be the cause of lower glucose disposal rates, and could be the result, at least in part, of the failure of insulin to inhibit cAMP-dependent protein kinase activity (protein kinase A, PKA). To examine this proposed mechanism, PKA activity was measured in skeletal muscle (vastus lateralis) samples freeze-clamped in situ under basal fasting conditions before, and again during a euglycemic hyperinsulinemic clamp in 27 rhesus monkeys. Nine of the monkeys were normal (normal fasting glucose and insulin), eight were prediabetic (normal fasting glucose and hyperinsulinemia) and ten had spontaneous non-insulin-dependent diabetes (hyperglycemia). Insulin lowered PKA activity ratio in normal monkeys (basal vs insulin-stimulated, 14.4 +/- 3.2 vs 8.1 +/- 1.8%, p < 0.05), but raised PKA activity ratio in prediabetic monkeys (5.4 +/- 1.4 vs 10.5 +/- 2.6%, p < 0.05). PKA activity ratio was unaffected by insulin in the diabetic monkeys (6.7 +/- 1.8 vs 7.5 +/- 1.4%). Basal PKA activity ratio was higher in normal monkeys compared to prediabetic (p < 0.05) and diabetic monkeys (p < 0.05). Basal PKA activity ratio was inversely related to the insulin-stimulated change in PKA activity ratio (r = -0.72, p < 0.001). We conclude that in vivo insulin during euglycemic hyperinsulinemic clamp decreases skeletal muscle PKA activity ratio in normal monkeys but fails to decrease the activity ratio of PKA in insulin resistant (prediabetic and diabetic) monkeys. The insulin resistant state is characterized by low basal fasting skeletal muscle PKA activity ratio.
Ortmeyer
H K
HK
Department of Physiology, School of Medicine, University of Maryland at Baltimore 21201, USA.
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000201:enzymology*; D004789:Enzyme Activation; D005260:Female; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000201:enzymology* / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D008253:Macaca mulatta; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology*
D001786:Blood Glucose; D007328:Insulin; D017868:Cyclic AMP-Dependent Protein Kinases