title: Paradoxical phosphorylation of skeletal muscle glycogen synthase by in vivo insulin in very lean young adult rhesus monkeys.
abstract: Calorie restriction (CR) has previously been shown to unexpectedly induce a reversal of in vivo insulin action (phosphorylation instead of dephosphorylation) on skeletal muscle glycogen synthase (GS) in four out of six long-term calorie-restricted (CR) monkeys. The purpose of the present study was to determine whether this increase in Ka (concentration of glucose 6-phosphate [G6P] at which GS activity is half-maximal) during insulin is also present in very lean (VL) young adult monkeys maintained on a controlled feeding regimen. Muscle samples from 10 VL monkeys (10 +/- 2% body fat; 7 years old) were obtained before and during a euglycemic hyperinsulinemic clamp and the Ka was determined and compared to the Ka of two other groups of monkeys, one matched in age but fully ad libitum (AL)-fed (n = 9.8 +/- 1 years old, 20 +/- 3% body fat, p = 0.01 vs. VL monkeys), and the other our previously described weight-clamped long-term CR monkeys (n = 6.20 +/- 1 years old, 21 +/- 2% body fat, p = 0.01 vs. VL monkeys). All of the AL monkeys had the expected decrease in Ka with insulin; however, similar to the 4 out of 6 CR monkeys, 7 out of 10 VL monkeys had an increase in Ka with insulin. The 11 monkeys with an increase in Ka (+Ka) (7 VL + 4 CR) were compared to the 14 monkeys with a decrease in Ka with insulin (-Ka) (3 VL + 2 CR + 9 AL). The +Ka monkeys had lower basal Ka (p = 0.0001), higher basal GS fractional activity (p = 0.0003), lower basal G6P content (p = 0.002), lower glycogen phosphorylase fractional activity (p = 0.01), and lower whole-body insulin-mediated glucose disposal rate (p < 0.05) than the -Ka monkeys. We conclude that the condition of steady-state restrained calorie intake (as in the CR monkeys and in the controlled feeding VL monkeys) produces the paradoxical action of in vivo insulin to phosphorylate muscle GS, and raises the possibility that the presence of the unusual response to insulin may serve as a marker in calorie-restrained individuals for the genotype of obesity, insulin resistance and/or Type 2 diabetes.
authors.affiliation: Department of Physiology, School of Medicine, University of Maryland, Baltimore 21201, USA. hortmeye@umaryland.edu
authors.forename: H K
authors.initials: HK
authors.lastname: Ortmeyer
authors.forename: N L
authors.initials: NL
authors.lastname: Bodkin
authors.forename: B C
authors.initials: BC
authors.lastname: Hansen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D002149:Energy Intake; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D008253:Macaca mulatta; D018482:Muscle, Skeletal / Q000201:enzymology*; D006005:Phosphorylases / Q000378:metabolism; D010766:Phosphorylation; D013851:Thinness / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D019298:Glucose-6-Phosphate; D006005:Phosphorylases; D006006:Glycogen Synthase