Elevated plasma cell membrane glycoprotein levels and diminished insulin receptor autophosphorylation in obese, insulin-resistant rhesus monkeys.
In obese humans, insulin resistance is accompanied by elevated levels of plasma cell membrane glycoprotein (PC-1) and decreased insulin receptor (IR) tyrosine kinase activity in skeletal muscle. PC-1 overexpression inhibits IR tyrosine kinase and possibly other downstream signaling events. The rhesus monkey in captivity is susceptible to obesity with concomitant insulin resistance. In the present study we analyzed obese (n = 10, 29.4% +/- 1.2% body fat) and non-obese (n = 12, 19.4% +/- 1.9% body fat) rhesus monkeys. Glucose clearance during an euglycemic hyperinsulinemic (400 mU/m(2) body surface area/min) clamp was lower for the obese group (non-obese, 9.7 +/- 0.9; obese, 3.2 +/- 0.7 mg/kg fat-free mass [FFM]/min; P <.01). We performed vastus lateralis muscle biopsies prior to and during the clamp. We measured PC-1 levels in these muscle samples to determine whether PC-1 content is elevated in this primate model of insulin resistance. PC-1 levels were determined by assay of phosphodiesterase activity and specific PC-1 enzyme-linked immunosorbent assay (ELISA). In the obese group, both PC-1 content and activity were 2-fold higher than in the non-obese group (P <.05). In order to investigate the ability of insulin to stimulate IR signaling in vivo in these 2 groups of monkeys, we then measured tyrosine autophosphorylation of the IR by specific ELISA. The increase in IR autophosphorylation in the non-obese group was twice that of the obese group (fold increase over basal: non-obese, 3.7 +/- 0.3; obese, 1.9 +/- 0.6; P <.05). We conclude that insulin resistance secondary to obesity in rhesus monkeys is associated with increased levels of PC-1 and decreased IR signaling capacity in skeletal muscle.
Pender
Celia
C
Diabetes and Obesity Research Center, School of Medicine, Department of Physiology, University of Maryland at Baltimore, Baltimore, MD, USA.
Ortmeyer
Heidi K
HK
Hansen
Barbara C
BC
Goldfine
Ira D
ID
Youngren
Jack F
JF
D000273:Adipose Tissue / Q000033:anatomy & histology; D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D005215:Fasting; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000097:blood*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011755:Pyrophosphatases; D011972:Receptor, Insulin / Q000378:metabolism*; D012016:Reference Values
D001786:Blood Glucose; D007328:Insulin; D008562:Membrane Glycoproteins; D011972:Receptor, Insulin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases