Hepatic overexpression of insulin-like growth factor-II in adulthood increases basal and insulin-stimulated glucose disposal in conscious mice.
The physiological role of circulating insulin-like growth factor-II (IGF-II) in adult humans is poorly understood. We recently generated an IGF-II transgenic murine model of persistent IGF-II production (plasma IGF-II approximately 30-fold increased above normal) through over-expression of the transgene driven by the major urinary protein promoter (Rinderknecht, E., and Humbel, R. E. (1978) J. Biol. Chem. 269, 13779-13784). To determine whether in vivo insulin action is improved in these transgenic mice, we performed euglycemic insulin (18 milliunits/kg.min) clamp studies in conscious IGF-II transgenic and in age- and weight-matched control mice. Plasma glucose and insulin concentrations were significantly lower in the IGF-II transgenic compared with both control grouoff Despite decreased plasma glucose concentration, basal hepatic glucose production (HGP) and glucose clearance were increased. During the insulin clamp studies in IGF-II transgenic mice compared with control mice (a) the rates of glucose infusion and glucose uptake were increased by approximately by 65 and approximately 55%, respectively; (b) glycolysis was increased by approximately 12% while glycogen synthesis was approximately 2-fold higher; (c) while the suppression of plasma free fatty acid was similar, the increment in plasma lactate concentration was significantly higher; (d) although HGP was similarly inhibited by insulin, phosphoenolpyruvate gluconeogenesis was enhanced and accounted for a larger portion of HGP (64% versus approximately 40% in control mice). Our data suggest that the persistence of circulating IGF-II in adult mice to levels commonly observed in adult humans (50-70 nM) causes a marked improvement in peripheral (skeletal muscle) insulin action, which is not due to changes in body composition. These results suggest that circulating IGF-II may exert a regulatory role on insulin sensitivity and body composition in humans.
Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
L
L
Rossetti
N
N
Barzilai
W
W
Chen
T
T
Harris
D
D
Yang
C E
CE
Rogler
D000328:Adult; D000818:Animals; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D014316:Tritium
D007328:Insulin; D014316:Tritium; D007335:Insulin-Like Growth Factor II; D006003:Glycogen; D006006:Glycogen Synthase; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose