Dysregulation of the insulin/IGF binding protein-1 axis in transgenic mice is associated with hyperinsulinemia and glucose intolerance.
The insulin/IGF binding protein-1 (IGFBP-1) axis is important in coordinating insulin- and IGF-mediated regulation of glucose metabolism and glycemia. Dysregulation of the axis may play a role in the pathophysiology of disorders of insulin deficiency and resistance. We have investigated this hypothesis by generating transgenic mice that overexpress hIGFBP-1. To study the axis in its true physiological context, we used a human (h) IGFBP-1 cosmid clone so that transgene expression is responsive to normal hormonal stimuli. hIGFBP-1 mRNA is expressed in a tissue-specific fashion, and measurement of serum protein levels by specific immunoassay indicates normal physiological regulation in response to fasting/feeding and appropriate post-translational modification as indicated by the detection of phosphorylated and nonphosphorylated isoforms of the protein. The hypoglycemic response to exogenous IGF-I is attenuated in transgenic mice. Transgenic mice exhibit an enhanced insulin secretory response to a glucose challenge, although basal and stimulated blood glucose levels are similar to controls. There is a sexual dimorphism in phenotypic expression: male transgenic mice had higher stimulated glucose and insulin levels than did females. Transgenic mice exhibit fasting hyperglycemia and hyperinsulinemia and glucose intolerance in later life, indicating an age-related decline in glucocompetence. These findings demonstrate the importance of the normal inverse relationship between serum insulin and IGFBP-1 levels in glucoregulation and that sustained dysregulation of the insulin/IGF-I/IGFBP-1 axis is associated with impaired glucose tolerance and abnormalities of insulin action.
Crossey
P A
PA
Department of Diabetes, Endocrinology and Internal Medicine, Guy's, King's and St Thomas' School of Medicine, London, UK. paul.crossey@kcl.ac.uk
Jones
J S
JS
Miell
J P
JP
D000375:Aging / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000503:physiopathology*; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology*; D007328:Insulin / Q000097:blood / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012727:Sex Characteristics
D001786:Blood Glucose; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I