Dysregulation of the insulin/IGF binding protein-1 axis in transgenic mice is associated with hyperinsulinemia and glucose intolerance.

Abstract

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. Tr a n s g e n i c 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. D i a b e t e s 4 9 :4 5 7-465, 2000

Preserved Glucoregulation but Attenuation of the Vascular Actions of Insulin in Mice Heterozygous for Knockout of the Insulin Receptor

“…Metabolic assessment. Intraperitoneal glucose and insulin tolerance tests were performed in conscious, fasted animals (18). Blood glucose was measured at 30-min intervals following intraperitoneal glucose (1 mg/g body wt) or insulin injection (0.75 units/kg; Actrapid, Novo Nordisk, Bagsvaerd, Denmark) using a glucometer (Hemocue, Sheffield, U.K.).…”

Increases in Free, Unbound Insulin-like Growth Factor I Enhance Insulin Responsiveness in Human Hepatoma G2 Cells in Culture

“…Administration of IGF-I to patients with type I or type II diabetes results in increased free IGF-I levels and improvement in insulin sensitivity (13,14). Conversely, administration of excess IGFBP-1 to normal rats results in an increase in blood glucose levels (15), and IGFBP-1 transgenic mice that overexpress rat IGFBP-1 show glucose intolerance (16,17). Thus, the concentration of IGF-I that has unrestricted access to receptors appears to be a determinant of glucose metabolism, and in diabetes the plasma insulin levels partially regulate free IGF-I by control of IGFBP-1 concentrations.…”

Serum concentrations of insulin-like growth factor-I, insulin-like growth factor binding protein-3 and cardiovascular risk factors in adolescents

“…For instance, IGFBP-1, the acute regulator of IGF-I bioavailability, is associated with insulin resistance and glucose intolerance in an animal model. 23 IGFBP-2, the second most abundant circulating IGFBP and the principal binding protein secreted by differentiating white preadipocytes during adipogenesis, is shown to protect against insulin resistance and the development of obesity in transgenic mice. 42 However, of the six IGFBPs, IGFBP-3 carries more than 80% of circulating IGF-I and thus the measurement of IGFBP-3 is of primary importance in assessing the biological effects of IGF-I.…”