Insulin-like Growth Factor (IGF-I) Induced Muscle Glucose Uptake and Interstitial IGF-1 Concentrations.

Background:

In healthy subjects, the liver extracts approximately 50 % of insulin. Therefore insulin given subcutaneously results in a relative insulin deficiency in the portal circulation of the liver, and a relative insulin excess in peripheral tissues. In comparison, normal physiological delivery of insulin from the pancreas to the portal circulation, results in markedly higher hepatic insulin exposure. The importance of hepatic insulin exposure for GH induced IGF-I synthesis comes from studies demonstrating that circulating IGF-I levels can be normalized by direct portal insulin infusion (1) or nearly normalized with intra-peritoneal insulin delivery (2). Approximately 80 % of circulating IGF-I is liver derived. Whether the GH induction of IGF-I production in other tissues such as fat, muscle and the growth plate is also insulin dependent has not been studied in humans. While locally produced IGF-I is important for linear growth, circulating IGF-I is essential for insulin sensitivity (3). Portal insulin deficiency results in uncoupling of GH induced IGF-I synthesis and subnormal circulating IGF-I levels in T1DM children with conventional therapy (4).

In newly diagnosed T1DM subcutaneous insulin treatment increases circulating IGF-I (5). The beneficial effects of 12 weeks adjuvant IGF-I treatment on metabolic control was demonstrated in conventionally insulin treated T1DM adolescents (6). There is also strong evidence for the role of IGF-I in the pathogenesis of diabetic kidney disease, atherosclerosis and proliferative retinopathy (7, 8, 9).

Interestingly, recent reports suggest an important role of IGF-I in stimulating beta cell regeneration (10). Thus a role for improvement of IGF-I in prolonging endogenous insulin secretion in the early phase of T1DM disease appears promising.

The Investigators have previously developed a microdialysis approach to measure local IGF-I protein levels from the human muscle tissue. The Investigators were in that study able to show that exercise increases local IGF-I levels. (11, 12) However, no further analysis concerning tissue-specific glucose metabolism was performed.