IGF-I/IGF-Binding Protein-3 Combination Improves Insulin Resistance By GH-Dependent and Independent Mechanisms

Abstract

IGF-I has been shown to enhance insulin sensitivity in patients with type I and type II diabetes. IGF-I suppresses GH, and this raises the question of whether its ability to enhance insulin sensitivity is mediated solely through a reduction in GH's antiinsulin actions. This study was conducted to determine whether administration of a GH receptor antagonist to patients with acromegaly and insulin resistance would result in improvement in insulin sensitivity and whether IGF-I had any additional insulin-sensitizing effects over and above those induced by its ability to suppress GH secretion. Five patients with active acromegaly were treated for 2 wk with a GH receptor antagonist. The GH receptor antagonist was effective, as IGF-I fell 65%, and mean GH values rose 42%. Mean fasting insulin fell from 39 +/- 6 to 30 +/- 7 micro U/ml, and this was accompanied by a 9% decrease in fasting glucose. After treatment the insulin sensitivity index was 2.7 +/- 1.0 x 10(-4)/min. micro U/ml compared with a baseline value of 1.65 +/- 0.8 x 10(-4)/min. micro U/ml (P < 0.015). Subsequently, the subjects were treated with the receptor antagonist plus IGF-I/IGF-binding protein-3 given by sc injection (1 mg/kg daily). After 2 wk of the combined treatment, fasting insulin fell from 49 +/- 9 to 29 +/- 7 micro U/ml, and fasting glucose fell by 14%. The insulin sensitivity index improved to 4.34 +/- 1.3 x 10(-4)/min. micro U/ml, which was significantly greater than the value obtained after treatment with the GH antagonist alone. Although only a limited number of subjects were studied, the results strongly suggest that IGF-I has insulin-sensitizing actions that are independent of its ability to suppress GH secretion. These findings necessitate further studies into the non-GH-related mechanism by which IGF-I enhances insulin sensitivity.

Inhibition of growth hormone action improves insulin sensitivity in liver IGF-1–deficient mice

“…insulin sensitization is improved by treatment with agents that block GH secretion in a substantial number of patients (51,52). In a recent study by O'Connell and Clemmons, a GHR antagonist was given to acromegalic patients for 6 months to block GH action (53). This study clearly demonstrated that GHR antagonist treatment significantly improved insulin sensitivity.…”

“…This study clearly demonstrated that GHR antagonist treatment significantly improved insulin sensitivity. Addition of IGF-1 in combination with the GHR antagonist resulted in substantially greater improvement in the insulin sensitivity, suggesting that IGF-1 exerts additional effects on insulin sensitivity that are not mediated through suppression of GH action (53). GH plays a role in the regulation of lipolysis and lipogenesis, as well as in the differentiation of preadipocytes (54,55).…”

Insulin Resistance in the Liver-Specific IGF-1 Gene-Deleted Mouse Is Abrogated by Deletion of the Acid-Labile Subunit of the IGF-Binding Protein-3 Complex

“…IGF-1 administration has also been demonstrated to improve insulin sensitivity in both type 1 diabetic and type 2 diabetic patients (28,29). In another clinical study involving patients with acromegaly (30), combined treatment with GH receptor antagonist plus IGF-1/IGFBP-3 was found to be more effective in improving insulin sensitivity than treatment with GH receptor antagonist itself, suggesting that the insulin-sensitizing effect of IGF-1 is partly independent of its ability to suppress GH secretion (30).…”

The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity

“…Administration of a GH antagonist to diabetics results in relative restoration of normal carbohydrate metabolism but does not completely ameliorate the defect in insulin sensitivity (10). Similarly, administration of a GH receptor antagonist to acromegalics improves insulin sensitivity but does not restore it to the normal range (11).…”