Growth hormone hypothesis and development of diabetic nephropathy in Type 1 diabetes.

In Type 1 diabetes, poor glycemic control is the key predictor for the development of microalbuminuria, an established early marker of overt nephropathy. However, the role of other pathways in the development of diabetic nephropathy may also be important. The growth hormone (GH) hypothesis suggests that the GH-insulin-like growth factor (IGF)-1 axis may play an important role in this disease process. In Type 1 diabetes, the characteristic pattern of GH hypersecretion and low circulating IGF-1 levels results from hepatic GH resistance owing to the lack of portal insulin. Clinical data indicate that high GH and low IGF-1 levels reduce insulin sensitivity and worsen glycemic control. Furthermore, despite hepatic GH resistance, GH receptors at the kidney remain intact. Experimental data show that excess GH stimulates renal GH receptors and, through paracrine IGF-1 production, results in pathophysiological changes consistent with diabetic nephropathy, namely nephromegaly, glomerular hyperfiltration and eventual proteinuria. These abnormalities are reversed by intervention to block or normalize the local effects of GH and IGF-1. Although such data in humans are limited, preliminary trials show that interventions to increase IGF-1 levels and reduce GH hypersecretion improve glycemic control and insulin sensitivity in the short term. However, their effects on early nephropathy and end points, such as the prevalence of end stage renal disease, have yet to be determined.