Elevated circulating levels of growth hormone (GH) and/or increased expression of the GH receptor in the kidney are associated with the development of nephropathy in type1 diabetes and acromegaly.
In consequence, we selected acromegaly and Laron syndrome due to GH receptor deficiency (GHRD) as models for excess and absence of GH action, and focused in the role of GH/GHR signaling in the genesis of cancer and diabetes.
Work on the GH receptor (R)-knockout (GHRKO) mice and results of studies on GH-resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition and aging/longevity.
The complex inter-relationship of obesity, diabetes and cancer risk is related to excess insulin and fuel supply, in the presence of heightened anti-apoptosis and uninhibited DNA damage when GHR function is normal.
We also observed reduced insulin concentrations (1.4 μU/ml versus 4.4 μU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects.
The delineation of the role of this repressosome complex in regulating tissue-specific expression of GHR in diabetes mellitus provides a molecular model for the role of GH in the genesis of certain microvascular complications of diabetes mellitus.
Clinical trials in patients with acromegaly show GHR blockade to be an exciting new mode of therapy for this condition, and pegvisomant may have a therapeutic role in diseases, such as diabetes and malignancy, in which abnormalities of the GH/IGF-I axis have been observed.
The recent development of specific inhibitors of GH action, i.e. specific GHR antagonists (GHRAs), has opened the possibility that this group of inhibitors may be used as therapeutic agents in conditions where GH and IGFs have been suggested to play a pathophysiological role, such as late complications of diabetes.