Growth hormone, IGF‐I and diabetic angiopathy revisited

A new hypothesis, `the IGF-I de®ciency hypothesis', concerning the pathogenesis of diabetic angiopathy has been proposed in this issue of Clinical Endocrinology (Janssen & Lamberts, 2000). This is the ®rst hormonal mechanism brought forward since the `growth hormone hypothesis' almost 30 years ago. The proposition that hypersecretion of growth hormone (GH) precipitates the development of vascular complications in diabetes was generated by Lundbaek et al. (1970). The original `growth hormone hypothesis' was supported by ®ndings of elevated circulating GH levels in diabetic subjects (in particular during poor metabolic control) and by preliminary observations showing that hypophysectomy halted the progression of diabetic retinopathy (Lundbaek et al., 1970) and was substantially strengthened when Sharp et al. (1987) were able to demonstrate complete lack of retinal neovascularization in a cohort of 100 diabetic patients 10 years after yttrium-90 pituitary implantation. After the discovery of insulin-like growth factors (IGF), IGF-I (at that time known as sulphation factor or somatomedin C) was included as a putative mediator of complications. A number of studies, however, showed that total circulating IGF-I concentrations were decreased in diabetes and most markedly so in patients with poor metabolic control and high GH levels (Amiel et al., 1984). In the current issue, Janssen & Lamberts (2000) provide a tantalizing point of view according to which the decreased levels of IGF-I in the blood may trigger diabetic angiopathy and hypothesize that `the premature and progressive decline in serum IGF-I bioactivity during ageing in diabetics ultimately results in insuf®cient protective effects by IGF-I in the kidneys, eyes and neurones. '. The new `IGF-I de®ciency hypothesis' rests to a great extent on circumstantial evidence, i.e. the observations that IGF-I levels are decreased in diabetic patients and with advancing age, and that neither short-term IGF-I therapy in diabetic patients nor coexistence of acromegaly and diabetes worsen diabetic complications. Several ®ndings are, however, still contradictory to the new hypothesis; it has been shown that patients with GH de®ciency (and low IGF-I levels) and diabetes have a decreased risk of retinopathy (Alzaid et al., 1994) and some studies have reported either no or a direct positive association between increasing circulating IGF-I and retinopathy (Dill et al., 1991) and decreased occurrence of retinopathy with advancing age (Klein et al., 1994). Along these lines it is puzzling that the authors so strongly emphasize the parallels between long-term diabetes and ageing. This association may be tenable as regards large vessel disease, but hardly microangiopathy. Adding to the above inconsistencies, studies in experimental diabetes in rodents have invariably highlighted the fact that suppression of GH and of IGF-I action ameliorates the progression of early nephropathy (Flyvbjerg et al., 1999) Therefore, it may appear that we are left with two incomplete and mutually contradictory hormonal hypotheses dealing with long established abnormalities of the GH±IGF-I axis in diabetes. Is it in any way possible to reconcile the two concepts? Bearing in mind that the ageing `growth hormone hypothesis' could not assign any role to IGF-I, it may be postulated that some initial event (e.g. low portal insulin levels and inappropriately high hepatic IGFBP1 secretion) leads to circulating IGF-I with low bioactivity, which in turn causes hypersecretion of GH. This notion would account for the high GH levels and the low IGF-I levels in diabetes and would predict that either lack of circulating IGF-I, excess of circulating GH or perhaps GH induced local hypersecretion of IGF-I would be potentially noxious. We maintain that experimental evidence to support any direct pathogenetic effect of reduced IGF-I in the circulation barely exists and that a substantial number of studies points in favour of GH being a pathogenetic factor; this does obviously not exclude the possibility that IGF-I therapy and normalization of GH secretion may be advantageous. The near future will probably see clinical trials of somatostatin analogues, GH receptor antagonists, IGF-I and perhaps even GH (in centrally obese type 2 diabetes) in this condition, which should then de®nitely show whether deranged GH secretion, deranged IGF-I secretion or both are to be considered more or less direct malefactors in the context of diabetic angiopathy.