Summary

Type 2, non-insulin-dependent diabetes has been increasing exponentially over the past decade and a half, and it is estimated that within short it will comprise more than 350 million patients. The pathophysiology of type 2 diabetes is complex, but has two dominating factors, insulin resistance (which is mainly due to obesity and physical inactivity), and deficient insulin production. Indeed, although ∼ 80 % of type 2 diabetics are obese, 2/3 of overweight or obese persons show normal glucose metabolism. Data accumulated over the past few decades unequivocally indicate that diabetes can not develop in the absence of a major deficiency of insulin secretion. This deficiency is characterised by an early loss of first-phase insulin response to glucose, followed by gradual collapse of the later insulin response as well as of the maximal secretory capacity of the beta-cell. Interestingly, functional modifications in the beta-cell do not present a discontinuity ; in fact, some of the characteristics of the diabetic beta-cell function can be found in a fraction of the healthy population. A major challenge has been to answer the question whether the population with decreased insulin secretory capacity represents the substratum from which future diabetics emerge. While many observations suggest that such may indeed be the case, conclusive evidence is still unavailable. The search for the beta-cell molecular mechanisms which prepare the ground for diabetes has been difficult and mainly limited to laboratory models of type 2 diabetes. Greater success has been achieved in elucidating the secondary beta-cell defects elicited once diabetes is established and the beta-cell exposed to chronically elevated glucose and fatty acid levels (so-called gluco-lipotoxicity). The latter reduces the responsiveness of insulin secretion to physiological stimuli, as it impairs the biosynthesis and processing of proinsulin. The leptin resistance of obesity certainly plays a role in this context, since leptin reduces, i.a., the lipid content of the islet. Similarly, the reduced adiponectin levels of obesity favour diminished beta-cell function. Nevertheless, it seems probable that the most important negative factor for the beta-cell in obesity is the inflammatory state. Indeed, several cytokines are deleterious for the beta-cell and may play a role in the pathogenesis of the islet dysfunction of diabetes, as demonstrated by the recent work of Donath and coworkers. We propose the working hypothesis that the ‘‘ prediabetic ’’ beta-cell in fact is a normal beta-cell whose functional capabilities (insulin secretion and biosynthesis, cell proliferation, resistance to stress…) is at the lower-end of the normal distribution. At times of ‘‘ reasonable ’’ metabolic requirements, i.e. reasonable energy balance, such a ‘‘ prediabetic ’’ beta-cell is fully adequate to cover the insulin needs of the organism. Insulin production by the ‘‘ prediabetic ’’ beta-cell becomes insufficient either when insulin needs become excessive, as is the case in over-nutrition (with or without insulin resistance), or when beta-cell function and adaptation are impaired by ‘‘ external ’’ factors such as the obesity-related inflammatory cytokines. Thus, deficient beta-cell function is seen as a relative factor against the metabolic background dictated by environmental factors. Type 2 diabetes is a hereditary disease, and many genes have been shown to be linked to diabetes. Our hypothesis is that such genes (or rather their polymorphism) define the range of the functional adaptability of the beta-cell to metabolic demand. This would be an excellent example of gene-environment interaction. Thus, we do not believe that sensu stricto diabetes genes exist. Against the above, optimal diabetes treatment would necessitate — reduction of the metabolic demand on the beta-cell, — support of its function and adaptive capabilities. Several new research avenues, discussed in the present meeting, may open new and improved therapeutic approaches for type 2 diabetes.