DEVELOPMENT AND CONSEQUENCES OF INSULIN-RESISTANCE - LESSONS FROM ANIMALS WITH HYPERINSULINEMIA

Studies involving genetically acid nutritionally induced diabetes in a nimals indicate that early hyperinsulinaemia is the causative factor o f tissue insulin resistance, leading to compensatory insulin over-secr etion and pancreatic beta-cell dysfunction. The models for this syndro me, which occurs in association with obesity (thus termed ''diabesity' ' here), concern either species with a sturdy pancreas, capable of lon g-lasting oversecretion, or those with labile beta cells which cannot sustain the initial oversecretion due to genomic modifiers enhancing g luco- or lipotoxicity. Examples of the latter are db/db mice mutants a nd desert gerbils susceptible to overnutrition, i.e. Psammomys obesus (sand rats). The latter also comprise spiny mice (Acomys cahirinus) wh ich do not manifest resistance. They are low insulin secretors and acc umulate insulin in beta cells which may disintegrate, producing insuli n-deficiency. P. obesus is characterised by low insulin-receptor densi ty. On a high energy diet, the capacity of insulin to activate recepto r tyrosine kinase (TK) is reduced, concomitant with hyperinsulinaemia. With subsequent hyperglycaemia, a vicious circle of insulinaemia-glyc aemia accentuates TK activation failure. This is attributable to multi site phosphorylation, including serine and threonine on the receptor b -subunit, which are inhibitory to TK activity. The compromised TK acti vation is reversible by diet restriction and normoinsulinaemia restora tion. Similar receptor TK malfunction is seen in other animal species with diabesity. Hyperinsulinaemia has also been shown to cause a varie ty of detrimental effects in vitro and in vivo. The beta-cell response to long-lasting stimulation and the receptor malfunction in diabesity have implications for a similar etiology in human insulin-resistance syndrome and non-insulin-dependent diabetes mellitus, particularly in populations emerging into nutritional abundance. It is postulated that the ''thrifty gene'' is focused on receptor TK, whose reduced functio n is the primary phenotypic expression of protracted hyperinsulinaemia .