title: Development and consequences of insulin resistance: lessons from animals with hyperinsulinaemia.
abstract: Studies involving genetically and nutritionally induced diabetes in animals indicate that early hyperinsulinaemia is the causative factor of tissue insulin resistance, leading to compensatory insulin oversecretion and pancreatic beta-cell dysfunction. The models for this syndrome, which occurs in association with obesity (thus termed "diabesity" here), concern either species with a sturdy pancreas, capable of long-lasting oversecretion, or those with labile beta cells which cannot sustain the initial oversecretion due to genomic modifiers enhancing gluco- or lipotoxicity. Examples of the latter are db/db mice mutants and desert gerbils susceptible to overnutrition, i.e. Psammomys obesus (sand rats). The latter also comprise spiny mice (Acomys cahirinus) which do not manifest resistance. They are low insulin secretors and accumulate insulin in beta cells which may disintegrate, producing insulin-deficiency. P. obesus is characterised by low insulin-receptor density. On a high energy diet, the capacity of insulin to activate receptor tyrosine kinase (TK) is reduced, concomitant with hyperinsulinaemia. With subsequent hyperglycaemia, a vicious circle of insulinaemia-glycaemia accentuates TK activation failure. This is attributable to multisite phosphorylation, including serine and threonine on the receptor b-subunit, which are inhibitory to TK activity. The compromised TK activation is reversible by diet restriction and normoinsulinaemia restoration. Similar receptor TK malfunction is seen in other animal species with diabesity. Hyperinsulinaemia has also been shown to cause a variety 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 function is the primary phenotypic expression of protracted hyperinsulinaemia.
authors.affiliation: Department of Biochemistry, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Shafrir
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000503:physiopathology* / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000503:physiopathology* / Q000628:therapy; D005849:Gerbillinae; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D008017:Life Expectancy; D008019:Life Style; D051379:Mice; D008817:Mice, Mutant Strains; D009115:Muridae; D051381:Rats; D011922:Rats, Mutant Strains; D011972:Receptor, Insulin / Q000378:metabolism / Q000502:physiology
chemical_list: D007328:Insulin; D011972:Receptor, Insulin