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ABSTRACT
We review the data suggesting that the spiny mouse Acomys cahirinus may be a suitable model for the early stages of the development of Type 2 diabetes mellitus in man. When raised under laboratory conditions, A. cahirinus develops glucose intolerance, obesity, and varying degrees of insulin resistance. As in Type 2 diabetes, it exhibits a reduced glucose clearance rate (Kg) following an IV glucose challenge, deficient β-cell sensitivity to glucose (Km), but no change in its capacity to secrete insulin (Vmax). Its islets are well granulated with processed insulin, but, as in Type 2 diabetes, an intrinsic defect in β-cell stimulus-secretion coupling hinders the ability to meet the increasing peripheral demand for insulin caused by the developing obesity. In vitro studies with isolated islets resemble whole animal studies: a reduced early-phase insulin response to glucose (decreased Vmax), delayed and deficient late-phase response, and increased Km indicative of reduced sensitivity to glucose. We demonstrated a defective link between glycolysis, the initial step in the glucose-dependent stimulus-secretion coupling and adenylyl cyclase, a major stimulus-amplifying signaling branch, as well as a defective “readout” of the cyclic AMP signal. Additional stimulus-secretion loci are probably involved in the defective β-cell response to glucose. An integrated model for the pathogenesis of Type 2 diabetes is presented.