To better understand mechanisms of high fat diet (HFD) induced β-cell apoptosis, gene expression profiling studies were conducted on β-cells/islets incubated in palmitate and/or oleate. These studies showed increased expression of genes associated with gluconeogenesis and fat oxidation, whilst expression of genes associated with glucose transport, glycolysis and insulin production was reduced. This would suggest that in response to chronic nutrient overload (eg HF) the β-cell attempts to protect itself from further damage by slowing down glucose metabolism, oxidation and insulin production, a situation we have recently termed ‘metabolic deceleration’. We have previously presented data from islet fructose-1,6-bisphosphatase transgenic mice, which have reduced glucose stimulated insulin secretion (GSIS) and showed that these mice are protected against HFD induced β-cell dysfunction. Conversely, we have now generated β-cell specific transgenic mice which overexpress SUR1 and Kir6.2 and have increased GSIS compared with controls. We therefore hypothesise that the insulin hypersecreting SUR1/Kir6.2 transgenic mice will develop impaired insulin secretion and glucose intolerance with age as a result of increased metabolic flux leading to β-cell exhaustion and apoptosis. To test this hypothesis we studied SUR1/Kir6.2 transgenic and control mice at 12 and 20 weeks old. Both cohorts of mice were weighed and underwent intra-peritoneal insulin tolerance test (IPITT), oral glucose tolerance test (OGTT) and intravenous glucose tolerance tests (IVGTT). There was no difference in body weight and IPITTs between transgenic and controls at 12 or 20 weeks of age. As expected following IVGTTs, 12 week old transgenic littermates hypersecreted insulin compared with controls. However, at 20 weeks of age SUR1/Kir6.2 transgenics showed both impaired insulin secretion and glucose intolerance compared with controls of the same age. We suggest that insulin hypersecretion is detrimental and that ‘metabolic deceleration’ may be a mechanism to protect the islet β-cell from the deleterious effects of a nutrient rich milieu.