Type 2 diabetes occurs when pancreatic beta cells become unable to compensate for the underlying insulin resistance. Insulin secretion requires beta cell insulin stores to be replenished by insulin biosynthesis, which is mainly regulated at the translational level. Such translational regulation often involves the 5'untranslated region (5'UTR). Recently, we identified a human insulin splice-variant altering only the 5'UTR and conferring increased translation efficiency.

We now describe a mouse insulin splice-variant (mSPV) that is found in the cytoplasm and exhibits increased translation efficiency resulting in more normal (prepro)insulin protein per RNA. The RNA stability of mSPV is not increased, but the predicted secondary RNA structure is altered, which may facilitate translation. To determine the role of mSPV in insulin resistance and diabetes, mSPV expression was measured by quantitative real-time RT-PCR in islets from three diabetic and/or insulin resistant, obese and non-obese, mouse models (BTBRob/ob, C57BL/6ob/ob, C57BL/6azip). Interestingly, mSPV expression was significantly higher in all diabetic/insulin resistant mice, compared with wild-type littermates, and was dramatically induced in primary mouse islets incubated at high glucose. This raises the possibility that the insulin splice-variant may represent a compensatory beta cell mechanism to enhance insulin biosynthesis when insulin requirements are elevated by hyperglycemia/insulin resistance.