It is well documented that individuals with low birth weight coupled with rapid catch-up growth are at increased risk of developing insulin resistance and type 2 diabetes. We previously demonstrated that maternal protein restriction in rats leads to fetal growth restriction, insulin resistance and type 2 diabetes. This is associated with specific changes in expression of components of the insulin-signaling pathway including reduced expression of PKCf and the p110b catalytic subunit of PI3 kinase. We also showed that young men who had a low birth weight have strikingly similar alterations in insulin signaling molecules in muscle and fat. These findings provide strong evidence for the importance of maternal diet in mediating the relationship between poor early growth and subsequent risk of diabetes. Our current findings in mice and recent observations in rats suggest that reduced expression of these key signaling molecules can be detected at an early age and could provide a molecular fingerprint for later adult diseases such as type 2 diabetes. Moreover, the protein can bind to and disassemble SNARE complexes in vitro in a way similar to the wild type protein. These observations, together with the fact that the hyh mouse presents a diminished Tubacin amount of aSNAP in brain, have lead to the conclusion that the alteration in brain development in these animals is principally due to an insufficient amount of protein and not to a malfunction of the mutated molecule. However, a functional defect of the mutated protein has never been ruled out. Our observations in sperm point to a different mechanism. We confirmed that the mutated protein has an altered steady state distribution in several tissues; the levels of aSNAP in testis and epididymis were significantly lower in the mutated animals. In contrast, we found normal amount of this protein in sperm. Therefore, it was unlikely that the defect in acrosomal exocytosis was due to a decreased amount of aSNAP. These observations suggested that the mutated protein has some intrinsic malfunction. This was confirmed by the fact that the mutated protein was less effective in restoring exocytosis than the wild type protein when added to permeabilized sperm from hyh mouse. Moreover, the mutated protein was inhibitory when added to normal mouse and human sperm. It is worth noticing that an excess of wild type aSNAP is also inhibitory, but at much higher concentrations. Our results indicate that the M105I mutation alters the normal steady state balance of aSNAP and also affects its function. The protein may bind SNARE complexes and may promote their disassembly as the wild type protein , but in the complexity of a cellular environment with several other interacting factors, the mutant behaves differently than the wild type protein in the acrosomal secretory processes. In fact, co-immunoprecipitation studies using brain lysates suggest that the M105I mutation may affect the aSNAP/SNARE complex interaction.