Insulin secretion, from the pancreatic beta-cell, is the only efficient means whereby the organism can rapidly decrease circulating glucose concentrations. Any glucose-induced insulin release is rapidly compensated for a corresponding increase in proinsulin biosynthesis, so that beta-cell insulin stores are constantly upheld. Thus, regulation of proinsulin biosynthesis an extremely important aspect of beta-cell function. Proinsulin biosynthesis is specifically regulated above that of the majority of beta-cell proteins by many factors, of which glucose is the most physiologically relevant. Unlike most protein synthesis which is regulated at the transcriptional level, the major control of proinsulin biosynthesis is specifically mediated at the translational level. Unfortunately, the metabolic stimulus- coupling and translational control mechanisms for specific glucose-induced proinsulin biosynthesis is poorly defined. This proposed research is intended to gain a better understanding of the molecular mechanism underlying metabolic translational regulation of proinsulin biosynthesis. Mitochondrial metabolism appears necessary to generate a metabolic-coupling signal for specific glucose-induced proinsulin biosynthesis translation, that is distinct from that to evoke insulin release. ATP is a necessary cofactor for general protein and proinsulin synthesis, but does not appear to be a coupling signal per se, as it is for insulin release. Thus, other exported products of mitochondrial metabolism are currently being investigated. Preliminary studies indicate that succinate (succinyl-CoA) is a promising stimulus- coupling factor for proinsulin biosynthesis translation, although this hypothesis needs to substantiated by further investigation. In addition, it is thought that the specific nature of glucose- induced proinsulin biosynthesis is mediated via specific motifs in the untranslated regions (UTRs) preproinsulin (PPI) mRNA. We have recently found that the 5'-UTR of PPI mRNA contains an element essential for translational regulation of proinsulin biosynthesis, likely residing in a conserved stem loop secondary structure. Moreover, the 3'-UTR of PPI mRNA appears to have a conserved primary sequence motif that may assist in the translational control mechanism by prolonging PPI mRNA stability. These initial observations need to be better characterized. A recombinant adenovirus system, using His-tagged proinsulin as a reporter, has been designed to define a minimal structure of the translational regulatory elements in the PPI mRNA UTRs. Once these element have been defined it will become important to identify a beta-cell protein(s) that specifically binds to a UTR in a regulated fashion as mediated by glucose and/or metabolic coupling factor. It is anticipated that novel components of the proinsulin biosynthesis translational mechanism will be found, that can then be used to determine a basis of beta-cell dysfunction, in terms of proinsulin production, found in NIDDM.
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