Insulin secretion is the only efficient means whereby the organism can rapidly decrease circulating glucose levels. Such a release of insulin is rapidly compensated for a corresponding glucose-induced increase in proinsulin biosynthesis, so that beta-cell insulin stores are constantly upheld. Thus, regulation of proinsulin biosynthesis is an 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 that is regulated at the transcriptional level, the major control of proinsulin biosynthesis is specifically mediated at the translational level. This proposed research is intended to gain a better understanding of the molecular mechanism underlying metabolic translational regulation of proinsulin biosynthesis. The metabolic stimulus-coupling for specific translational control of glucose-induced proinsulin biosynthesis is not well defined. Increased mitochondrial anaplerosis, as a consequence of increased glycolytic flux, is necessary to generate a metabolic-coupling signal for specific glucose-induced proinsulin biosynthesis translation, which is distinct from that to evoke insulin release. Increased generation of a Krebs-cycle intermediate, and its subsequent export to the a-cell cytosol appears to be an important secondary signal. Succinate (and/or succinyl-CoA) is the most promising stimulus-coupling factor for proinsulin biosynthesis translation, although this hypothesis needs to be substantiated. The specific nature of glucose-induced proinsulin biosynthesis is mediated via certain motifs in the untranslated regions (UTRs) preproinsulin (PPI) mRNA. The 3'-UTR of PPI mRNA has a highly conserved 'UUGAA cis-element' that assists in the translational control mechanism by prolonging PPI mRNA stability. The 5'-UTR of PPI mRNA contains an element essential for translational regulation of proinsulin biosynthesis. Preliminary data is narrowing down on a conserved 'CAUCA cis-element' within the 5'-UTR structure to which an islet cytosolic protein associates in a glucose-dependent manner, correlative with translational control of proinsulin biosynthesis. Moreover, we have also unveiled a distinct islet cytosolic protein that specifically interacts with the 'UUGAA cis-element' in 3'-UTR in a glucose-dependent fashion. These 5'-/3'-UTR cis-elements require further functional characterization, but an emphasis will be placed on identifying the beta-cell cytosolic trans-acting proteins that associate to these in response to glucose. From this, it is anticipated that novel components and insight into the proinsulin biosynthesis translational mechanism will be found, that can then be used to determine a basis of dysfunction in proinsulin production found in NIDDM.
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