Insulin gene expression and biosynthesis

Abstract

The insulin gene is expressed specifically and at very high levels in pancreatic β-cells. Most of its tissue-specific expression and metabolic regulation are conferred by approximately 340 bp upstream of the transcription initiation site. Several glucose-responsive elements have been identified within this region, and physiological regulation of insulin gene expression relies on the cooperative and synergistic interactions between DNA-binding factors and coactivators. Glucose is the major regulator of insulin gene expression. It activates transcription and stabilizes insulin mRNA. In addition, insulin gene expression is stimulated by glucagon-like peptide 1, growth hormone, and lactogenic hormones, and inhibited by epinephrine, somatostatin, glucagon, and leptin. In type 2 diabetes, chronic elevations of blood glucose and fatty acid levels impair insulin gene expression. Under most circumstances, the production of insulin is also highly regulated at the translational level. Indeed, this is the predominant control mechanism in the β-cell whereby intracellular insulin stores are efficiently maintained in the short term. Essentially, translation of the preproinsulin mRNA template to preproinsulin protein occurs in a fashion typical of most eukaryotic mRNAs. In general, nutrients that stimulate insulin secretion, of which glucose is the most physiologically relevant, also stimulate proinsulin biosynthesis at the translational level. Recently, it has been shown that specific control of glucose-induced proinsulin biosynthesis in the β-cell resides in cis-elements in the 5′- and 3′-untranslated regions of preproinsulin mRNA itself. After proinsulin is translocated into the lumen of the rough endoplasmic reticulum, correctly folded proinsulin can then be delivered in transport vesicles to the cis-Golgi apparatus in an ATP-dependent process. The major site for processing of the proinsulin to biologically active insulin is the immature granule compartment of the β-cell. Production of insulin occurs via limited proteolysis of the proinsulin precursor molecule, which is catalyzed by two endopeptidases, proprotein convertase 2 (PC2) and proprotein convertase 3 (PC3) (also known as PC-1), and an exopeptidase, carboxypeptidase-H (CP-H). Similar to their deleterious effects on insulin gene expression, chronic hyperglycemia and hyperlipidiemia impair proinsulin biosynthesis. Keywords: insulin gene; promoter; transcription factor; proinsulin; translation; biosynthesis; hyperglycemia; hyperlipidemia