Brief description of insulin mRNA quantity and quality

Brief description of insulin mRNA quantity and quality Many factors may contribute to the control of insulin mRNA levels (1, 2), including transcriptional networks that control β cell function (3) as well as mRNA stability (4). While a detailed analysis of the transcriptional regulation of β cell development, differentiation, and dedifferentiation is beyond the scope of this Review, it is certainly clear that PDX1 and NEUROD1 can act together to directly stimulate transcription from the INS promoter (5). Moreover, PDX1, in combination with NKX2.2 (downstream of NEUROG3; ref. 6) and FOXA2, stimulates the expression of the β cell–specific activator MafA (7); in turn, MafA homodimers (or MafA/MafB heterodimers) help support β cell INS gene transcription (8) (two alleles in humans, four alleles in mice and rats), along with additional upstream factors (9). A number of human diabetes–related genes associated with INS mRNA expression are summarized in Table 1. Classic studies of the islets of insulin-resistant C57BL/KsJ db/db mice, a genetic model of type 2 diabetes (T2D), have shown that at 5 weeks of age (when glycemia is not yet significantly perturbed and pancreatic insulin content is still similar to that in +/db controls), there is an elevation of Ins mRNA that is likely to be disproportional to β cell mass, which helps to provide the insulin needed to mount a hyperinsulinemic response in these animals (10). The db/db mice then progress to diabetes, and with this, the abundance of Ins mRNA is not sustained (although interventions to limit obesity and diabetes with diet or medications that provide β cell rest tend to preserve some of the elevation of Ins mRNA levels, as well as insulin secretory capacity; refs. 10, 11). Thus, regulating INS mRNA level is at least part of the response by which β cells compensate for insulin resistance, although this may not be maintained as hyperglycemia progresses. Accumulated clinical and basic research data suggest that declining INS mRNA levels may be just one feature of a larger phenomenon of β cell dedifferentiation, and this may be a relatively early signature of β cell failure in the natural progression of T2D in humans and animal models (12–15). Not surprisingly, many genes associated with β cell differentiation (including INS mRNA expression) also appear as (loss-of-function) GWAS candidates for T2D in humans (Tables 1, 2, 3, and 4). There are also murine models in which hyperglycemia (from experimentally induced partial insulin deficiency) appears to lead directly to decreased β cell transcription factors (PDX1, Nkx6.1, HNF1A, and MafA — all of which contribute to differentiated function) in pancreatic islets, along with downregulation of β cell– enriched genes (Glut2 and Gck) and accompanied by increased endocrine progenitor markers (Ngn3) and β cell–disallowed genes (Ldha and G6pc). The effects of hyperglycemia have also been observed in residual islets after incomplete pancreatectomy (16), Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β cell identity), or β cell dedifferentiation, or β cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for β cell failure in type 1 diabetes. Normal and defective pathways in biogenesis and maintenance of the insulin storage pool