Insulin begets insulin.

The pathogenesis of type 2 diabetes is characterized by insulin resistance, primarily in skeletal muscle, fat and liver, and a relative failure of the pancreatic b-cell (1, 2). Considerable controversy surrounds the issue of which of these deficiencies is the primary cause of diabetes. In some studies, the earliest observed defect is dysfunctional secretion and in others insulin resistance appears to be the first detectable problem. Some important new studies open a new perspective to these questions. Glucose is the principal regulator of insulin secretion from pancreatic b-cells. Insulin is secreted immediately in response to elevated glucose concentrations. After insulin secretion, an immediate response takes place within the b-cell to replenish insulin stores through activation of insulin biosynthesis at the transcriptional (3) as well as translational levels (4, 5). The signals that govern the signal transduction pathway that link the glucose stimulus to the initiation of insulin gene transcription have been largely unclear. Intraislet interactions as well as extrapancreatic hormones and neural inputs exert an important level of control over insulin synthesis and secretion and ultimately glucose homeostasis. Several lines of evidence support the possibility of an autocrine action of insulin on b-cells. Insulin binds to the surface of b-cells (6, 7), and functional insulin receptors and insulin receptor substrates (IRSs) identical to those found in peripheral tissues have been identified in both clonal and primary b-cells (6, 8, 9). Glucose stimulation of b-cell lines activates the b-cell insulin receptor much in the same way as application of exogenous insulin, suggesting that insulin secreted from b-cells binds to the insulin receptor eliciting a physiological response (10). The complete physiological consequences of insulin receptor activation of the b-cell have yet to be completely elucidated, but at least one effect is initiation of protein synthesis at both transcriptional and translational levels (11). However, there remains controversy on the effects of insulin on b-cell secretion. Several reports have shown that glucose-stimulated insulin or C-peptide secretion from islets or perfused pancreas is suppressed in the presence of exogenous insulin, leading to the concept of a negative feedback of insulin secretion by insulin (12–18). Under similar conditions, however, other investigators have found little or no effect of insulin on glucose-stimulated insulin secretion (19– 21). Furthermore, these data have been difficult to interpret because of neuronal and intraislet hormonal regulatory mechanisms that could interact with exogenous insulin, and the use of high glucose levels in these studies could per se evoke the effects of substantial stimulation of the b-cell insulin receptors masking the effect of exogenous insulin. Experiments with purified b-cells have also generated conflicting evidence for insulin feedback. Glucosestimulated insulin secretion from purified b-cell lines is inhibited by exogenous insulin levels (1 mmol/l) (21). In contrast, measurements of the effect of insulin on C-peptide secretion in bTC3 cells failed to show direct evidence of secretory regulation by insulin. Furthermore, transfected bTC6-F7 cells in which the insulin receptor was overexpressed showed enhanced basal and glucose-stimulated insulin secretion, but fractional secretory levels remained unchanged at all glucose concentrations whereas cells expressing kinase negative (inactive) insulin receptors showed decreased glucosestimulated insulin secretion (11). These results suggest an autocrine pathway regulating one or more of the following: insulin secretion, insulin synthesis, and glucose sensing/utilization. Several studies have revisited the question on whether insulin may have an autocrine effect on insulin synthesis and secretion. Leibiger et al. (22) studied the effects on insulin gene transcription of depolarization of b-cells by adding (i) glucose, (ii) KCl, or (iii) sulfonylureas to the culture medium. The depolarization, which takes place in all three cases and induces insulin secretion, was also accompanied by an increase in insulin gene transcription as assessed by reverse transcription PCR and by transfected insulin-promoter–green fluorescent protein reporter constructs. By adding various pharmacological inhibitors of the signal transduction pathway, the investigators delineated two pathways leading to an increased insulin gene transcription rate: the PI-3 kinase/p70 s6 and the CaM kinase II. Furthermore, stimulation of hamster insulinoma (HIT) cells with glucose or insulin led to increased PI-3 kinase activity in immunoprecipitates obtained with anti-IRS-2 antibodies. These same pathways are also involved in insulin receptor signal transduction. Thus the investigators studied the effect of overexpression of type A and B insulin receptors in HIT cells and found that the overexpression of type A led to an enhanced insulin European Journal of Endocrinology (1999) 141 95–97 ISSN 0804-4643 H IG H L IG H T