Aging and insulin secretion

Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Under some conditions of hyperglycemic challenge, insulin levels are lower in older people, suggesting beta-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, beta-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired beta-cell compensation to age-related insulin resistance may predispose older people to develop postchallenge hyperglycemia and type 2 diabetes. An improved understanding of the metabolic alterations associated with aging is essential for the development of preventive and therapeutic interventions in this population at high risk for glucose intolerance.     

BIG3 inhibits insulin granule biogenesis and insulin secretion

While molecular regulation of insulin granule exocytosis is relatively well understood, insulin granule biogenesis and maturation and its influence on glucose homeostasis are relatively unclear. Here, we identify a novel protein highly expressed in insulin-secreting cells and name it BIG3 due to its similarity to BIG/GBF of the Arf-GTP exchange factor (GEF) family. BIG3 is predominantly localized to insulin- and clathrin-positive trans-Golgi network (TGN) compartments. BIG3-deficient insulin-secreting cells display increased insulin content and granule number and elevated insulin secretion upon stimulation. Moreover, BIG3 deficiency results in faster processing of proinsulin to insulin and chromogranin A to β-granin in β-cells. BIG3-knockout mice exhibit postprandial hyperinsulinemia, hyperglycemia, impaired glucose tolerance, and insulin resistance. Collectively, these results demonstrate that BIG3 negatively modulates insulin granule biogenesis and insulin secretion and participates in the regulation of systemic glucose homeostasis.     

Endogenous hyperlactatemia and insulin secretion]

In the normal anesthetized dog, the endogenous hyperlactatemia induced either by intense muscular work or by a high dose of phenformin (20 mg/kg subtucaneously) is followed by an increase in the pancreaticoduodenal insulin output. A previous perfusion of sodium dichloroacetate (50 mg/kg. h) opposes the hyperlactatemia, and reduces or suppresses the increase in insulin output.     

Extracellular bicarbonate ions and insulin secretion

The role of bicarbonate ions in insulin release was studied with incubated and perifused isolated rat islets of Langerhans. In the absence of NaHCO₃, the early phase of glucose-induced secretion was completely abolished and the second phase inhibited by approximately 65%. The insulinotropic effect of the sugar was totally restored after reintroduction of the ion in the medium. The monophasic secretory response to tolbutamide was also markedly diminished by omission of NaHCO₃, whereas the release evoked by a high concentration of K⁺ was very little affected. CO₂ was unable to substitute for HCO₃⁻, but small concentrations of the anion (3 to 5 mM) were sufficient to ensure a normal response to glucose.     

Diffusion induced oscillatory insulin secretion

Oscillatory secretion of insulin has been observed in many different experimental preparations. Here we examine a mathematical model for in vitro insulin secretion from pancreatic beta cells in a flow-through reactor. The analysis shows that oscillations result because of an important interplay between flow rate of the reactor and insulin diffusion. In particular, if the ratio of flow rate to volume of the reaction bed is too large, oscillations are eliminated, in contradiction to the conclusions of Maki and Keizer (L. W. Maki and Keizer J. Mathematical analysis of a proposed mechanism for oscillatory insulin secretion in perifused HIT-15 cells. Bull. Math. Biol., 57 (1995), 569–591). Furthermore, with reasonable numbers for the experimental parameters and the diffusion of insulin, the model equations do not exhibit oscillations.     

Control of fetal insulin secretion

In this study, we investigated the way in which fetal insulin secretion is influenced by interrelated changes in blood glucose and sympathoadrenal activity. Experiments were conducted in late gestation sheep fetuses prepared with chronic peripheral and adrenal catheters. The fetus mounted a brisk insulin response to hyperglycemia but with only a minimal change in the glucose-to-insulin ratio, indicating a tight coupling between insulin secretion and plasma glucose. In well-oxygenated fetuses, alpha(2)-adrenergic blockade by idazoxan effected no change in fetal insulin concentration, indicating the absence of a resting sympathetic inhibitory tone for insulin secretion. With hypoxia, fetal norepinephrine (NE) and epinephrine secretion and plasma NE increased markedly; fetal insulin secretion decreased strikingly with the degree of change related to extant plasma glucose concentration. Idazoxan blocked this effect showing the hypoxic inhibition of insulin secretion to be mediated by a specific alpha(2)-adrenergic mechanism. alpha(2)-Blockade in the presence of sympathetic activation secondary to hypoxic stress also revealed the presence of a potent beta-adrenergic stimulatory effect for insulin secretion. However, based on an analysis of data at the completion of the study, this beta-stimulatory mechanism was seen to be absent in all six fetuses that had been subjected to a prior experimentally induced hypoxic stress but in only one of nine fetuses not subjected to this perturbation. We speculate that severe hypoxic stress in the fetus may, at least in the short term, have a residual effect in suppressing the beta-adrenergic stimulatory mechanism for insulin secretion.     

Inhibition of PKCepsilon improves glucose-stimulated insulin secretion and reduces insulin clearance

In type 2 diabetes, pancreatic beta cells fail to secrete sufficient insulin to overcome peripheral insulin resistance. Intracellular lipid accumulation contributes to beta cell failure through poorly defined mechanisms. Here we report a role for the lipid-regulated protein kinase C isoform PKCepsilon in beta cell dysfunction. Deletion of PKCepsilon augmented insulin secretion and prevented glucose intolerance in fat-fed mice. Importantly, a PKCepsilon-inhibitory peptide improved insulin availability and glucose tolerance in db/db mice with preexisting diabetes. Functional ablation of PKCepsilon selectively enhanced insulin release ex vivo from diabetic or lipid-pretreated islets and optimized the glucose-regulated lipid partitioning that amplifies the secretory response. Independently, PKCepsilon deletion also augmented insulin availability by reducing both whole-body insulin clearance and insulin uptake by hepatocytes. Our findings implicate PKCepsilon in the etiology of beta cell dysfunction and highlight that enhancement of insulin availability, through separate effects on liver and beta cells, provides a rationale for inhibiting PKCepsilon to treat type 2 diabetes.