Mathematical analysis of a proposed mechanism for oscillatory insulin secretion in perifused HIT-15 cells

Oscillatory secretion of insulin has been observed in many different experimental preparations ranging from pancreatic islets to the whole pancreas. Here we examine the mathematical features underlying a possible model for oscillatory secretion from the perifused, insulin-secreting cell line, HIT-15. The model includes the kinetics of uptake of glucose by GLUT transporters, the rate of glucose metabolism within the cell, and the effect of glucose on the rate of insulin secretion. Putative feedback by insulin on the rate of glucose transport into the cells is treated phenomenologically and leads to insulin oscillations similar to those observed experimentally in HIT cells. The resulting set of ordinary differential equations is simplified by time-scale analysis to a two-variable set of ordinary differential equations. Because of this simplification we can explore, in great detail, the characteristics of the oscillations and their sensitivity to parameter variation using phase plane analysis.     

Extracellular ATP potentiates the secretion of insulin induced by tolbutamide

Our experiments were carried out on the isolated perfused rat pancreas. The effect of extracellular ATP (8 microM) on insulin secretion induced by tolbutamide (0.04 mM) was studied in the presence of substimulating glucose concentration 4.2 mM (0.75 g/l). ATP (8 microM), ineffective per se at this concentration, highly potentiated the insulin secretion induced by tolbutamide (0.04 mM).     

3H-serotonin as a marker of oscillatory insulin secretion in clonal beta-cells (INS-1)

Serotonin release from preloaded pancreatic beta-cells has been used as a marker for insulin release in studying exocytosis from single cells using the amperometric technique. We found that single pancreatic beta-cells exhibited oscillations in exocytosis with a period of 1-1.5 min as measured amperometrically by serotonin release. We also show that 3H-serotonin can be used to monitor exocytosis from intact and streptolysin-O permeabilized clonal insulin-secreting cells preloaded with labeled serotonin and that serotonin release correlated with insulin secretion in the same cells. The use of 3H-serotonin provides a real-time indicator of exocytosis from populations of clonal insulin-secreting cells.     

Adiponectin reverses β-Cell damage and impaired insulin secretion induced by obesity

Obesity significantly decreases life expectancy and increases the incidence of age-related dysfunctions, including β-cell dysregulation leading to inadequate insulin secretion. Here, we show that diluted plasma from obese human donors acutely impairs β-cell integrity and insulin secretion relative to plasma from lean subjects. Similar results were observed with diluted sera from obese rats fed ad libitum, when compared to sera from lean, calorically restricted, animals. The damaging effects of obese circulating factors on β-cells occurs in the absence of nutrient overload, and mechanistically involves mitochondrial dysfunction, limiting glucose-supported oxidative phosphorylation and ATP production. We demonstrate that increased levels of adiponectin, as found in lean plasma, are the protective characteristic preserving β-cell function; indeed, sera from adiponectin knockout mice limits β-cell metabolic fluxes relative to controls. Furthermore, oxidative phosphorylation and glucose-sensitive insulin secretion, which are completely abrogated in the absence of this hormone, are restored by the presence of adiponectin alone, surprisingly even in the absence of other serological components, for both the insulin-secreting INS1 cell line and primary islets. The addition of adiponectin to cells treated with plasma from obese donors completely restored β-cell functional integrity, indicating the lack of this hormone was causative of the dysfunction. Overall, our results demonstrate that low circulating adiponectin is a key damaging element for β-cells, and suggest strong therapeutic potential for the modulation of the adiponectin signaling pathway in the prevention of age-related β-cell dysfunction.     

Effect of antrectomy on gastric secretion induced by insulin hypoglycemia in dogs]

Antrectomy was shown to cause a sharp and stable suppression of the secretory reaction of the fundal glands of the stomach in response to insulin hypoglycemia. Acid and pepsin secretion was reduced two-fold (on the average) as compared to that after histamine stimulation. A tendency to restoration of the secretory parameters was seen in 3 to 5 months; the next 7 months they persisted on a constant level.     

Influence of temperature on insulin secretion induced by different concentrations of glucose]

Lowering of the temperature from 37.5 degrees C to 28 degrees C provokes a decrease in the response of the beta cell to the stimulation by glucose (1.5 g/1, 3 g/1 and 5 g/1). The insulin secretion obtained at 28 degrees C, compared to that obtained at 37.5 degrees C, is weaker for strongly stimulating concentrations (3 g/1 and 5 g/1) than for a slightly stimulating concentration (1.5 g/1).     

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.     

Increase in insulin secretion induced by plasma from mice injected with allogeneic lymphocytes

Plasma from BALB/c mice bled 90 minutes after allogeneic lymphocyte injection significantly rises glucose induced insulin secretion. This rise is observed in pancreas either from non-treated or from allogeneized mice. This rise is time and dose-dependent. An 1/40 dilution is enough to bring about a significant increase on insulin secretion. This effect is seen when mice are bled between 60 and 180 minutes after injection with a maximum effect at 90-120 minutes. Plasma from BALB/c mice injected with C57BL/6 J lymphocytes rises insulin secretion from BALB/c, C57BL/6 J, C3h and C57BL/KsJ mice pancreas. Plasma from streptozotocin diabetic BALB/c mice and from genetically diabetic C57BL/KsJ mdb-mdb mice injected with allogeneic lymphocytes stimulates glucose induced insulin secretion but to a lesser extent than plasma from normal non-diabetic mice does.     

Involvement of stretch-activated cation channels in hypotonically induced insulin secretion in rat pancreatic beta-cells

In isolated rat pancreatic -cells, hypotonic stimulation elicited an increase in cytosolic Ca²⁺ concentration ([Ca²⁺]_c) at 2.8 mM glucose. The hypotonically induced [Ca²⁺]_c elevation was significantly suppressed by nicardipine, a voltage-dependent Ca²⁺ channel blocker, and by Gd³⁺, amiloride, 2-aminoethoxydiphenylborate, and ruthenium red, all cation channel blockers. In contrast, the [Ca²⁺]_c elevation was not inhibited by suramin, a P₂ purinoceptor antagonist. Whole cell patch-clamp analyses showed that hypotonic stimulation induced membrane depolarization of -cells and produced outwardly rectifying cation currents; Gd³⁺ inhibited both responses. Hypotonic stimulation also increased insulin secretion from isolated rat islets, and Gd³⁺ significantly suppressed this secretion. Together, these results suggest that osmotic cell swelling activates cation channels in rat pancreatic -cells, thereby causing membrane depolarization and subsequent activation of voltage-dependent Ca²⁺ channels and thus elevating insulin secretion. calcium ion; swelling; patch-clamp; gadolinium     

Glucose intolerance in young TallyHo mice is induced by leptin-mediated inhibition of insulin secretion

The pathophysiology of TallyHo mouse, a recently established animal model for type 2 diabetes mellitus, was analyzed at prediabetic state to examine the inherent defects which contribute to the development of diabetes. At 4 weeks of age, the TallyHo mice already revealed glucose intolerance while their peripheral tissues exhibited normal insulin sensitivity. On the other hand, decreased plasma insulin concentration was observed with little differences in pancreatic insulin contents, indicating the impaired insulin secretion. Such defect, however, was not found in the isolated islets, which suggests a role of endocrine factor in impaired insulin secretion of TallyHo mice. Treatment of leptin inhibited the glucose-stimulated insulin secretion from the isolated islets of TallyHo mice, while in vivo administration of anti-leptin antibody lowered plasma glucose concentration with increased insulin level in TallyHo mice. Expression of glucokinase mRNA was decreased both in whole pancreas and leptin treated islets of TallyHo mice compared with whole pancreas in C57BL/6 mice and untreated islets of TallyHo mice, respectively. These results suggest that elevated plasma leptin can, through the inhibition of insulin secretion, induce glucose intolerance in TallyHo mice.