Patients with type II diabetes mellitus display an abnormal pattern of insulin secretion when challenged with intravenous glucose. The mechanism of this change in insulin secretion is not clear. Rat islets exposed to a stimulatory concentration (>10 mM) of glucose for a prolonged period of time display a markedly diminished insulin secretory response upon subsequent challenge with glucose. This phenomenon is known as time- dependent suppression and is similar to the change in insulin secretion seen in type II diabetics. Prolonged exposure to agents which stimulate PI hydrolysis (e.g., acetylcholine) or to agents that increase cAMP (e.g., forskolin or GIP) also induce time-dependent suppression. Previous studies have suggested that glucose-stimulated insulin secretion is temporally mediated by an increase in ATP which decreases K+ conductance and membrane potential leading to an increased Ca2+ influx which, in turn, activates PI- specific phospholipase C activity. The purpose of the present studies is to define the role(s) of phosphatidylinositol turnover (PI), phospholipase Cs and protein kinase C in time-dependent suppression of insulin secretion. Our working hypothesis is that time-dependent suppression depends on changes in either PI turnover and/or the activity of one or more isoforms of PI-specific phospholipase C and/or to alterations in PKC translocation or activity. To investigate this hypothesis, the time dependent suppression of insulin secretion caused by acetylcholine and by gastric inhibitory peptide will be characterized. The behavior of suppressed islets will be analyzed in terms of: 1) glucose utilization and oxidation; 2) membrane potential and electrical activity; 3) ion channel function; 4) intracellular free Ca2+; 5) inositol 1,4,5-trisphosphate production; 6) PKC translocation and activity; 7) DAG synthesis; and 8) phosphorylation of PI- specific phospholipase C. These studies should lead to a better understanding of the disordered signaling events that are responsible for altered patterns of insulin secretion.
| Kelley, G G; Ondrako, J M; Reks, S E (2001) Fuel and hormone regulation of phospholipase C beta 1 and delta 1 overexpressed in RINm5F pancreatic beta cells. Mol Cell Endocrinol 177:107-15 |
| Zawalich, W S; Zawalich, K C; Kelley, G G et al. (1995) Islet phosphoinositide hydrolysis and insulin secretory responses from prediabetic fa/fa ZDF rats. Biochem Biophys Res Commun 209:974-80 |
| Zawalich, W S; Kelley, G G (1995) The pathogenesis of NIDDM: the role of the pancreatic beta cell. Diabetologia 38:986-91 |
| Zawalich, W S; Zawalich, K C; Kelley, G G (1995) Effects of short-term culturing on islet phosphoinositide and insulin secretory responses to glucose and carbachol. Acta Diabetol 32:158-64 |
| Kelley, G G; Zawalich, K C; Zawalich, W S (1994) Calcium and a mitochondrial signal interact to stimulate phosphoinositide hydrolysis and insulin secretion in rat islets. Endocrinology 134:1648-54 |
