Heterogeneity in glucose sensitivity among pancreatic beta-cells is correlated to differences in glucose phosphorylation rather than glucose transport.

Abstract

Rat beta‐cells differ in their individual rates of glucose‐induced insulin biosynthesis and release. This functional heterogeneity has been correlated with intercellular differences in metabolic redox responsiveness to glucose. The present study compares glucose metabolism in two beta‐cell subpopulations that have been separated on the basis of the presence (high responsive) or absence (low responsive) of a metabolic redox shift at 7.5 mM glucose. Mean rates of glucose utilization and glucose oxidation in high responsive beta‐cells were 2‐ to 4‐fold higher than in low responsive beta‐cells, whereas their leucine and glutamine oxidation was only 10–50% higher. This heterogeneity in glucose metabolism cannot be attributed to differences in GLUT2 mRNA levels or in glucose transport. In both cell subpopulations, the rates of glucose transport (13–19 pmol/min/10(3) beta‐cells) were at least 50‐fold higher than corresponding rates of glucose utilization. On the other hand, rates of glucose phosphorylation (0.3–0.7 pmol/min/10(3) beta‐cells) ranged within those of total glucose utilization (0.2–0.4 pmol/min/10(3) beta‐cells). High responsive beta‐cells exhibited a 60% higher glucokinase activity than low responsive beta‐cells and their glucokinase mRNA level was 100% higher. Furthermore, glucose phosphorylation via low Km hexokinase was detected only in the high responsive beta‐cell subpopulation. Heterogeneity in glucose sensitivity among pancreatic beta‐cells can therefore be explained by intercellular differences in glucose phosphorylation rather than in glucose transport.

Beta-cell hypersensitivity to glucose following 24-h exposure of rat islets to fatty acids

“…When considering our results, an important issue is the normal beta-cell sensor for glucose metabolism and insulin secretion is glucokinase, the high K m glucose phosphorylation enzyme [35,36]. Hexokinase is present in beta-cells in amounts comparable to glucokinase [37], but it normally has a minimal regulatory role over glucose metabolism because of insensitivity to physiological levels of glucose and endproduct inhibition by glucose 6-phosphate [38,39]. As such, a shift in the glucose set-point for insulin secretion would be predicted to reflect a variation in glucokinase activity.…”

Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts

“…In rodents, beta cell heterogeneity was also observed in terms of metabolic, signalling [27,28] and biosynthetic activities [12,29]. Mechanisms explaining heterogeneity of beta cells are totally unknown.…”

Proinsulin processing in the diabetic Goto-Kakizaki rat

“…All the proteins in question are localized to the secretory granule and the observed changes are consistent with cell-to-cell differences in granulation, yet the overall insulin content per islet was not altered in these animals (C-G Östenson, V Poitout & J C Hutton, unpublished observations). The heterogeneity is possibly the result of the differences in the thresholds of individual -cells for glucose-activated metabolism (Heimberg et al 1993, Bennett et al 1996, granule exocytosis and insulin biosynthesis (Kiekens et al 1992), or a feedback mechanism that interconnects these processes. It is conceivable that changes in paracrine relationships between the -cell and -cell could play a role given the marked changes in -cell distribution that characterize the islets of the GK rat and other diabetic models (Movassat et al 1997).…”