beta-cell hypertrophy in falfa rats is associated with basal glucose hypersensitivity and reduced SNARE protein expression

In normal isolated beta-cells, the response to glucose is heterogeneous and characterized by an increasing number of secretory cells as glucose concen tration rises (Pipeleers DG, Kiekens R, Ling Z, Wilikens A, Schuit F: Physi ologic relevance of heterogeneity in the pancreatic beta-cell population. D iabetologia 37 (Suppl. 2):S57-S64, 1994). We hypothesized that fasting hype rinsulinemia in obesity might be explained by altered beta-cell heterogenei ty of signal transduction mechanisms, possibly involving exocytotic protein s. Insulin secretion from individual beta-cells sorted according to the siz e of the islet donor (<125 mu m, <250 mu m, and intermediate diameter) was measured by reverse hemolytic plaque assay. beta-cells from fa/fa rats were hypertrophied 25-40%, independent of donor islet size. This was accompanie d by an increased proportion of secretory cells (recruitment) at 5.5-11.0 m mol/l glucose, increased secretion per cell at 2.8 mmol/l glucose, and decr eased insulin content after acute glucose exposure without an increase in s ecretion per cell. Decreased expression of exocytotic (soluble N-ethylmalei mide-sensitive fusion protein receptor [SNARE]) proteins, vesicle-associate d membrane protein isoform 2 (VAMP-2), synaptosomal protein of 25 kDa (SNAP -25), and syntaxin-1 and -2 in fa/fa beta-cells may contribute to the failu re to sustain excessive plaque size at higher glucose concentrations. Easti ng hyperinsulinemia may be maintained by increased recruitment and an exagg erated secretory response in all fa-derived islet populations. Glucose regu lates beta-cell responsiveness in the short term, and these effects may inv olve altered expression of SNARE proteins.