Physiologic relevance of heterogeneity in the pancreatic beta-cell population

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Abstract
In vitro studies on purified rat beta cells have indicated a functional diversity among insulincontaining cells. Intercellular differences were found in the rates of glucose-induced insulin synthesis and release. They are attributed to differences in cellular thresholds for glucose utilization and oxidation, as can be caused by varying activities in rate limiting steps such as glucokinase-dependent phosphorylation. The percent of functionally active beta cells increases dose-dependently with the glucose concentration, making cellular heterogeneity and its regulation by glucose major determinants for the dose-response curves of the total beta-cell population. Beta cells which are already responsive to low glucose concentrations are characterized by a higher content in pale immature granules; their activated biosynthetic and secretory activity accounts for preferential release of newly-formed hormone by the total beta-cell population. At any glucose level, the amplitude of insulin release depends on the percent glucose-activated cells and their cyclic AMP content, an integrator of (neuro)hormonal influences. The in vitro described heterogeneity in beta-cell functions may bear physiological relevance as several of its characteristics are also detectable in intact pancreatic tissue; furthermore, in vitro signs of heterogeneity can be altered by prior in vivo treatment indicating that they express properties of the cells in their in situ configuration. Elevated basal levels of (pro)insulin may reflect the existence of an increased number of beta cells that are activated at low physiologic glucose concentrations. Reductions in stimulated insulin levels can be caused by decreased numbers of beta cells that are activated at the prevailing glucose concentration or by insufficient cyclic AMP levels in beta cells, possibly as a result of inadequate signalling from hormones of local or distal origin. Only few markers are currently available with which to explore these mechanisms in vivo. Additional markers and tests should help assess the possible role of variations in beta-cell heterogeneity in the pathogenesis of diabetes mellitus.