In vitro studies on purified rat beta cells have indicated a functiona
l diversity among insulin-containing eels. Intercellular differences w
ere found in the rates of glucose-induced insulin synthesis and releas
e. They are attributed to differences in cellular thresholds for gluco
se utilization and oxidation, as can be caused by varying activities i
n rate limiting steps such as glucokinase-dependent phosphorylation. T
he percent of functionally active beta cells increases dose-dependentl
y with the glucose concentration, making cellular heterogeneity and it
s regulation by glucose major determinants for the dose-response curve
s of the total beta-cell population. Beta cells which are already resp
onsive to low glucose concentrations are characterized by a higher con
tent in pale immature granules; their activated biosynthetic and secre
tory activity accounts for preferential release of newly-formed hormon
e by the total beta-cell population. At any glucose level, the amplitu
de of insulin release depends on the percent glucose-activated cells a
nd their cyclic AMP content, an integrator of (neuro)hormonal influenc
es. The in vitro described heterogeneity in beta-cell functions may be
ar 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 th
at 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 p
revailing glucose concentration or by insufficient cyclic AMP levels i
n beta cells, possibly as a result of inadequate signalling from hormo
nes of local or distal origin. Only few markers are currently availabl
e with which to explore these mechanisms in vivo. Additional markers a
nd tests should help assess the possible role of variations in beta-ce
ll heterogeneity in the pathogenesis of diabetes mellitus.