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1 The Diabetes Research Center and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
2 Pharmacological Research 1, Novo Nordisk, Bagsvaerd, Denmark
3 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
* To whom correspondence should be addressed. E-mail: nicolai{at}mail.med.upenn.edu.
Inhibition of ATP-sensitive K+ channels (KATP channels) by an increase in the ATP/ADP ratio and
the resultant membrane depolarization are considered essential in the process leading to insulin
release (IR) from pancreatic 
-cells stimulated by glucose. It is therefore surprising that mice
lacking the sulfonylurea type 1 receptor (SUR1-/-) in -cells remain euglycemic even though the
knockout is expected to cause hypoglycemia. To complicate matters, isolated islets of SUR1-/- mice
secrete little insulin in response to high glucose, which extrapolates to hyperglycemia in the intact
animal. It remains thus unexplained how euglycemia is maintained. In recognition of the essential
role of neural and endocrine regulation of IR we evaluated the effects of acetylcholine (Ach) and
GLP-1 on IR and free intracellular Ca2+ ([Ca2+]i) of freshly isolated or cultured islets of SUR1-/-
mice and B6D2F1 controls (SUR1+/+). IBMX, a phosphodiesterase inhibitor, was also used to
explore cAMP dependent signaling in IR. Most striking and in contrast to controls, SUR1-/- islets
are hypersensitive to Ach and IBMX as demonstrated by a marked increase of IR even in the
absence of glucose. The hypersensitivity to acetylcholine was reproduced in control islets by
depolarization with the SUR1R inhibitor glyburide. Pretreatment of perifused SUR1-/- islets with
Ach or IBMX restored glucose stimulation of IR, an effect expectedly insensitive to diazoxide. The
calcium channel blocker verapamil reduced but did not abolish Ach-stimulated IR supporting a role
of intracellular Ca2+ stores in stimulus-secretion coupling. The effect of Ach on IR was greatly
potentiated by GLP-1 (10 nM). Ach caused a dose-dependent increase in [Ca2+]i (at 0.1 -1 µM) or
biphasic changes (an initial sharp increase in [Ca2+]i
followed by a sustained phase of low [Ca2+]i) at
1-100 µM. The latter effects were observed in substrate-free medium or in the presence of 16.7 mM
glucose. We conclude that SUR1 deletion depolarizes the -cells and markedly elevates basal
[Ca2+]i. Elevated [Ca2+]i in turn sensitizes the -cells to the secretory effects of Ach and IBMX.
Priming by the combination of high [Ca2+]i, Ach and GLP-1 restores the defective glucose
responsiveness precluding the development of diabetes but not effective enough to cause
hyperinsulinemic hypoglycemia.
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