Many mechanistic steps underlying nutrient-stimulated insulin secretion (NSIS) are poorly understood. The influence of intracellular pH (pH_i) on insulin secretion is widely documented, and can be used as an investigative tool. This study demonstrates previously unknown effects of pH_i-alteration on insulin secretion in mouse islets, which may be utilized to correct defects in insulin secretion.

Different components of insulin secretion in mouse islets were monitored in the presence and absence of forced changes in pH_i. The parameters measured included time-dependent potentiation of insulin secretion by glucose, and direct insulin secretion by different mitochondrial and non-mitochondrial secretagogues. Islet pH_i was altered using amiloride, removal of medium Cl^-, and changing medium pH. Resulting changes in islet pH_i were monitored by confocal microscopy using a pH-sensitive fluorescent indicator. To investigate the underlying mechanisms of the effects of pH_i-alteration, cellular NAD(P)H levels were measured using two-photon excitation microscopy (TPEM). Data were analyzed using Student's t test.

Time-dependent potentiation, a function normally absent in mouse islets, can be unmasked by a forced decrease in pH_i. The optimal range of pH_i for NSIS is 6.4–6.8. Bringing islet pH_i to this range enhances insulin secretion by all mitochondrial fuels tested, reverses the inhibition of glucose-stimulated insulin secretion (GSIS) by mitochondrial inhibitors, and is associated with increased levels of cellular NAD(P)H.

Pharmacological alteration of pH_i is a potential means to correct the secretory defect in non-insulin dependent diabetes mellitus (NIDDM), since forcing islet pH_i to the optimal range enhances NSIS and induces secretory functions that are normally absent.