Pancreatic β Cells From db/db Mice Show Cell-specific [Ca2+]i and NADH Responses to Glucose but Not to α-Ketoisocaproic Acid

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We recently showed that timing and magnitude of the glucose-induced cytoplasmic calcium [Ca2+]i response are reproducible and specific for the individual beta cell. We now wanted to identify which step(s) of stimulus-secretion coupling determine the cell specificity of the [Ca2+]i response and whether cell specificity is lost in beta-cells from diabetic animals. Besides glucose, we studied the effects of glyceraldehyde, a glycolytic intermediate, and alpha-ketoisocaproic acid (KIC), a mitochondrial substrate. Early [Ca2+]i changes were studied stimulations in fura-2-labeled dispersed beta cells from lean, ob/ob, and db/db mice. Lag time and peak height were compared during 2 consecutive stimulations with the same stimulator. Nicotinamide adenine dinucleotide (NADH) responses to glucose and KIC were studied as a measure of metabolic flux. Both glyceraldehyde and KIC induced cell-specific temporal responses in lean mouse beta cells with a correlation between lag times for [Ca2+]i rise during the first and second stimulation. Beta cells from ob/ob and db/db mice showed cell-specific temporal [Ca2+]i responses to glucose and glyceraldehyde but not to KIC. Glucose induced cell-specific NADH responses in all 3 models, but KIC did so only in lean mouse [beta] cells. A cell-specific response may be induced at several steps of beta-cell stimulus-secretion coupling. Mitochondrial metabolism generates a cell-specific response in normal beta cells but not in db/db and ob/ob mouse beta cells.