Noninsulin-dependent diabetes mellitus (NIDDM) is an increasingly common disease, which brings a number of life-threatening complications. In rats with experimentally induced diabetes, there is an increase in the capacity of the intestine to absorb monosaccharides. We have examined the activity and the expression of monosaccharide transporters in the intestine of patients suffering from NIDDM. Na(+)-dependent D-glucose transport was 3.3-fold higher in brush-border membrane (BBM) vesicles isolated from duodenal biopsies of NIDDM patients compared with healthy controls. Western analysis indicated that SGLT1 and GLUT5 protein levels were also 4.3- and 4.1-fold higher in diabetic patients. This was associated with threefold increases in SGLT1 and GLUT5 mRNA measured by Northern blotting. GLUT2 mRNA levels were also increased threefold in the intestine of diabetic patients. Analysis of other BBM proteins indicated that the activity and abundance of sucrase and lactase were increased by 1.5- to 2-fold and the level of the structural proteins villin and beta-actin was enhanced 2-fold in diabetic patients compared with controls. The increase in the capacity of the intestine to absorb monosaccharides in human NIDDM is due to a combination of intestinal structural change with a specific increase in the expression of the monosaccharide transporters SGLT1, GLUT5, and GLUT2.

In normal pancreatic acinar cells, the oxidant menadione evokes repetitive cytosolic Ca2+ spikes, partial mitochondrial depolarisation,cytochrome c release and apoptosis. The physiological agonists acetylcholine and cholecystokinin also evoke cytosolic Ca2+ spikes but do not depolarise mitochondria and fail to induce apoptosis. Ca2+ spikes induced by low agonist concentrations are confined to the apical secretory pole of the cell by the buffering action of perigranular mitochondria. Menadione prevents mitochondrial Ca2+ uptake, which permits rapid spread of Ca2+ throughout the cell. Menadione-induced mitochondrial depolarisation is due to induction of the permeability transition pore. Blockade of the permeability transition pore with bongkrekic acid prevents activation of caspase 9 and 3. In contrast, the combination of antimycin A and acetylcholine does not cause apoptosis but elicits a global cytosolic Ca2+ rise and mitochondrial depolarisation without induction of the permeability transition pore. Increasing the cytosolic Ca2+buffering power by BAPTA prevents cytosolic Ca2+ spiking, blocks the menadione-elicited mitochondrial depolarisation and blocks menadione-induced apoptosis. These results suggest a twin-track model in which both intracellular release of Ca2+ and induction of the permeability transition pore are required for initiation of apoptosis.

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