The nature of ATP-sensitive K+ (K+ATP) channel-independent, insulinotropic action of glucose was investigated using non-glucose-primed pancreatic islets. When the beta-cell was depolarized with K+, glucose dose dependently stimulated insulin release despite inhibition of the K+ATP channel closure by diazoxide. K+ depolarization could be replaced with BAY K 8644, a calcium channel agonist. Prior fasting of rats and lowering ambient temperature greatly suppressed glucose oxidation and utilization by the islet cells and abolished insulin release in response to high glucose alone. However, under these conditions, the K+ATP channel-independent, glucose-induced insulin release was clearly demonstrable. p-Nitrophenyl-alpha-D-glucopyranoside (sweet taste inhibitor) but not its beta-isomer, neomycin (phospholipase C inhibitor) and staurosporine (C kinase blocker) inhibited the K+ATP channel-independent, insulinotropic action of glucose. For the K+ATP channel-independent glucose-induced insulin release 1) elevation of cytosolic calcium is required, 2) minute glucose metabolism is enough, if glucose metabolism is necessary, and 3) direct recognition of glucose molecule, phospholipase C, and protein kinase C appear to be involved.

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The mechanism of glucose-induced biphasic insulin release by the B cell was investigated using isolated rat pancreatic islets. In perifusion experiments, 16.7 mM glucose in combination with 25 mM K+ transformed the high K(+)-induced monophasic insulin release into a biphasic one in the presence of diazoxide (Dz), an ATP-sensitive K+ channel opener. Inclusion of Dz during the initial 6 min of glucose stimulation abolished the first phase, but was without effect on the second phase. In batch incubation experiments, fuels, including 16.7 mM glucose, 6 mM D-glyceraldehyde, and 10 mM 2-ketoisocaproate, but not sulfonylurea, caused time-dependent potentiation of the B cell so that the response to 25 mM K+, applied later, was increased in the fuel-primed islets. Inclusion of Dz or lowering extracellular Ca2+ (to micromolar range) during the priming, which eliminates the initiation of insulin release, did not eradicate the potentiation. We conclude that high glucose closes ATP-sensitive K+ channels, leading to membrane depolarization, Ca2+ influx, and initiation of insulin release (first phase), and subsequently self-augments insulin release in an ATP-sensitive K+ channel-independent manner (second phase), acting at steps distal to cytosolic Ca2+ elevation. The biphasic insulin release is thus generated by an interaction of ATP-sensitive K+ channel-dependent and -independent glucose actions.

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To evaluate the role of adrenal androgens in the development of arteriosclerosis, serum dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), aortic calcification and pulse wave velocity (PWV) were measured in 69 males and 119 females without overt cardiovascular disease. The steroids decreased with age in both sexes, and the reduction was significantly steeper in younger (≤40 years) than in older ( > 40 years) subjects only in females. When adjusted for age, the steroids were significantly lower in subjects with aortic calcification than in those without it, and the PWV was significantly slower in the latter. Adrenal androgens appear to retard the development and/or progression of arteriosclerosis.