Effects of antihypertensive therapy on glucose tolerance: focus on calcium antagonists.

The prohormone form of insulin is contained in the secretory granules of the pancreatic beta-cell and released as the mature peptide sequence by exocytosis. One of the factors believed to trigger the movement of the secretory granules to the cell surface and their fusion with the plasma membrane is an increase in the cytosolic Ca2+ concentration [Ca2+]i. Extracellular glucose depolarizes the cells and favours the opening of voltage-dependent Ca2+ channels, which results in a rise in [Ca2+]i and activation of protein kinases. The phosphorylation of proteins associated with the functions of the secretory granules will influence the movement of the granules towards the plasma membrane. Due to their effects on voltage-dependent Ca2+ channels, it is suspected that calcium antagonists influence glucose-stimulated insulin release. Current information on calcium antagonists suggests that they may have different effects on glucose tolerance in non-diabetic and diabetic subjects. In non-diabetic hypertensives, fasting blood glucose is generally not affected by verapamil, diltiazem or nifedipine taken in therapeutic doses, although some reports indicate that high-dose nifedipine or diltiazem may deteriorate glucose homeostasis. Studies of the effect of single doses of calcium antagonists on the response to a glucose challenge have yielded somewhat conflicting results. The general picture, however, is that under these circumstances glucose tolerance in non-diabetic individuals remains largely unaffected, although higher doses of verapamil and nifedipine have impaired glucose tolerance slightly in some studies. In patients with non-insulin-dependent diabetes mellitus (NIDDM), acute administration of calcium antagonists with or without glucose challenge does not generally cause any changes in the blood glucose or insulin profiles. During short-term calcium antagonist therapy, conflicting results have been obtained. Overall, the data suggest that these drugs do not significantly modify glucose homeostasis. However, some reports do suggest that diabetic patients may deteriorate on nifedipine treatment. There are as yet no clear indications of any consistent changes in glucose homeostasis during long-term administration of verapamil, diltiazem or nifedipine. However, isolated case reports have indicated unfavourable changes in glucose homeostasis in patients treated with calcium antagonists of the dihydropyridine type, such as nifedipine.(ABSTRACT TRUNCATED AT 400 WORDS)