Sulfonylurea-induced inhibition of glucagon secretion from the perfused rat pancreas: evidence for a direct, non-paracrine effect.
The effects of sulfonylurea on glucagon secretion were characterized in the perfused rat pancreas using glibenclamide (1 microgram/ml) or tolazamide (10 micrograms/ml) in the presence of 3.3 mmol/l glucose. Glucagon release, which was unaffected by glibenclamide at 2.75 mmol/l calcium, was suppressed at 1.19 and 0.64 mmol/l but transiently stimulated at 0.25 mmol/l extracellular calcium. The insulinogenic effect of glibenclamide at 0.64 and 0.25 mmol/l calcium was enhanced by 35% and 89%, respectively, compared to the response at 2.75 mmol/l calcium. The stimulatory effect of the compound on somatostatin secretion, however, was lost at the lower calcium levels. The effects of tolazamide at 2.75 and 0.64 mmol/l calcium mimicked those of glibenclamide, thus indicating that our results with the latter compound may be representative for all sulfonylureas. In pancreata from insulin-deficient alloxan-diabetic rats, glibenclamide completely lost its inhibitory effect on glucagon release at 0.64 mmol/l calcium. Inhibition was not restored by adding insulin (25 U/l) to the perfusate. However, when diabetic rats had been treated with insulin for 6-7 days, glibenclamide suppressed glucagon release at low calcium levels in the absence of stimulated insulin and somatostatin release. It is concluded that, at low calcium concentrations, sulfonylureas suppress glucagon secretion by a direct action on the A cell and not through paracrine interactions by insulin and somatostatin. Prolonged insulin deficiency impairs the sulfonylurea action on glucagon secretion.
D000818:Animals; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005934:Glucagon / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014042:Tolazamide / Q000494:pharmacology
D001786:Blood Glucose; D013453:Sulfonylurea Compounds; D005934:Glucagon; D014042:Tolazamide; D005905:Glyburide