Patients with non-insulin-dependent diabetes mellitus (NIDDM) who have chronic hyperglycemia lose acute incremental insulin responses to glucose but are able to briskly respond to other β-cell secretagogues. To investigate whether this is a defect specific for glucose or represents a more general phenomenon, we measured the insulin responses to acute intravenous tolbutamide in 10 obese patients with NIDDM both before and during sulfonylurea therapy with tolazamide. Comparable glycemia was achieved with oral dextrose 2 h before intravenous testing. To assess β-cell responsiveness to a nonsulfonylurea secretagogue, 1 mg glucagon was administered intravenously during tolazamide therapy. In seven patients, the mean peak insulin increment 5 or 10 min after intravenous tolbutamide was 54 ± 11 μU/ml when not receiving tolazamide (0.14 ± 1 . 3 μU/ ml) with tolazamide (P < .001), even though serum insulin responded rapidly to intravenous glucagon. In four patients tested for reversibility of their refractoriness to intravenous tolbutamide during chronic tolazamide therapy, the mean peak insulin increment 1 wk after discontinuing tolazamide was 79 ± 22 (μU/ml. A relatively rapid development of refractoriness was documented in four patients who were tested only 12 h after beginning tolazamide therapy; the mean peak insulin increments 5–10 min after intravenous tolbutamide were undetectable (−0.5 (μU/ml), yet responses to intravenous glucagon were evident. In these NIDDM patients, exposure of pancreatic pcells to sustained levels of sulfonylureas induces a reversible state of refractoriness to acute stimulation with sufonylureas but not to another secretagogue. This phenomenon has features in common with the effect of sustained hyperglycemia on desensitization of the β-cell response to intravenous glucose with implications regarding the pathogenesis of NIDDM. More over, it suggests that the insulinotropic effect of sulfonylureas might be more effective, particularly in cases of NIDDM with “secondary failure” to sulfonylureas, if these drugs are administered either on an intermittent schedule or as “pulse” therapy, using a form with a shorter duration of action.

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