Selective Unresponsiveness of Pancreatic β-Cells to Acute Sulfonylurea Stimulation During Sulfonylurea Therapy in NIDDM

Abstract

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 p-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 p-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 ixU/ml when not receiving tolazamide (0.14 ± 1 . 3 |xU/ 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 (xU/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 (xU/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 p-cell response to intravenous glucose with implications regarding the pathogenesis of NIDDM. Moreover, 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. DIABETES 1986; 35:1314-20.

Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

“…Approximately 30 years ago a reversible impairment of insulin secretion by sulfonylureas, such as tolbutamide or glibenclamide, was noted (36). The sulfonylurea-induced desensitization was described to be selective for sulfonylureas (37,38), but in vitro experimentation showed that exposure of islets to sulfonylureas also markedly reduced glucose-induced insulin secretion (39 -41). In vitro, the onset of an inhibitory effect of tolbutamide on insulin secretion became visible after 30 min (42).…”

Chronic exposure to tolbutamide and glibenclamide impairs insulin secretion but not transcription of KATP channel components

“…Insulinotropic sulphonylureas such as tolbutamide and Although sulphonylureas are known to exert acute stimu-39 latory effects upon insulin secretion [3], several studies have 40 suggested that chronic treatment with these drugs leads to 41 a decline in their insulinotropic activity [8][9][10][11], an observa-42 tion which has been attributed to a direct desensitisation of 43 the pancreatic beta-cell to the actions of these drugs [12,13]. 44 This desensitisation effect has been suggested to be due to 45 a decline in beta-cell K ATP channel activity [14,15].…”

Long-term gliclazide treatment improves the in vitro glucose-induced insulin release in rats with Type 2 (non-insulin-dependent) diabetes induced by neonatal streptozotocin

“…It has been recently reported in humans with Type 2 diabetes that sustained exposure to sulfonylurea induces a selective unresponsiveness of the B cells to short-term sulfonylurea stimulation [37]. Such a desensitization to gliclazide was not detected in the n-STZ models at least over the 30-day treatment period.…”