Acute and chronic effects of sulfonylurea drugs on pancreatic islet function in man

The pancreatic islet can be viewed as an integrator of nutrient, neural, and hormonal signals. In normal people, glucose directly stimulates insulin release and also plays a key role as a potentiator of nonglucose stimulants of the B-cells. In patients with non-insulin-dependent diabetes mellitus (NIDDM), the direct effect of glucose on insulin secretion is markedly impaired. However, as hyperglycemia develops, basal insulin levels and insulin responses to nonglucose signals are maintained in many NIDD patients by the potentiating effect of hyperglycemia. Both acute and chronic administration of sulfonylurea drugs results in enhanced B-cell sensitivity to the potentiating effect of glucose. During sulfonylurea therapy this effect initially causes an increase in insulin level. However, as the glucose level falls during therapy the insulin level may tend to return toward pretreatment values, thereby masking the improvement of B-cell function. In NIDD patients with mild to moderate hyperglycemia (fasting plasma glucose less than 200 mg/dl), chronic sulfonylurea therapy results in the maintenance of near-normal insulin levels, but at a lower plasma glucose level. In patients with more severely impaired B-cell function, whose insulin levels before therapy are subnormal despite marked hyperglycemia, there is a net absolute increase in insulin levels during chronic sulfonylurea administration. Thus, some NIDD patients may show an increase in basal insulin levels during chronic sulfonylurea therapy while others may not; however, all patients who respond to sulfonylureas demonstrate increased B-cell sensitivity to glucose. Acute and chronic sulfonylurea treatment also results in a suppression of glucagon levels, an effect that may be secondary to the enhancement of B-cell function. The fall of plasma glucose during chronic sulfonylurea therapy is associated with a decrease in hepatic glucose production in NIDD patients. The magnitude of this effect is correlated with the degree of enhancement of basal insulin secretion. Thus, chronic sulfonylurea therapy clearly enhances pancreatic islet function in patients with NIDDM. We postulate that the major antihyperglycemic action of sulfonylurea therapy is mediated by this pancreatic effect.