Objective— To ascertain whether the effect of sulfonylureas on glucose-mediated insulin release persists for years to decades in patients with maturity-onset diabetes of the young.

Research Design and Methods— The effect of sulfonylurea treatment on glucose-induced insulin secretion was ascertained prospectively for up to 33 yr in 12 diabetic patients of the maturity-onset diabetes of the young RW pedigree, who are genetically homogeneous because they share DNA markers on chromosome 20q. In 7 of these patients, paired glucose tolerance tests, given while the patients were on and off sulfonylureas, were performed after 7–31 yr.

Results— Glucose-induced insulin secretion showed an average increase of 68% in diabetic patients who remained responsive to chlorpropamide after having been on and off the drug for decades. In most patients, however, glucose-induced insulin secretion declines over time (1–4%/yr). Some patients become unresponsive to sulfonylureas after 3–25 yr and then have very small or no increases in glucose-induced insulin secretion and require treatment with insulin to normalize fasting hyperglycemia.

Conclusions— Increase in glucose-induced insulin secretion remains the most important mechanism of the action of sulfonylureas during long-term administration.

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