The purpose of this study was to examine the effects of glyburide on peripheral (muscle) and hepatic insulin sensitivity in patients with non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) as well as in healthy control subjects. In protocol 1, 10 patients with NIDDM and seven young healthy control subjects were studied. Changes in insulin sensitivity (40 mU/m2.min euglycemic insulin clamp), hepatic glucose production (3-[3H]glucose turnover), and insulin secretion (+125 mg/dL hyperglycemic clamp) were measured before and after 3 months (in patients with NIDDM) and 6 weeks (in young control subjects) of glyburide therapy. In protocol 2, five patients with IDDM and eight patients with insulin-treated NIDDM were evaluated before and after two months of glyburide therapy (20 mg per day). Changes in daily insulin requirements, 24-hour plasma glucose profiles, glycohemoglobin, glucagon-stimulated C-peptide secretion, insulin sensitivity, and hepatic glucose production were measured. In protocol 1, glyburide significantly improved insulin sensitivity (p less than 0.01) and insulin secretion (p less than 0.01) in the NIDDM patients. The elevated rates of hepatic glucose production (2.4 +/- 0.3 mg/kg.min) were reduced after glyburide therapy (1.7 +/- 0.2 mg/kg.min; p less than 0.01) and were highly correlated with an improvement in fasted plasma glucose levels (r = 0.92; p less than 0.001). Insulin sensitivity also improved in the young healthy control subjects after glyburide therapy (6.5 +/- 0.5 to 7.6 +/- 0.7 mg/kg.min; p less than 0.05). In protocol 2, glyburide treatment produced no change in daily insulin requirement (54 +/- 8 versus 53 +/- 7 units per day), mean 24-hour glucose levels (177 +/- 20 versus 174 +/- 29 mg/dL), glycohemoglobin (10.1 +/- 1.0 percent versus 9.5 +/- 7 percent), C-peptide secretion, insulin sensitivity, or basal hepatic glucose production (p values not significant) in the IDDM patients. In contrast, the insulin-treated NIDDM patients had significant reductions in mean daily insulin requirement (72 +/- 6 versus 58 +/- 9 units per day; p = 0.05), mean 24-hour plasma glucose levels (153 +/- 10 to 131 +/- 5 mg/dL; p less than 0.05), and glycohemoglobin levels (10.3 +/- 0.7 percent to 8.0 +/- 0.4 percent; p less than 0.05) and an improvement in C-peptide secretion (0.24 +/- 0.07 to 0.44 +/- 0.09 pmol/mL; p = 0.08). Stimulated C-peptide levels were highly correlated with a reduction in insulin dose observed during the 2-month treatment period (r = 0.93; p less than 0.001). Insulin sensitivity improved slightly but not significantly after glyburide treatment.(ABSTRACT TRUNCATED AT 400 WORDS)