How does glibenclamide lower plasma glucose concentration in patients with type 2 diabetes

Twelve patients with Type 2 diabetes and uncontrolled hyperglycaemia, never before treated with anti-diabetic drugs, were studied before and after several months of glibenclamide therapy. Fasting plasma glucose fell significantly (p<0.01) from 12.5±1.1 (mean±SE) to 8.3±0.4 mmol−1 with glibenclamide therapy, as did glycosylated haemoglobin (from 12.0±0.9 to 8.4±0.7%). The improvement in blood glucose control was accompanied by an increase in postprandial plasma insulin concentration measured hourly from 0800 to 1600 h (p<0.001). Over the same period, plasma NEFA and lactate levels were significantly (p<0.001) lower after treatment with glibenclamide. Mean (±SE) insulin-mediated glucose metabolic clearance rate was evaluated during glucose clamp studies, and was significantly higher (p<0.001) after glibenclamide therapy at steady-state insulin levels of ˜ 10 mU I−1 (53±3 vs 38±2 ml m−2 min−1) and ˜70 mU I−1 (78±9 vs 55±6 ml m−2 min−1). Hepatic glucose production was also lower following glibenclamide treatment at both the lower (56±5 vs 68±5 mg m−2 min−1) and higher (22±4 vs 32±6 mg m−2 min−1) insulin levels. Although all metabolic variables measured appeared to improve in association with the administration of glibenclamide, the only statistically significant correlations with the decrease in plasma glucose concentration were the increase in integrated plasma insulin concentration (r=-0.64, p<0.02) and the decrease in integrated plasma NEFA concentration (r=0.68, p<0.01). Based upon these findings we propose that the increase in ambient insulin level was primarily responsible for the decline in plasma glucose level following glibenclamide therapy, possibly by lowering plasma NEFA concentrations.