Oral sulfonylurea agents suppress hepatic glucose production in non-insulin-dependent diabetic individuals

In the present paper we have reviewed the literature concerning the mechanisms of action of the oral sulfonylurea agents on glucose metabolism. In addition, we report our results examining the effect of glyburide in 10 non-insulin-dependent diabetic patients. Before therapy the fasting glucose concentration averaged 198 ± 19 mg/dl and the oral glucose tolerance test (OGTT) was markedly abnormal. Following 3 mo of glyburide therapy, the fasting glucose had declined to 141 ± 16 mg/dl (P < 0.01 vs. preglyburide) and the OGTT (absolute plasma glucose concentration) was improved (P < 0.001). However, the incremental increase (i.e., above basal) in plasma glucose during the OGTT was not significantly altered. In the postabsorptive state the fasting plasma glucose concentration is determined by only two factors: (1) the rate of glucose entry into the body, which is essentially equal to the rate of hepatic glucose production (HGP) and (2) the rate of glucose removal from the body or the glucose clearance. In the basal state HGP was slightly increased compared to age-matched controls and averaged 2.35 ± 0.28 mg/kg.min. Following 3 mo of glyburide, HGP decreased to 1.72 ± 0.18 mg/kg.min (P < 0.01) and the decrease in HGP was strongly correlated with the decrease in fasting glucose (r = 0.85, P < 0.005). Basal glucose clearance in non-insulin-dependent diabetes was reduced compared to controls (1.22 ± 0.04 vs. 2.32 ± 0.03 ml/kg.min, P < 0.001) but did not change after glyburide (1.25 ± 0.10). These results indicate that the primary effect of glyburide to enhance glucose tolerance results from an effect on the liver to decrease glucose output.