Changes in Carbohydrate Metabolism in Association With Glipizide Treatment of Type 2 Diabetes

Nineteen patients with Type 2 diabetes were treated with glipizide for 2.5–6 months, and measurements made of metabolic variables before and after glipizide treatment. For purposes of analysis, the glipizide associated decrease in fasting plasma glucose concentration was used to divide patients into ‘good’ responders (decrease of 4.0 mmol I−1 or more, n = 9) or ‘fair’ responders (decrease of 3.0 mmol I−1 or less, n = 10). Good responders had a significantly greater fall in their mean (± SE) hourly plasma glucose (6.3 ± 0.6 vs 2.7 ± 0.3 mmol I−1, p < 0.001) and NEFA (164 ± 40 vs 60 ± 37 μ-mol I−1, p < 0.05) concentrations from 0800 to 1600 h in response to meals (0800 and 1200h) than did the fair responders. However, the increase in hourly plasma insulin concentration following glipizide treatment was the same in the good (323 ± 103 to 413 ± 124 pmol I−1) and fair (276 ± 42 to 345 ± 43 pmol I−1) responders. Good responders also had a significant increase in glucose metabolic clearance rate (MCR) following glipizide treatment during glucose clamp studies performed at plasma insulin concentrations of approximately 100 pmol I−1 (39 ± 4 to 53 ± 5 ml min−1 m−2, p < 0.02) and 600 pmol I−1 (109 ± 15 to 172 ± 32 ml min−1 m−2, p < 0.05), whereas in fair responders a significant improvement in glucose MCR was seen during the clamp performed at 100 pmol I−1 (46 ± 4 to 51 ± 3 ml min−1 m−2, p < 0.05), but not when insulin concentration was increased to 600 pmol I−1 (101 ± 13 to 105 ± 15 ml min−1 m−2, NS). Although glucose MCR increased in both glucose clamp studies in the good responders, the magnitude of the insulin-induced increment in glucose uptake did not change significantly in response to glipizide therapy in this group. Glucose transport by adipocytes isolated from good responders (n = 4) was significantly higher (p < 0.001) after glipizide treatment in both the absence and presence of insulin, but the response to insulin did not change significantly with treatment. Basal hepatic glucose production also fell significantly (p < 0.05) in good responders (0.53 ± 0.06 to 0.29 ± 0.02 mmol min−1 m−2, n = 6), but not in fair responders (0.45 ± 0.04 to 0.42 ± 0.04 mmol min−1 m−2, n = 4, NS). Neither the ability of insulin to inhibit hepatic glucose production nor insulin binding to isolated adipocytes changed significantly following glipizide treatment. These results emphasize the variability in the blood glucose response to glipizide in patients with Type 2 diabetes, and demonstrate that those individuals with the best clinical response were characterized by a greater fall in circulating NEFA levels, a significant decrease in basal hepatic glucose production, and both in vivo and in vitro evidence of enhanced glucose uptake