The Effect of Chronic Sulfonylurea Therapy on Hepatic Glucose Production in Non-insulin-dependent Diabetes

Abstract

In 20 patients with untreated non-insulin-dependent diabetes mellitus (NIDDM), there was a positive relationship between fasting plasma glucose (FPG) and glucose production rate, calculated by the isotope dilution technique (r = 0.72, P less than 0.001). This suggests that glucose production rate is an important determinant of FPG in untreated NIDDM. Fifteen patients were also studied during therapy with chlorpropamide for 3-6 mo. During therapy, FPG was lower (133 +/- 9 vs. 216 +/- 20 mg/dl, mean +/- SEM; P less than 0.001), glucose production was lower (59.5 +/- 2.0 vs 77.6 +/- 4.9 mg/m2/min; P less than 0.005), and there was a significant correlation between the fall in glucose production and the fall in FPG (r = 0.59, P less than 0.05). Fasting IRI levels increased in some, but not all, patients during chlorpropamide (untreated 18 +/- 2, treated 21 +/- 2 muU/ml; P= NS). However, there was a significant relationship between the percent rise in IRI and the fall in glucose production during treatment (r = 0.75, P less than 0.001). Patients with a rise in fasting insulin during therapy had a greater fall in glucose production than those whose insulin did not rise (25.4 +/- 8.1 vs. 7.8 +/- 2.4 mg/m2/min; P less than 0.005). When a low-dose insulin infusion was given to approximate the increases of portal venous insulin during therapy, similar falls of glucose production occurred. We conclude that inhibition of endogenous glucose production during chronic chlorpropamide therapy is an important mechanism for the lowering of FPG and that enhanced insulin secretion is the reason for the major part of this inhibition. The small fall in glucose production in those patients whose insulin level did not rise during therapy suggests an additional contribution by some other mechanism.

Glyburide Decreases Insulin Requirement, Increases (β-Cell Response to Mixed Meal, and Does Not Affect Insulin Sensitivity: Effects of Short- and Long-Term Combined Treatment in Secondary Failure to Sulfonylurea

“…At similar plasma insulin, other authors have reported no (8,9) or minimal (2) effects of sulfonylurea on insulin sensitivity. Conversely, at high insulin concentrations (150-10,000 uAJ/ml), sulfonylurea improved insulin sensitivity (2,3) and enhanced suppression of glucose production (35,36). The observation that insulin action was improved only at insulin concentrations of ^ 150 jjiU/ml makes it difficult to extrapolate this finding to conditions of daily living.…”

Comparison of Pharmacokinetics, Metabolic Effects and Mechanisms of Action of Glyburide and Glipizide During Long-Term Treatment

“…Moreover, the lower fasting plasma glucose level during GB therapy coincided with higher fasting insulin concentrations. The latter, in turn, should result in greater suppression of basal hepatic glucose production (3,5,6). Hepatic glucose production determines fasting plasma glucose, and suppression of hepatic glucose production results in lowering of fasting plasma glucose (3,5,6,10,29,30).…”

“…Both pharmacokinetic and pharmacodynamic factors may contribute to these differences. Diabetes Care 10:671-78, 1987 T he mechanisms by which sulfonylurea drugs lower plasma glucose involve stimulation of insulin secretion, enhancement of peripheral glucose utilization, and suppression of hepatic glucose production (1)(2)(3)(4)(5)(6)(7). Stimulation of insulin secretion seems to dominate during short-term treatment (2,7,8), whereas the importance of enhanced insulin sensitivity increases during long-term treatment (4)(5)(6)(7).…”

Insulin Secretagogues, Sulfonylurea Receptors and KATP Channels

“…The use of sulfonylureas has been complicated by their potential to produce hypoglycemia, by possible extra-pancreatic effects because the same and similar channels are found in other tissues, and by a lack of compounds that selectively target the K ATP channel isoforms. Following the introduction of tolbutamide in 1956 [6] and glibenclamide, a 'second' generation hypoglycemic agent, in 1982, it was clear these agents were therapeutically useful because they acted rapidly, were inexpensive, and could be *Address correspondence to this author at the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston Texas, 77030, USA; Tel: (713)-798-4007; Fax: (713)-790-0545; E-mail: jbryan@bcm.tmc.edu given once a day to achieve normoglycemia in patients with diabetes [7,8]. The efficacy of different sulfonylureas was related to the affinity for their receptor (100 µM for tolbutamide vs 0.1-1 nM for glibenclamide or glimiperide).…”