Effects of glimepiride and glyburide on glucose counterregulation and recovery from hypoglycemia
Introduction
Sulfonylureas are commonly used to treat type 2 diabetes mellitus. Their most serious side effect is hypoglycemia [1], which often is an impediment for achieving optimal glycemic control [2].
The frequency of severe hypoglycemia varies considerably among sulfonylureas [3]. Potency and duration of action have generally been considered the most important factors [4]. However, despite the fact that glyburide and glimepiride have roughly similar efficacies and durations of action [1], [5], the frequency of severe hypoglycemia appears to be several-fold greater in patients treated with glyburide than those treated with glimepiride [6]. Thus, some factor(s) other than potency and duration of action may be important [7].
In addition to different actions on pancreatic beta cells [8], [9], [10], a differential effect on pancreatic alpha cells is a possibility. Pancreatic alpha cells, such as pancreatic beta cells, contain sulfonylurea receptors linked to K-ATP–sensitive potassium channels [11], [12], [13], [14], [15]. After the demonstration by Samols et al [16] of a suppressive effect of tolbutamide on plasma glucagon in ducks, numerous in vitro studies have shown an inhibitory effect of several sulfonylureas (gliclazide, glyburide, tolazamide, and tolbutamide) on glucagon secretion [17], [18], [19], [20], [21], [22]. In contrast, glimepiride has not been found to affect glucagon secretion in vitro [23].
In human studies, long-term sulfonylurea treatment with tolazamide, chlorpropamide, tolbutamide, or acetohexamide has been reported to suppress postprandial glucagon secretion in patients with type 2 diabetes mellitus [24]. Moreover, both tolbutamide [25] and glyburide [26], [27] have been reported to reduce glucagon responses to hypoglycemia. However, no data are currently available on the effects of glimepiride in human beings.
We therefore undertook these studies to test the hypothesis that suppression of the glucagon response to hypoglycemia by glyburide but not by glimepiride might be an important factor explaining the difference in frequency of severe hypoglycemia with these 2 sulfonylureas. In addition, we compared insulin secretory kinetics and the responses of other counterregulatory hormones (growth hormone, epinephrine, and cortisol) during a 2-hour hyperinsulinemic hypoglycemic (∼2.45 mmol) clamp experiment and during a 3-hour recovery period.
Section snippets
Subjects
Informed written consent was obtained from 16 healthy volunteers (6 men and 10 women) after the protocol had been approved by the University of Rochester Institutional Review Board. Subjects were 40 ± 3 years and had a body mass index of 27 ± 1 kg/m2. Their screening history, physical examination, and routine laboratory tests (hemoglobin A1c, metabolic profile, lipid panel, thyroid-stimulating hormone, complete blood count, and urinalysis) were normal.
Protocol
All subjects were studied on 3 occasions,
Plasma glucose and insulin concentrations
Baseline plasma glucose and insulin concentrations were comparable in all experiments. During the 120-minute insulin infusion, plasma insulin increased to comparable levels, and plasma glucose was clamped at virtually identical levels in each experiment (∼2.5 mmol/L). After stopping the insulin infusion, plasma glucose increased in all experiments but less with glyburide. Values at the end of the recovery period (3 hours after stopping the insulin infusion) were 3.7 ± 0.2 mmol/L in glyburide
Discussion
We found that neither glyburide nor glimepiride affected plasma glucagon, epinephrine, and growth hormone responses during hypoglycemia. However, both sulfonylureas caused a modest (∼10%) reduction in plasma cortisol responses. Previous studies have not found sulfonylureas to affect epinephrine and cortisol responses [26], [27], [38], whereas one study, but not others, found reduced growth hormone responses [39]. The reason for these discrepancies and their clinical significance is unclear.
Both
Acknowledgment
The present work was supported in part by a General Clinical Research Center grant (5MO1 RR-00044) from the National Center for Research Resources, National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases grant DK-20411 to John Gerich, an American Diabetes Association Career Development Award to Christian Meyer, and a grant from Aventis Pharmaceuticals.
We thank Mary Little for her excellent editorial assistance and the nursing and laboratory staff of
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