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Glyburide Enhances the Responsiveness of the β-Cell to Glucose but Does not Correct the Abnormal Patterns of Insulin Secretion in Noninsulin-Dependent Diabetes Mellitus^*

E. TIMOTHY SHAPIRO, EVE VAN CAUTER, HARTMUT TILLIL, BRUCE D. GIVEN, LAWRENCE HIRSCH, CHRISTINE BEEBE, ARTHUR H. RUBENSTEIN and KENNETH S. POLONSKY

Department of Medicine, University of Chicago, Pritzker School of Medicine Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Kenneth S. Polonsky, M.D., Department of Medicine, Box 435, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637.

Eleven patients with noninsulin-dependent diabetes mellitus were studied before and after 6-10 weeks of glyburide therapy. Patients were studied during a 24-h period on a mixed diet comprising 30 Cal/kg divided into three meals. The following day a hyperglycemic clamp study was performed, with glucose levels clamped at 300 mg/dL (16.7 mmol/L) for a 3-h period. Insulin secretion rates were calculated by deconvolution of peripheral C-peptide concentrations using individual C-peptide clearance kinetics derived after bolus injection of biosynthetic human C-peptide. After 6-10 weeks on glyburide, the identical studies were repeated.

In response to glyburide, the fasting plasma glucose level decreased from 12.3+–1.2 to 6.8+–0.9 mmol/L. Although the mean glucose over the 24 h of the meal study decreased from 12.7+–1.4 to 10.8+–1.2 mmol/L, postprandial hyperglycemia persisted on therapy, and after breakfast, glucose levels exceeded 10 mmol/L and did not return to fasting levels for the remainder of the day. Fasting serum insulin, plasma C-peptide, and the insulin secretion rate were not different before (152+–48 pmol/ L, 0.82+–0.16 pmol/mL, and 196+–34 pmol/min, respectively) and after (186+–28 pmol/L, 0.91+–0.11 pmol/mL, and 216+–23 pmol/min, respectively) glyburide treatment despite lowering of the glucose level. However, average insulin and C-peptide concentrations over the 24-h period increased from 366+–97 pmol/L and 1.35+–0.19 pmol/mL to 434+–76 pmol/L and 1.65+–0.15 pmol/mL, respectively. The total amount of insulin secreted over the 24-h period rose from 447+–58 nmol before therapy to 561+–55 nmol while receiving glyburide. Insulin secretion was demonstrated to be pulsatile in all subjects, with periodicity ranging from 2-2.5 h. The number of insulin secretory pulses was not altered by glyburide, whereas pulse amplitude was enhanced after lunch and dinner, suggesting that the increased insulin secretion is characterized by increased amplitude of the individual pulses.

In response to a hyperglycemic clamp at 300 mg/dL (16.7 mmol/L), insulin secretion rose more than 2-fold, from 47+–9 nmol over the 3-h period before treatment to 103+–21 nmol after glyburide therapy.

We conclude that the predominant mechanism of action of glyburide in patients receiving therapy for 6-10 weeks is to increase the responsiveness of the β-cell to glucose. This effect may be masked under fasting conditions due to a reduction in the plasma glucose level and is seen most clearly under hyperglycemic conditions and in the postprandial state.

^* This work was supported in part by Grants DK-31842, DK-13941, and DK-20595 from the NIH and the Clinical Research Center at the University of Chicago (RR-00055), Eli Lilly Co., Upjohn Co., and grants from the Belgian Ministere de la Politique Scientifique (Actions Concertees) and the Belgian Fonds National de la Recherche Scientifique Medicale.

Supported by the Deutsche Forschungsgemeinschaft (Training Grant Ti 154/1-1) and the Deutsche Diabetes-Gesellschaft (Junior Science Award).

Recipient of a Research Career Development Award from the NIH (DK-01234).

Received February 3, 1989.

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