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*

Abstract

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 beta-cell to glucose.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute and Short-Term Administration of a Sulfonylurea (Gliclazide) Increases Pulsatile Insulin Secretion in Type 2 Diabetes

“…These specific mechanistic findings are in accordance with the previous observation that acute tolbutamide infusion in healthy humans can increase the amplitude of insulin concentration profiles without modifying the high-frequency oscillatory rate (11). Similarly, glyburide enhanced insulin secretion in diabetic patients by augmenting oscillatory amplitude in a 24-h study of ultradian oscillations (12). In nondiabetic dogs, tolbutamide infusion and ingestion likewise stimulated insulin secretion by dual effects on pulsatile secretion and basal secretion.…”

“…Substrates (glucose), hormones (glucagon-like peptide [GLP]-1, somatostatin, and IGF-1), and antidiabetic compounds that regulate insulin secretion seem to exert their actions primarily via modulation of insulin secretory burst mass rather than frequency (11)(12)(13)(14)(15)(16)(17)(18)(19). Despite the widespread clinical use of insulin secretagogues in the treatment of type 2 diabetes, the influence of these antidiabetic drugs on the oscillatory pattern of insulin release has been elucidated only sparingly in diabetic humans (12).…”

“…Despite the widespread clinical use of insulin secretagogues in the treatment of type 2 diabetes, the influence of these antidiabetic drugs on the oscillatory pattern of insulin release has been elucidated only sparingly in diabetic humans (12).…”

Glucagon-Like Peptide 1 Increases Secretory Burst Mass of Pulsatile Insulin Secretion in Patients With Type 2 Diabetes and Impaired Glucose Tolerance

“…This could not generally be expected because the pulsatility of insulin secretion has been found impaired in previous studies in type 2 diabetic patients (2,4,13,16) and even in nondiabetic first-degree relatives of type 2 diabetic patients (14,15). Given the impaired insulin secretory capability of B-cells in type 2 diabetic patients (29) and the reduced effectiveness of insulin secretagogues like glucose (30) and sulfonylureas (31), it may even be considered remarkable that GLP-1 is able to elicit a similar effect on insulin secretory burst mass as has previously been demonstrated in healthy subjects (11). A difference to this previous study is, however, that a fourfold increment in secretory burst mass was described in healthy subjects (11), whereas in the present study, GLP-1 led to an increment of only 68 and 45% in type 2 diabetic patients and subjects with IGT, respectively (Fig.…”

Nateglinide and Mitiglinide, but Not Sulfonylureas, Induce Insulin Secretion through a Mechanism Mediated by Calcium Release from Endoplasmic Reticulum

“…However, sulfonylureas, as the long-acting insulin secretagogues, probably cause hypoglycemia and body weight gain and are insufficient to control postprandial hyperglycemia (Shapiro et al, 1989;UK Prospective Diabetes Study Group, 1998). Furthermore, problems including secondary failure have been suggested previously (Salas and Caro, 2002).…”