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

¹ Department of Medicine M (Endocrinology and Diabetes), Aarhus University Hospital, Århus, Denmark
² Department of Medicine, Kolding Sygehus Kolding, Denmark
³ Guilford, Connecticut
⁴ Department of Medicine, General Clinical Research Center and National Science Foundation Center for Biological Timing, University of Virginia, Charlottesville, Virginia
⁵ Department of Clinical Pharmacology, Aarhus University, Århus, Denmark

The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 ± 2 years, BMI 27.5 ± 1.1 kg/m², fasting plasma glucose 9.8 ± 0.8 mmol/l, HbA_1c 7.5 ± 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40–80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means ± SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 ± 0.9 vs. 7.8 ± 0.6 mmol/l; placebo, 10.0 ± 0.8 vs. 11.0 ± 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 ± 12.0 vs. 61.0 ± 17.0 pmol · l^–1 · pulse^–1; placebo, 36.1 ± 8.4 vs. 30.3 ± 7.4 pmol · l^–1 · pulse^–1, P = 0.047; 5 weeks-elevated: gliclazide vs. placebo, 49.7 ± 13.3 vs. 37.1 ± 9.5 pmol · l^–1 · pulse^–1, P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 ± 2.2 vs. 16.7 ± 4.3 pmol · l^–1 · pulse^–1; placebo, 5.9 ± 0.9 vs. 7.2 ± 0.9 pmol · l^–1 · pulse^–1, P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 ± 2.5 vs. 9.4 ± 2.1 pmol · l^–1 · pulse^–1, P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between individual values for the acute improvement of regularity, as measured by ApEn, and the decrease in fasting plasma glucose during short-term (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coarse ApEn, respectively). In conclusion, the sulfonylurea agent gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity. The data suggest a possible relationship between the improvement in short-term glycemic control and the acute improvement of regularity of the in vivo insulin release process.

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