Acute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetes

The high-frequency oscillatory pattern, of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatm ent of this disease, their effect on insulin release patterns is not well e stablished. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin sec retory 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/m(2), fasting plas ma glucose 9.8 +/- 0.8 mmol/l, HbA(1c), 7.5 +/- 0.3%) were studied in a dou ble-blind placebo-controlled prospective crossover design. Patients receive d 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 blo od sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h afte r the first dose (80 mg) of gliclazide (acute) with the plasma glucose conc entration clamped at the baseline value, 3) after 5 weeks of treatment (5 w eeks), and 4) after 5 weeks of treatment with the plasma glucose concentrat ion clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by d econvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gl iclazide versus placebo; results are means +/- SE. Fasting plasma glucose w as 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 m mol/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 <plus/minus> 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 freque ncy 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 t he decrease in fasting plasma glucose during shortterm (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coars e ApEn, respectively). In conclusion, the sulfonylurea, agent gliclazide au gments insulin secretion by concurrently increasing pulse mass and basal in sulin secretion without changing secretory burst frequency or regularity. T he data suggest a possible relationship between the improvement in short-te rm glycemic control and the acute improvement of regularity of the in vivo insulin release process.