Tolbutamide stimulates insulin secretion in vivo by amplification of the mass of insulin secretory bursts

In the fasting basal state (BAS) 70% of insulin secretion is derived from the pulsatile mode of insulin secretion. While it is known that sulphonyureas stimulate insulin secretion, it is unknown if this is achieved by modulation of the pulsatile or non-pulsatile component of insulin secretion and, if the former, through stimulation of the frequency and/or mass of insulin secretory bursts. We employed a recently validated canine model employing deconvolution of portal vein insulin concentration profiles obtained for 40 minutes before (BAS) and 40 minutes during (TOL) a tolbutamide infusion 0.2 mg/kg/min in 7 dogs; the plasma glucose being clamped at euglycemia by a glucose infusion. The mean arterial (85±12 to 325±66 pmol/l, BAS to TOL) and portal vein (345±55 to 1288± 230 pmol/l, BAS to TOL) insulin concentrations increased during tolbutamide. This increase was due to an increase in insulin secretion rate from 2.4±0.3 to 10.0±2.0 pmol/kg/min (p<0.01) with no change in insulin clearance (0.8±0.1 vs 0.8± 0.1 l/min). The percentage of insulin derived from pulsatile insulin secretion before or during tolbutamide was unchanged at ∼70%. Thus, the predominant increase in insulin secretion with TOL was derived by increased pulsatile insulin secretion which was achieved by a 220% increase in pulse mass (266±64 vs 817±144 pmol/pulse, BAS vs TOL, p<0.005), but no change in pulse frequency (10.1±0.6 vs 11.1±0.8 pulses/hour, BAS vs TOL, p=0.33). We conclude that sulphonylurea mediated insulin secretion is mediated by amplification of insulin secretory burst mass.