Mechanisms of sulfonylurea's stimulation of insulin secretion in vivo: Selective amplification of insulin secretory burst mass

Niels K. Pørksen, Stephen R. Munn, Jeffery L. Steers, Ole Schmitz, Johannes D Veldhuis, Peter C. Butler

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Although sulfonylureas enhance insulin secretion, it is unknown whether these hypoglycemic chemicals stimulate insulin secretion through the augmentation of the pulsatile or basal modes of insulin release. Enhanced pulsatile insulin could occur in turn through amplification of the burst mass or an increase in burst frequency. To address the mechanism of sulfonylurea action, we employed a recently validated canine model with a portal vein sampling catheter and flow probe to measure pulsatile insulin secretion in vivo directly in response to tolbutamide infusion or ingestion. After a 16-h fast, seven dogs were studied in the postabsorptive basal state and during a tolbutamide (0.2 mg/min) infusion when their plasma glucose concentrations were clamped at euglycemia. Insulin concentrations in the carotid artery (basal vs. tolbutamide, 85 ± 12 vs. 325 ± 66 pmol/l; P < 0.01) and portal vein (basal vs. tolbutamide, 345 ± 55 vs. 1, 288 ± 230 pmol/l; P < 0.01) increased during tolbutamide infusion, but the portal vein plasma flow did not change. Increased plasma insulin concentrations were achieved by a fourfold increase in the total insulin secretion rate (2.3 ± 0.2 to 9.4 ± 1.9 pmol · kg-1 · min-1; basal vs. tolbutamide, P < 0.01). The augmented total insulin secretion was achieved mechanistically via a marked and selective increase in the insulin secretory burst mass (basal vs. tolbutamide, 266 ± 64 vs. 817 ± 144 pmol/pulse; P < 0.01), with no change in portal-vein insulin pulse frequency (basal vs. tolbutamide, 10.1 ± 0.6 vs. 11.1 ± 0.8 pulses/h; P = 0.3). Oral (250 mg) tolbutamide also magnified the endogenous insulin secretion rate by the preferential amplification of the secretory pulse mass (basal vs. tolbutamide, 167 ± 37 vs. 362 ± 50 pmol/pulse; P < 0.01). Neither the infusion nor the ingestion of tolbutamide changed the calculated clearance rates of endogenously secreted insulin. We conclude that sulfonylurea (tolbutamide) induced insulin secretion in vivo is achieved by the highly selective amplification of insulin secretory burst mass with no change in basal insulin release or the frequency of the β- cell-network pacemaker.

Original languageEnglish (US)
Pages (from-to)1792-1797
Number of pages6
JournalDiabetes
Volume45
Issue number12
StatePublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

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    Pørksen, N. K., Munn, S. R., Steers, J. L., Schmitz, O., Veldhuis, J. D., & Butler, P. C. (1996). Mechanisms of sulfonylurea's stimulation of insulin secretion in vivo: Selective amplification of insulin secretory burst mass. Diabetes, 45(12), 1792-1797.