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Tolbutamide controls glucagon release from mouse islets differently than glucose: involvement of K(ATP) channels from

Rui Cheng-Xue1, Ana Gómez-Ruiz, Nancy Antoine

  • 1Pôle d'Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.

Diabetes
|February 6, 2013
PubMed

Insights

Glucose inhibits glucagon secretion independently of K(ATP) channels, somatostatin, and Zn²⁺. K(ATP) channel closure impacts glucagon via direct α-cell stimulation and indirect δ-cell somatostatin inhibition.

Area of Science:

  • Endocrinology
  • Islet Biology
  • Cell Signaling

Background:

  • Glucagon secretion is tightly regulated by glucose levels.
  • The roles of ATP-sensitive potassium (K(ATP)) channels, somatostatin, and zinc (Zn²⁺) in this regulation are complex and interconnected.

Purpose of the Study:

  • To elucidate the independent and combined roles of K(ATP) channels, somatostatin, and Zn²⁺ in mediating glucose-stimulated glucagon secretion.
  • To understand the mechanisms by which glucose and K(ATP) channel modulators affect glucagon release from pancreatic islets.

Main Methods:

  • Utilized genetically modified mouse models (Sur1(-/-), Sst(-/-), ZnT8(-/-)) and pharmacological agents (diazoxide, tolbutamide, pertussis toxin).
  • Assessed glucagon secretion from isolated pancreatic islets under varying glucose concentrations (1 mmol/L and 7 mmol/L).

Main Results:

  • Glucose inhibited glucagon secretion independently of K(ATP) channels, somatostatin, and Zn²⁺ transporter ZnT8.
  • K(ATP) channel closure by tolbutamide or diazoxide inhibited glucagon at low glucose but its effect was modulated by high glucose.
  • Somatostatin removal enhanced basal glucagon secretion and unmasked tolbutamide's stimulatory effect at high glucose, but did not abolish glucose's inhibitory effect.

Conclusions:

  • Glucose directly inhibits glucagon secretion from α-cells, independent of K(ATP) channels, somatostatin, and Zn²⁺.
  • K(ATP) channel activity influences glucagon secretion through both direct effects on α-cells and indirect effects mediated by somatostatin from δ-cells.
  • The net regulation of glucagon secretion involves a balance between direct and indirect signaling pathways.

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