Abstract
ATP-sensitive potassium channels (KATP channels) are critical nutrient sensors in many mammalian tissues. In the pancreas, KATP channels are essential for coupling glucose metabolism to insulin secretion. While orthologous genes for many components of metabolism–secretion coupling in mammals are present in lower vertebrates, their expression, functionality and ultimate impact on body glucose homeostasis are unclear. In this paper, we demonstrate that zebrafish islet β-cells express functional KATP channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts. We further show that pharmacological activation of native zebrafish KATP using diazoxide, a specific KATP channel opener, is sufficient to disturb glucose tolerance in adult zebrafish. That β-cell KATP channel expression and function are conserved between zebrafish and mammals illustrates the evolutionary conservation of islet metabolic sensing from fish to humans, and lends relevance to the use of zebrafish to model islet glucose sensing and diseases of membrane excitability such as neonatal diabetes.
Highlights
In the pancreatic β-cell, ATP-sensitive potassium (KATP) channels link glucose metabolism and insulin secretion and are essential to the normal regulation of plasma glucose and other nutrients [1,2].2017 The Authors
We show that zebrafish β-cells express functional KATP channels with similar regulation, subunit composition and pharmacology to their mammalian counterparts, and that pharmacologic KATP channel openers can disrupt glucose tolerance in adult fish
Orthologues of major genes involved in mammalian insulin secretion exist in zebrafish
Summary
In the pancreatic β-cell, ATP-sensitive potassium (KATP) channels link glucose metabolism and insulin secretion and are essential to the normal regulation of plasma glucose and other nutrients [1,2]. Intracellular [ATP]/[ADP] is low, and KATP channels are open, hyperpolarizing the cell 2 membrane. It enters β-cells through glucose transporter 2 (GLUT2), increasing [ATP]/[ADP] which closes KATP channels, inducing plasma membrane depolarization and opening voltage-dependent Ca2+ channels (VDCCs). Calcium influx through VDCCs subsequently triggers insulin secretion (electronic supplementary material, figure S1a). Loss-of-function mutations result in congenital hyperinsulinism [3], whereas gain-of-function (GOF) mutations cause neonatal diabetes mellitus (NDM) [4,5], and polymorphisms are associated with the development of type 2 diabetes [6]
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