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.

Together, our results suggest that restriction of dietary carbohydrates and caloric replacement by fat can induce metabolic changes that are beneficial in reducing glucotoxicity and secondary consequences of diabetes in a mouse model of insulin-secretory deficiency.

Gain-of-function (GOF) mutations in ATP-sensitive potassium (K) channel cause neonatal diabetes. Despite the well-established genetic root of the disease, the pathways modulating disease severity and treatment effectiveness remain poorly understood. Patient phenotypes can vary from severe diabetes to remission, even in individuals with the same mutation and within the same family; suggesting that subtle modifiers can influence disease outcome. We have tested the underlying mechanism of transient vs permanent neonatal diabetes in K-GOF mice treated for 14-days with glibenclamide. Some K-GOF mice show remission of diabetes and enhanced insulin sensitivity long-after diabetes treatment ended, compared with severely insulin-resistant non-remitting mice. However, insulin sensitivities are not different between the two groups before or during diabetes induction, suggesting that improved sensitivity is a consequence, rather than the cause of remission; implicating other factors modulating glucose early in diabetes progression. Leptin, glucagon, insulin and GLP-1 are not different between remitters and non-remitters. However, liver glucose production is significantly reduced before transgene induction in remitter, relative to non-remitter and non-treated mice. Surprisingly, while subsequent remitter animals exhibited normal serum cytokines, non-remitter mice showed increased cytokines, which paralleled the divergence in blood glucose. Together, these results suggest that systemic inflammation may play a role in the transient vs permanent form of neonatal diabetes. Supporting this conclusion, treatment with the anti-inflammatory Meloxicam significantly increased the fraction of remitting animals. Beyond neonatal diabetes, the potential for inflammation and glucose production to exacerbate other forms of diabetes from a compensated state to a glucotoxic state should be considered.

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