KATP channels and neonatal diabetes: from molecule to new therapy and beyond
ATP-sensitive potassium (KATP) channels are critical for coupling changes in blood glucose to insulin secretion. Gain-of-function mutations in KATP channels cause a rare inherited form of diabetes that manifest soon after birth (neonatal diabetes). This talk shows how understanding KATP channel function has enabled many neonatal diabetes patients to switch from insulin injections to sulphonylurea drugs that block KATP channel activity, with considerable improvement in their clinical condition and quality of life. Using a mouse model of neonatal diabetes, we also found that as little as 2 weeks of diabetes led to dramatic changes in gene expression, protein levels and metabolite concentrations. This reduced glucose-stimulated ATP production and insulin release. It also caused substantial glycogen storage and β-cell apoptosis. This may help explain why older neonatal diabetes patients with find it more difficult to transfer to drug therapy, and why the drug dose decreases with time in many patients. It also suggests that altered metabolism may underlie both the progressive impairment of insulin secretion and reduced β-cell mass in type 2 diabetes.