Dysregulated secretion of insulin, genetically determined and mediated by biochemical (e.g., phosphorylation) or biophysical (e.g., opening/closing of ion or voltage-gated channels) mechanisms is responsible for disorders of glucose homeostasis at both hyper- and hypo extremes of the glycemic spectrum (1–3). For hyperglycemia, the discoveries relating to genetic control of the development of the pancreas and the regulation of insulin secretion have revolutionized understanding of the etiology of rare and more common forms of diabetes. In addition, these insights enable rational treatments as best exemplified by the use of sulfonylureas to restore endogenous insulin secretion and ameliorate neurological impairment in neonatal diabetes caused by mutations in the ATP-sensitive K+ channel (KATP) channel (3). For hypoglycemia, the current model recognizes nine genes involved in syndromes associated with dysregulated and excessive insulin secretion and hypoglycemia in infancy (HI), presenting, with some exceptions, mostly in the first year of life (Fig. 1) (1,2). An identical clinical (macrosomia) and biochemical (hypoglycemia, hypoketonemia, and hypo-fatty acidemia) phenotype, but with virtually undetectable insulin concentrations in serum, can result from activating mutations in AKT2, part of the insulin receptor signal transduction cascade (4). In this syndrome there is asymmetrical growth, as also occurs with activating mutations in AKT1 (5) (Proteus syndrome) and AKT3 (6), indicating that each isoform has a specific role in growth and metabolism, rather than representing evolutionary redundancy. The most common mutations involved in excessive insulin secretion are in the KATP genes, predominantly ABCC8 specifying the protein SUR-1 and occasionally the KCNJ11 gene, which specifies the inward rectifying potassium channel itself (KIR 6.2) (Fig. 1). Although autosomal recessive and some autosomal dominant forms of KATP channel defects result in diffuse involvement of the pancreatic islets, about 50% of neonatal HI caused by KATP mutations …