Kir6.1- and SUR2-dependent KATP overactivity disrupts intestinal motility in murine models of Cantú syndrome.

Cantú syndrome (CS), caused by gain-of-function (GOF) mutations in pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunit genes, is frequently accompanied by gastrointestinal (GI) dysmotility, and we describe 1 CS patient who required an implanted intestinal irrigation system for successful stooling. We used gene-modified mice to assess the underlying KATP channel subunits in gut smooth muscle and to model the consequences of altered KATP channels in CS gut.

ABCC8 R1420H Loss-of-Function Variant in a Southwest American Indian Community: Association With Increased Birth Weight and Doubled Risk of Type 2 Diabetes.

Missense variants in KCNJ11 and ABCC8, which encode the KIR6.2 and SUR1 subunits of the β-cell KATP channel, have previously been implicated in type 2 diabetes, neonatal diabetes, and hyperinsulinemic hypoglycemia of infancy (HHI). To determine whether variation in these genes affects risk for type 2 diabetes or increased birth weight as a consequence of fetal hyperinsulinemia in Pima Indians, missense and common noncoding variants were analyzed in individuals living in the Gila River Indian Community.

Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP-induced diabetes.

Objective: Neonatal diabetes mellitus (NDM) can be caused by gain-of-function ATP-sensitive K(+) (K(ATP)) channel mutations. This realization has led to sulfonylurea therapy replacing insulin injections in many patients. In a murine model of K(ATP)-dependent NDM, hyperglycemia and consequent loss of β-cells are both avoided by chronic sulfonylurea treatment.

HMR 1098 is not an SUR isotype specific inhibitor of heterologous or sarcolemmal K ATP channels.

Murine ventricular and atrial ATP-sensitive potassium (K(ATP)) channels contain different sulfonylurea receptors (ventricular K(ATP) channels are Kir6.2/SUR2A complexes, while atrial K(ATP) channels are Kir6.2/SUR1 complexes).

Hyperinsulinism and diabetes: genetic dissection of beta cell metabolism-excitation coupling in mice.

The role of metabolism-excitation coupling in insulin secretion has long been apparent, but in recent years, in parallel with studies of human hyperinsulinism and diabetes, genetic manipulation of proteins involved in glucose transport, metabolism, and excitability in mice has brought the central importance of this pathway into sharp relief. We focus on these animal studies and how they provide important insights into not only metabolic and electrical regulation of insulin secretion, but also downstream consequences of alterations in this pathway and the etiology and treatment of insulin-secretion diseases in humans.

Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus.

ATP-insensitive K(ATP) channel mutations cause neonatal diabetes mellitus (NDM). To explore the mechanistic etiology, we generated transgenic mice carrying an ATP-insensitive mutant K(ATP) channel subunit. Constitutive expression in pancreatic beta cells caused neonatal hyperglycemia and progression to severe diabetes and growth retardation, with loss of islet insulin content and beta cell architecture.

Chronic antidiabetic sulfonylureas in vivo: reversible effects on mouse pancreatic beta-cells.

Background: Pancreatic beta-cell ATP-sensitive potassium (K ATP) channels are critical links between nutrient metabolism and insulin secretion. In humans, reduced or absent beta-cell K ATP channel activity resulting from loss-of-function K ATP mutations induces insulin hypersecretion. Mice with reduced K ATP channel activity also demonstrate hyperinsulinism, but mice with complete loss of K ATP channels (K ATP knockout mice) show an unexpected insulin undersecretory phenotype.

Transgenic overexpression of SUR1 in the heart suppresses sarcolemmal K(ATP).

The lack of pathological consequences of cardiac ATP-sensitive potassium channel (K(ATP)) channel gene manipulation is in stark contrast to the effect of similar perturbations in the pancreatic beta-cell. Because the pancreatic and cardiac channel share the same pore-forming subunit (Kir6.2), the different effects of genetic manipulation likely reflect, at least in part, the tissue-specific expression of the regulatory subunit (SUR1 in pancreas vs.

Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels.

Reducing the ATP sensitivity of the sarcolemmal ATP-sensitive K(+) (K(ATP)) channel is predicted to lead to active channels in normal metabolic conditions and hence cause shortened ventricular action potentials and reduced myocardial inotropy. We generated transgenic (TG) mice that express an ATP-insensitive K(ATP) channel mutant [Kir6.2(deltaN2-30,K185Q)] under transcriptional control of the alpha-myosin heavy chain promoter.