Adenosine triphosphate-sensitive potassium channels are involved in insulin-mediated glucose transport in humans

Abstract

We investigated the influence of treatment with nicorandil, a K-channel opener currently used for angina, on glucose homeostasis in patients with non-insulin-dependent diabetes mellitus (NIDDM) and coronary artery disease (CAD). Adenosine triphosphate (ATP)-sensitive K (K-ATP) channels are present in various tissues, including pancreatic B cells and skeletal muscle, and are the putative targets of this agent. Nine NIDDM patients with CAD and five healthy subjects participated in the study. Fasting plasma levels (mean ± SEM) of glucose (144 ± 11 to 180 ± 22 mg/dL, P < .05) and insulin (5.8 ± 1.6 to 7.0 ± 1.8 μU/mL, P < .05) and hemoglobin A 1c (7.54 ± 0.47 to 8.11 ± 0.55, P < .01) increased significantly in nine NIDDM patients after treatment with nicorandil at a dose of 5 mg three times daily for 2 to 8 months. Glucose tolerance as examined by an identical meal test deteriorated ( P < .001), but the insulin response did not change significantly. A washout of nicorandil for 1 to 4 months restored glucose tolerance almost to pretreatment levels in four patients. A 5- to 7-day trial of nicorandil (5 mg three times daily) in five healthy subjects resulted in a marginal to twofold increase in fasting plasma insulin, reflecting the progression of insulin resistance. In addition, three healthy subjects showed a substantial reduction in the glucose infusion rate (GIR) required in the euglycemic-hyperinsulinemic clamp study. Since the therapeutic dose of nicorandil did not affect pancreatic B-cell function but caused insulin resistance in both healthy and NIDDM subjects, we conclude that K-ATP channels play a regulatory role in insulin-mediated glucose transport in humans.