Abstract 20460: Hypotension and Diabetes Due to Kir6.1 Mutants Gain-of-Function in Vivo
KATP channels link metabolic state to excitability in multiple tissues including the heart and vasculature. They are assembled from 4 pore-forming subunits (Kir6.1 or Kir6.2) and 4 regulatory subunits (SUR1 or SUR2); Loss of the Kir6.2 subunit results in hypoglycemia and hyperinsulinemia, whereas loss of Kir6.1 causes Prinzmetal angina and hypertension in mice. Our previous work showed that overactivity of Kir6.2 in pancreatic β-cells induces neonatal diabetes in mice, leading to the subsequent discovery of similar mutations as causal in human neonatal diabetes mellitus (NDM). The effects of Kir6.1 overactivity are unknown, so to examine this we generated transgenic (TG) mice expressing wild type Kir6.1 (WT), or mildly ATP-insensitive Kir6.1[G343D] (GD), or severely ATP-insensitive Kir6.1[G343D,Q53R] (GD-QR) subunits under Cre-recombinase control. Expression was targeted to pancreatic β cells, cardiac myocytes and smooth muscle cells by crossing with Pdx-Cre-ER, αMHC-Cre or SM-MHC-Cre-ER mice, respectively and treatment with tamoxifen in the ER mice. Three weeks after tamoxifen induction, the blood pressure (systolic/diastolic,mmHg) was significantly lower in mice which over expressed the GD single mutant (82.6±2.0 /55.8±1.6 TG, versus 92.3±2.1/64.7±1.6 non-TG, n=13,17) and GD-QR double mutant (non-TG 91.0±2.9 /65.0±1.7, n=10; TG 83.3±2.5/59.8±1.8,n=8) in smooth muscle cells, whereas blood pressure was normal in mice which over expressed the WT transgene ( non-TG 92.5±2.1 /63.4±2.0, n=6;TG 90.9±3.7/64.8±2.5,n=8). Overexpression of the GD mutant in pancreatic β cells led to significant increase in blood sugar (non-TG vs TG,mg/dl @ 45 days after tamoxifen induction) (128±3 vs 146±7, n=34,16), and mice overexpressing GD-QR in pancreatic β cells developed severe diabetes(non-TG vs TG,mg/dl, 129±2 vs 600±0, n=22,16), whereas blood sugar levels were normal in mice overexpressing WT (non-TG vs TG,mg/dl, 125±6 vs 128±8, n=14,7). No pathological phenomenon was monitored by scanning electrocardiogram(ECG) in transgenic mice which over expressed WT, GD or GD-QR in cardiac myocytes. The data indicate that overactivity of KATP channel activity in vascular smooth muscle cells or pancreatic β cells can cause hypotension and diabetes.
- © 2010 by American Heart Association, Inc.