Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- And Aging-Induced Glucose Intolerance in Mice

PLoS One. 2016 Sep 29;11(9):e0163568. doi: 10.1371/journal.pone.0163568. eCollection 2016.

Abstract

We previously demonstrated that the sodium/hydrogen exchanger NHA2, also known as NHEDC2 or SLC9B2, is critical for insulin secretion by β-cells. To gain more insights into the role of NHA2 on systemic glucose homeostasis, we studied the impact of loss of NHA2 during the physiological aging process and in the setting of diet-induced obesity. While glucose tolerance was normal at 2 months of age, NHA2 KO mice displayed a significant glucose intolerance at 5 and 12 months of age, respectively. An obesogenic high fat diet further exacerbated the glucose intolerance of NHA2 KO mice. Insulin levels remained similar in NHA2 KO and WT mice during aging and high fat diet, but fasting insulin/glucose ratios were significantly lower in NHA2 KO mice. Peripheral insulin sensitivity, measured by insulin tolerance tests and hyperinsulinemic euglycemic clamps, was unaffected by loss of NHA2 during aging and high fat diet. High fat diet diminished insulin secretion capacity in both WT and NHA2 KO islets and reduced expression of NHA2 in WT islets. In contrast, aging was characterized by a gradual increase of NHA2 expression in islets, paralleled by an increasing difference in insulin secretion between WT and NHA2 KO islets. In summary, our results demonstrate that loss of the sodium/hydrogen exchanger NHA2 exacerbates obesity- and aging-induced glucose intolerance in mice. Furthermore, our data reveal a close link between NHA2 expression and insulin secretion capacity in islets.

Grant support

This work was supported by the Swiss National Centre of Competence in Research (NCCR) TransCure, the Swiss National Science Foundation (grants # 31003A_135503 and # 31003A_152829) and by a Medical Research Position Award of the Foundation Prof. Dr. Max Cloëtta. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.