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

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

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Free PMC article

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

Christine Deisl et al. PLoS One. .
Free PMC article

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Intraperitoneal glucose tolerance tests in NHA2 WT and KO mice fed normal chow diet at different ages.
A) Blood glucose concentrations following ip. glucose challenge (2g/kg body weight) at 2 months; n+/+ = 8, n-/- = 8. B) Blood glucose concentrations following ip. glucose challenge (2g/kg body weight) at 5 months; n+/+ = 9, n-/- = 9. C) Blood glucose concentrations following ip. glucose challenge (1g/kg body weight) in 12 months old mice; n+/+ = 9, n-/- = 9. D) Area under the curve (AUC) of intraperitoneal glucose tolerance tests (IPGTT) at 2, 5 and 12 months of age. E) Serum insulin concentrations following ip. glucose challenge (2g/kg body weight) at 2 months; n+/+ = 8, n-/- = 8. F) Serum insulin concentrations following ip. glucose challenge (2g/kg body weight) at 5 months; n+/+ = 9, n-/- = 9. G) Serum insulin concentrations following ip. glucose challenge (1g/kg body weight) at 12 months; n+/+ = 9, n-/- = 9. H) Peak (15 minutes) to basal (0 minutes) insulin ratios during ip. glucose challenges at 2, 5 and 12 months of age. I) Fasting insulin to glucose ratios at 2, 5 and 12 months of age. Data are mean values ± SEM, (* p<0.05, WT vs KO; NS = not significant, WT vs KO).
Fig 2
Fig 2. Intraperitoneal insulin tolerance tests in NHA2 WT and KO mice fed normal chow diet at different ages.
A) Blood glucose concentration in % of baseline glucose following ip. insulin challenge (1 U/kg body weight) at 2 months; n+/+ = 10, n-/- = 10. B) Blood glucose concentration in % of baseline glucose following ip. insulin challenge (1 U/kg body weight) at 5 months; n+/+ = 11, n-/- = 12. C) Blood glucose concentration in % of baseline glucose following ip. insulin challenge (1 U/kg body weight) at 12 months; n+/+ = 9, n-/- = 12. D) Area under the curve (AUC) of intraperitoneal insulin tolerance tests (IPITT) at 2, 6 and 12 months of age. E) Plasma glucagon concentration at baseline and 30 minutes after ip. administration of insulin (1 U/kg body weight) in 2 months old mice. F) Plasma glucagon concentration at baseline and 30 minutes after ip. administration of insulin (1 U/kg body weight) in 12 months old mice. Data are mean values ± SEM, (* p<0.05, WT vs KO; NS = not significant, WT vs KO).
Fig 3
Fig 3. High fat diet in NHA2 WT and KO mice.
A) Weight gain of mice during 12 weeks of HFD. HFD was started at 8 weeks of age. B) Nasal to anal length at week 12 of HFD. C) BMI at week 12 of HFD. D) Organ and fat pad weights at week 12 of HFD. E) Hepatic total lipid content at week 12 of HFD. F) Fasting blood glucose concentration at baseline and at indicated week during HFD. G) Fasting serum insulin concentration at baseline and at indicated week during HFD. H) Fasting insulin to glucose ratios at indicated time points during HFD. I) Fasting plasma glucagon concentrations at week 12 of HFD. J) Fasting serum leptin concentrations at baseline and at indicated week of HFD. K) Fasting serum adiponectin concentrations at baseline and at indicated week of HFD. Data are mean values ± SEM, (* p<0.05, WT vs KO; NS = not significant, WT vs KO).
Fig 4
Fig 4. Intraperitoneal glucose tolerance test and hyperinsulinemice euglycemic clamp in NHA2 WT and KO mice after 12 weeks of HFD.
A) Blood glucose concentrations following ip. glucose challenge (1g/kg body weight); n+/+ = 12, n-/- = 10. B) Area under the curve (AUC) of the intraperitoneal glucose tolerance test (IPGTT). C) Serum insulin concentrations following ip. glucose challenge (1g/kg body weight); n+/+ = 12, n-/- = 10. D) Peak (15 minutes) to basal (0 minutes) insulin ratios after 12 weeks of HFD. E) Glucose infusion rates during hyperinsulinemic euglycemic clamps; n+/+ = 8, n-/- = 8. Data are mean values ± SEM, (* p<0.05, WT vs KO; NS = not significant, WT vs KO).
Fig 5
Fig 5. In vitro insulin secretion of NHA2 WT and KO islets.
A) Basal (2 mM) and glucose (20 mM) induced insulin secretion of islets isolated from 2 or 5 months old mice fed a normal chow (NFD) or from 5 months old mice fed a high fat diet (HFD) for 12 weeks; n = 300 islets per genotype and condition. Data are mean values ± SEM, (* p<0.05, WT vs KO; NS = not significant, WT vs KO; # p<0.05, WT vs WT or KO vs KO. B) NHA2 mRNA expression in islets of 2, 3.5, 5 and 12 months old mice fed a normal chow (NFD) or from 5 months old mice fed a high fat diet (HFD) for 12 weeks; n = 300–500 islets of 3–5 mice/group. Data are mean values ± SEM, (* p<0.05, vs indicated condition; # p<0.05, vs all other conditions).

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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.
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