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In adenosine A2B knockouts acute treatment with inorganic nitrate improves glucose disposal, oxidative stress, and AMPK signaling in the liver.

Peleli M, Hezel M, Zollbrecht C, Persson AE, Lundberg JO, Weitzberg E, Fredholm BB, Carlström M - Front Physiol (2015)

Bottom Line: Recent findings demonstrate therapeutic effects by boosting the nitrate-nitrite-NO pathway, which is an alternative pathway for NO formation.Finally, injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A(-/-) 2B as observed with nitrate.Acute treatment with nitrate improved the metabolic profile in it, at least partly via reduction in oxidative stress and improved AMPK signaling in the liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden.

ABSTRACT

Rationale: Accumulating studies suggest that nitric oxide (NO) deficiency and oxidative stress are central pathological mechanisms in type 2 diabetes (T2D). Recent findings demonstrate therapeutic effects by boosting the nitrate-nitrite-NO pathway, which is an alternative pathway for NO formation. This study aimed at investigating the acute effects of inorganic nitrate on glucose and insulin signaling in adenosine A2B receptor knockout mice (A(-/-) 2B), a genetic mouse model of impaired metabolic regulation.

Methods: Acute effects of nitrate treatment were investigated in aged wild-type (WT) and A(-/-) 2B mice. One hour after injection with nitrate (0.1 mmol/kg, i.p.) or placebo, metabolic regulation was evaluated by intraperitoneal glucose and insulin tolerance tests. NADPH oxidase-mediated superoxide production and AMPK phosphorylation were measured in livers obtained from non-treated or glucose-treated mice, with or without prior nitrate injection. Plasma was used to determine insulin resistance (HOMA-IR) and NO signaling.

Results: A(-/-) 2B displayed increased body weight, reduced glucose clearance, and attenuated overall insulin responses compared with age-matched WT mice. Nitrate treatment increased circulating levels of nitrate, nitrite and cGMP in the A(-/-) 2B, and improved glucose clearance. In WT mice, however, nitrate treatment did not influence glucose clearance. HOMA-IR increased following glucose injection in the A(-/-) 2B, but remained at basal levels in mice pretreated with nitrate. NADPH oxidase activity in livers from A(-/-) 2B, but not WT mice, was reduced by nitrate treatment. Livers from A(-/-) 2B displayed reduced AMPK phosphorylation compared with WT mice, and this was increased by nitrate treatment. Finally, injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A(-/-) 2B as observed with nitrate.

Conclusion: The A(-/-) 2B mouse is a genetic mouse model of metabolic syndrome. Acute treatment with nitrate improved the metabolic profile in it, at least partly via reduction in oxidative stress and improved AMPK signaling in the liver.

No MeSH data available.


Related in: MedlinePlus

IPITT and HOMA-IR. Plasma glucose levels in response to insulin injection were not influenced by nitrate treatment in WT (A) and A2BKO mice (B). HOMA-IR, a measure of insulin resistance, increased following glucose injection in A2BKO mice, which was prevented by prior nitrate treatment (C). Values are mean ± SEM, n = 10–16/group. #p < 0.05 vs. WT; *p < 0.05 among the indicated groups.
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Figure 3: IPITT and HOMA-IR. Plasma glucose levels in response to insulin injection were not influenced by nitrate treatment in WT (A) and A2BKO mice (B). HOMA-IR, a measure of insulin resistance, increased following glucose injection in A2BKO mice, which was prevented by prior nitrate treatment (C). Values are mean ± SEM, n = 10–16/group. #p < 0.05 vs. WT; *p < 0.05 among the indicated groups.

Mentions: Insulin sensitivity after insulin injection (IPITT) was lower in A−/−2B mice (Figure 3B) compared to WT (Figure 3A) resulting in higher AUC. Glucose clearance did not differ between placebo or nitrate treated animals of both genotypes. In addition, insulin resistance (expressed as HOMA-IR) during fasting condition was similar in both genotypes but increased following glucose injection in the A−/−2B mice (Figure 3C). This could be prevented by prior injection with nitrate.


In adenosine A2B knockouts acute treatment with inorganic nitrate improves glucose disposal, oxidative stress, and AMPK signaling in the liver.

Peleli M, Hezel M, Zollbrecht C, Persson AE, Lundberg JO, Weitzberg E, Fredholm BB, Carlström M - Front Physiol (2015)

IPITT and HOMA-IR. Plasma glucose levels in response to insulin injection were not influenced by nitrate treatment in WT (A) and A2BKO mice (B). HOMA-IR, a measure of insulin resistance, increased following glucose injection in A2BKO mice, which was prevented by prior nitrate treatment (C). Values are mean ± SEM, n = 10–16/group. #p < 0.05 vs. WT; *p < 0.05 among the indicated groups.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4528163&req=5

Figure 3: IPITT and HOMA-IR. Plasma glucose levels in response to insulin injection were not influenced by nitrate treatment in WT (A) and A2BKO mice (B). HOMA-IR, a measure of insulin resistance, increased following glucose injection in A2BKO mice, which was prevented by prior nitrate treatment (C). Values are mean ± SEM, n = 10–16/group. #p < 0.05 vs. WT; *p < 0.05 among the indicated groups.
Mentions: Insulin sensitivity after insulin injection (IPITT) was lower in A−/−2B mice (Figure 3B) compared to WT (Figure 3A) resulting in higher AUC. Glucose clearance did not differ between placebo or nitrate treated animals of both genotypes. In addition, insulin resistance (expressed as HOMA-IR) during fasting condition was similar in both genotypes but increased following glucose injection in the A−/−2B mice (Figure 3C). This could be prevented by prior injection with nitrate.

Bottom Line: Recent findings demonstrate therapeutic effects by boosting the nitrate-nitrite-NO pathway, which is an alternative pathway for NO formation.Finally, injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A(-/-) 2B as observed with nitrate.Acute treatment with nitrate improved the metabolic profile in it, at least partly via reduction in oxidative stress and improved AMPK signaling in the liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, Karolinska Institutet Stockholm, Sweden.

ABSTRACT

Rationale: Accumulating studies suggest that nitric oxide (NO) deficiency and oxidative stress are central pathological mechanisms in type 2 diabetes (T2D). Recent findings demonstrate therapeutic effects by boosting the nitrate-nitrite-NO pathway, which is an alternative pathway for NO formation. This study aimed at investigating the acute effects of inorganic nitrate on glucose and insulin signaling in adenosine A2B receptor knockout mice (A(-/-) 2B), a genetic mouse model of impaired metabolic regulation.

Methods: Acute effects of nitrate treatment were investigated in aged wild-type (WT) and A(-/-) 2B mice. One hour after injection with nitrate (0.1 mmol/kg, i.p.) or placebo, metabolic regulation was evaluated by intraperitoneal glucose and insulin tolerance tests. NADPH oxidase-mediated superoxide production and AMPK phosphorylation were measured in livers obtained from non-treated or glucose-treated mice, with or without prior nitrate injection. Plasma was used to determine insulin resistance (HOMA-IR) and NO signaling.

Results: A(-/-) 2B displayed increased body weight, reduced glucose clearance, and attenuated overall insulin responses compared with age-matched WT mice. Nitrate treatment increased circulating levels of nitrate, nitrite and cGMP in the A(-/-) 2B, and improved glucose clearance. In WT mice, however, nitrate treatment did not influence glucose clearance. HOMA-IR increased following glucose injection in the A(-/-) 2B, but remained at basal levels in mice pretreated with nitrate. NADPH oxidase activity in livers from A(-/-) 2B, but not WT mice, was reduced by nitrate treatment. Livers from A(-/-) 2B displayed reduced AMPK phosphorylation compared with WT mice, and this was increased by nitrate treatment. Finally, injection with the anti-diabetic agent metformin induced similar therapeutic effects in the A(-/-) 2B as observed with nitrate.

Conclusion: The A(-/-) 2B mouse is a genetic mouse model of metabolic syndrome. Acute treatment with nitrate improved the metabolic profile in it, at least partly via reduction in oxidative stress and improved AMPK signaling in the liver.

No MeSH data available.


Related in: MedlinePlus