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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

Experimental Protocol. Diagram of the experimental procedures on aged WT or A2BKO mice undergoing intraperitoneal glucose (IPGTT), pyruvate or insulin (IPITT) tolerance tests. In the termination series, plasma and liver were collected at 0 or 30 min. NaCl, sodium chloride; NaNO3, sodium nitrate; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test.
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Figure 1: Experimental Protocol. Diagram of the experimental procedures on aged WT or A2BKO mice undergoing intraperitoneal glucose (IPGTT), pyruvate or insulin (IPITT) tolerance tests. In the termination series, plasma and liver were collected at 0 or 30 min. NaCl, sodium chloride; NaNO3, sodium nitrate; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test.

Mentions: This study was approved by the Institutional Animal Care and Use Committee (IACUC) in Stockholm, and performed according to the National Institutes of Health guidelines for the conduct of experiments in animals. Experiments were conducted on aged (12–16 months) adenosine A2B receptor gene-deleted and WT mice from heterozygous breeding pairs. A−/−2B mice (a gift from professor M. Sitkovsky at Northwestern University, Boston, Mass) were backcrossed 11 times to a C57BL/6J background at Northwestern University. Both sexes were used, with equal distribution for all experimental series. Mice were housed in temperature-controlled rooms with 12 h light/dark cycles and received a standard rodent chow (4% fat, R34, Lactamin AB, Kimstad, Sweden) and tap water ad libitum. An overview of the experimental protocol is shown in Figure 1.


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)

Experimental Protocol. Diagram of the experimental procedures on aged WT or A2BKO mice undergoing intraperitoneal glucose (IPGTT), pyruvate or insulin (IPITT) tolerance tests. In the termination series, plasma and liver were collected at 0 or 30 min. NaCl, sodium chloride; NaNO3, sodium nitrate; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Experimental Protocol. Diagram of the experimental procedures on aged WT or A2BKO mice undergoing intraperitoneal glucose (IPGTT), pyruvate or insulin (IPITT) tolerance tests. In the termination series, plasma and liver were collected at 0 or 30 min. NaCl, sodium chloride; NaNO3, sodium nitrate; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test.
Mentions: This study was approved by the Institutional Animal Care and Use Committee (IACUC) in Stockholm, and performed according to the National Institutes of Health guidelines for the conduct of experiments in animals. Experiments were conducted on aged (12–16 months) adenosine A2B receptor gene-deleted and WT mice from heterozygous breeding pairs. A−/−2B mice (a gift from professor M. Sitkovsky at Northwestern University, Boston, Mass) were backcrossed 11 times to a C57BL/6J background at Northwestern University. Both sexes were used, with equal distribution for all experimental series. Mice were housed in temperature-controlled rooms with 12 h light/dark cycles and received a standard rodent chow (4% fat, R34, Lactamin AB, Kimstad, Sweden) and tap water ad libitum. An overview of the experimental protocol is shown in Figure 1.

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