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Effects of 1-Methylnicotinamide (MNA) on Exercise Capacity and Endothelial Response in Diabetic Mice.

Przyborowski K, Wojewoda M, Sitek B, Zakrzewska A, Kij A, Wandzel K, Zoladz JA, Chlopicki S - PLoS ONE (2015)

Bottom Line: MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile.Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals.In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA.

View Article: PubMed Central - PubMed

Affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland.

ABSTRACT
1-Methylnicotinamide (MNA), which was initially considered to be a biologically inactive endogenous metabolite of nicotinamide, has emerged as an anti-thrombotic and anti-inflammatory agent with the capacity to release prostacyclin (PGI2). In the present study, we characterized the effects of MNA on exercise capacity and the endothelial response to exercise in diabetic mice. Eight-week-old db/db mice were untreated or treated with MNA for 4 weeks (100 mg·kg-1), and their exercise capacity as well as NO- and PGI2-dependent response to endurance running were subsequently assessed. MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile. However, insulin sensitivity was improved (P<0.01). In MNA-treated db/db mice, the time to fatigue for endurance exercise was significantly prolonged (P<0.05). Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals. In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA. In conclusion, we demonstrated for the first time that MNA improves endurance exercise capacity in mice with diabetes, and may also decrease the cardiovascular risk of exercise.

No MeSH data available.


Related in: MedlinePlus

Effect of 4 weeks treatment with MNA on diabetic profile.Intraperitoneal glucose tolerance test (IPGTT) (A) (n = 18–20), blood glucose area under the curve (AUC) for IPGTT (B) (n = 18–20), blood HbA1c concentration (C) (n = 7), lipid profile (D) (n = 7). TC (total cholesterol), LDL (low-density lipoprotein), HDL (high-density lipoprotein), and TG (triglycerides). MNA-treated db/db mice were supplemented with MNA in drinking water for 4 weeks at a dose of 100 mg·kg-1. The effects of MNA on blood HbA1c concentration and lipid profile were evaluated in sedentary db/db mice. Data are presented as the mean ±SEM. Statistical analysis was performed using the Mann-Whitney test or unpaired t-test depending on the results of the normality test. ***P<0.001 vs. control db/db mice at 8 weeks of age, ##P<0.01 vs. control db/db mice at 12 weeks of age.
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pone.0130908.g002: Effect of 4 weeks treatment with MNA on diabetic profile.Intraperitoneal glucose tolerance test (IPGTT) (A) (n = 18–20), blood glucose area under the curve (AUC) for IPGTT (B) (n = 18–20), blood HbA1c concentration (C) (n = 7), lipid profile (D) (n = 7). TC (total cholesterol), LDL (low-density lipoprotein), HDL (high-density lipoprotein), and TG (triglycerides). MNA-treated db/db mice were supplemented with MNA in drinking water for 4 weeks at a dose of 100 mg·kg-1. The effects of MNA on blood HbA1c concentration and lipid profile were evaluated in sedentary db/db mice. Data are presented as the mean ±SEM. Statistical analysis was performed using the Mann-Whitney test or unpaired t-test depending on the results of the normality test. ***P<0.001 vs. control db/db mice at 8 weeks of age, ##P<0.01 vs. control db/db mice at 12 weeks of age.

Mentions: At the beginning of current experiment 8-week-old db/db mice were diabetic, as evidenced by higher blood glucose area under the curve (AUC) in IPGTT in comparison with wild-type mice (75.70±2.76 vs. 60.58±4.10 in wild-type mice, P<0.05, n = 39–6). As shown in Fig 2A and 2B, 4 weeks of treatment with MNA (100 mg·kg-1) significantly reduced insulin resistance in 12-week-old db/db mice as compared to 12-week-old untreated db/db mice (90.2±4.0 vs. 112.9±6.9, respectively, P<0.01, n = 18). However, there were no differences between MNA-treated and MNA-untreated 12-week-old db/db mice as regards to HbA1c concentration (14.02±0.87 vs. 13.81±1.17%, respectively, n = 7, Fig 2C) and fasting glucose concentration (1.545±0.087 vs. 1.410±0.092 mmol. l-1, respectively, n = 18). Furthermore, MNA treatment did not affect the lipid profile (Fig 2D), blood cell count or the haematocrit (HCT) and haemoglobin (HGB) concentrations (Table 1). Finally, treatment with MNA did not diminish but rather tended to increase body weight gain in db/db mice (3.97±0.67 vs. 6.03±1.10 g for MNA-treated group, n = 10). In MNA-treated mice MNA and Met-2PY + Met-4PY concentrations in the urine were elevated by approximately four-fold and three-fold, respectively, as compared with untreated mice (e.g. the MNA concentration increased from 0.687±0.065 to 2.606±0.602 μmol. μmol creatinine-1, P<0.01, n = 7–6, Fig 3).


Effects of 1-Methylnicotinamide (MNA) on Exercise Capacity and Endothelial Response in Diabetic Mice.

Przyborowski K, Wojewoda M, Sitek B, Zakrzewska A, Kij A, Wandzel K, Zoladz JA, Chlopicki S - PLoS ONE (2015)

Effect of 4 weeks treatment with MNA on diabetic profile.Intraperitoneal glucose tolerance test (IPGTT) (A) (n = 18–20), blood glucose area under the curve (AUC) for IPGTT (B) (n = 18–20), blood HbA1c concentration (C) (n = 7), lipid profile (D) (n = 7). TC (total cholesterol), LDL (low-density lipoprotein), HDL (high-density lipoprotein), and TG (triglycerides). MNA-treated db/db mice were supplemented with MNA in drinking water for 4 weeks at a dose of 100 mg·kg-1. The effects of MNA on blood HbA1c concentration and lipid profile were evaluated in sedentary db/db mice. Data are presented as the mean ±SEM. Statistical analysis was performed using the Mann-Whitney test or unpaired t-test depending on the results of the normality test. ***P<0.001 vs. control db/db mice at 8 weeks of age, ##P<0.01 vs. control db/db mice at 12 weeks of age.
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getmorefigures.php?uid=PMC4482656&req=5

pone.0130908.g002: Effect of 4 weeks treatment with MNA on diabetic profile.Intraperitoneal glucose tolerance test (IPGTT) (A) (n = 18–20), blood glucose area under the curve (AUC) for IPGTT (B) (n = 18–20), blood HbA1c concentration (C) (n = 7), lipid profile (D) (n = 7). TC (total cholesterol), LDL (low-density lipoprotein), HDL (high-density lipoprotein), and TG (triglycerides). MNA-treated db/db mice were supplemented with MNA in drinking water for 4 weeks at a dose of 100 mg·kg-1. The effects of MNA on blood HbA1c concentration and lipid profile were evaluated in sedentary db/db mice. Data are presented as the mean ±SEM. Statistical analysis was performed using the Mann-Whitney test or unpaired t-test depending on the results of the normality test. ***P<0.001 vs. control db/db mice at 8 weeks of age, ##P<0.01 vs. control db/db mice at 12 weeks of age.
Mentions: At the beginning of current experiment 8-week-old db/db mice were diabetic, as evidenced by higher blood glucose area under the curve (AUC) in IPGTT in comparison with wild-type mice (75.70±2.76 vs. 60.58±4.10 in wild-type mice, P<0.05, n = 39–6). As shown in Fig 2A and 2B, 4 weeks of treatment with MNA (100 mg·kg-1) significantly reduced insulin resistance in 12-week-old db/db mice as compared to 12-week-old untreated db/db mice (90.2±4.0 vs. 112.9±6.9, respectively, P<0.01, n = 18). However, there were no differences between MNA-treated and MNA-untreated 12-week-old db/db mice as regards to HbA1c concentration (14.02±0.87 vs. 13.81±1.17%, respectively, n = 7, Fig 2C) and fasting glucose concentration (1.545±0.087 vs. 1.410±0.092 mmol. l-1, respectively, n = 18). Furthermore, MNA treatment did not affect the lipid profile (Fig 2D), blood cell count or the haematocrit (HCT) and haemoglobin (HGB) concentrations (Table 1). Finally, treatment with MNA did not diminish but rather tended to increase body weight gain in db/db mice (3.97±0.67 vs. 6.03±1.10 g for MNA-treated group, n = 10). In MNA-treated mice MNA and Met-2PY + Met-4PY concentrations in the urine were elevated by approximately four-fold and three-fold, respectively, as compared with untreated mice (e.g. the MNA concentration increased from 0.687±0.065 to 2.606±0.602 μmol. μmol creatinine-1, P<0.01, n = 7–6, Fig 3).

Bottom Line: MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile.Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals.In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA.

View Article: PubMed Central - PubMed

Affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland.

ABSTRACT
1-Methylnicotinamide (MNA), which was initially considered to be a biologically inactive endogenous metabolite of nicotinamide, has emerged as an anti-thrombotic and anti-inflammatory agent with the capacity to release prostacyclin (PGI2). In the present study, we characterized the effects of MNA on exercise capacity and the endothelial response to exercise in diabetic mice. Eight-week-old db/db mice were untreated or treated with MNA for 4 weeks (100 mg·kg-1), and their exercise capacity as well as NO- and PGI2-dependent response to endurance running were subsequently assessed. MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile. However, insulin sensitivity was improved (P<0.01). In MNA-treated db/db mice, the time to fatigue for endurance exercise was significantly prolonged (P<0.05). Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals. In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA. In conclusion, we demonstrated for the first time that MNA improves endurance exercise capacity in mice with diabetes, and may also decrease the cardiovascular risk of exercise.

No MeSH data available.


Related in: MedlinePlus