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Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy.

Tessari P, Cecchet D, Cosma A, Vettore M, Coracina A, Millioni R, Iori E, Puricelli L, Avogaro A, Vedovato M - Diabetes (2010)

Bottom Line: A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy.Also the fraction of arginine flux converted to NOx (basal, 0.22 +/- 0.05% vs. 0.65 +/- 0.25%; hyperinsulinemia, 0.32 +/- 0.06% vs. 1.03 +/- 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA).In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Medicine, Metabolism Division, University of Padova, Italy. paolo.tessari@unipd.it

ABSTRACT

Objective: Nitric oxide (NO) is a key metabolic and vascular regulator. Its production is stimulated by insulin. A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy. However, whether the decreased NOx excretion in type 2 diabetes is caused by a defective NOx production from arginine in response to hyperinsulinemia has never been studied.

Research design and methods: We measured NOx fractional (FSR) and absolute (ASR) synthesis rates in type 2 diabetic patients with diabetic nephropathy and in control subjects, after l-[(15)N(2)-guanidino]-arginine infusion, and use of precursor-product relationships. The study was conducted both before and after an euglycemic hyperinsulinemic ( approximately 1,000-1,200 pmol/l) clamp.

Results: In type 2 diabetes, NOx FSR was reduced both under basal (19.3 +/- 3.9% per day, vs. 22.9 +/- 4.5% per day in control subjects) and hyperinsulinemic states (24.0 +/- 5.6% per day, vs. 37.9 +/- 6.4% per day in control subjects; P < 0.03 by ANOVA). Similarly, in type 2 diabetes, NOx ASR was lower than in control subjects under both conditions (basal, 0.32 +/- 0.06 vs. 0.89 +/- 0.34 mol per day; hyperinsulinemia, 0.35 +/- 0.07 vs. 1.15 +/- 0.38 mol per day; P = 0.01 by ANOVA). In type 2 diabetes, the ability of insulin to stimulate both the FSR (4.7 +/- 3.2% per day) and the ASR (0.03 +/- 0.04 mol per day) of NOx was several-fold lower than that in control subjects (15.0 +/- 2.9% per day and 0.25 +/- 0.07 mol per day, P < 0.03 and P < 0.02, respectively). Also the fraction of arginine flux converted to NOx (basal, 0.22 +/- 0.05% vs. 0.65 +/- 0.25%; hyperinsulinemia, 0.32 +/- 0.06% vs. 1.03 +/- 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA).

Conclusions: In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states. This defect extends the concept of insulin resistance to NO metabolism.

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Related in: MedlinePlus

(Upper panel) NOx FSR, expressed as percent of pool per day, and (bottom panel) NOx ASR (expressed as mol per day), in the type 2 diabetic (black bars, n = 8) and in the control subjects (white bars, n = 10) in the basal and in the clamp periods. Asterisks indicate a significant change versus basal (P < 0.005 by ANOVA, post hoc Tukey test) within a group, whereas the P values indicate the significant difference between the two groups by considering both periods together (by ANOVA, either interaction or group effect).
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Figure 4: (Upper panel) NOx FSR, expressed as percent of pool per day, and (bottom panel) NOx ASR (expressed as mol per day), in the type 2 diabetic (black bars, n = 8) and in the control subjects (white bars, n = 10) in the basal and in the clamp periods. Asterisks indicate a significant change versus basal (P < 0.005 by ANOVA, post hoc Tukey test) within a group, whereas the P values indicate the significant difference between the two groups by considering both periods together (by ANOVA, either interaction or group effect).

Mentions: In the fasting state, NOx FSR in the type 2 diabetic patients (19.3 ± 3.9% per day) was ∼15% lower than that in control subjects (22.9 ± 4.5% per day) (Fig. 4). After hyperinsulinemia, NOx FSR did not increase in the patients (to 24.0 ± 5.6% per day, not significant versus baseline), whereas it increased significantly in the control subjects (to 37.9 ± 6.4% per day, P < 0.001 vs. baseline by the paired t test; P < 0.03 by ANOVA between groups, interaction effect). These differences between groups were maintained also when subject #2, who exhibited somehow extreme data, as reported in the lower panel of Fig. 3, was excluded. An inverse relationship between NOx FSR during the clamp and plasma creatinine within the entire subjects' set was found (R = −0.52, P < 0.05).


Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy.

Tessari P, Cecchet D, Cosma A, Vettore M, Coracina A, Millioni R, Iori E, Puricelli L, Avogaro A, Vedovato M - Diabetes (2010)

(Upper panel) NOx FSR, expressed as percent of pool per day, and (bottom panel) NOx ASR (expressed as mol per day), in the type 2 diabetic (black bars, n = 8) and in the control subjects (white bars, n = 10) in the basal and in the clamp periods. Asterisks indicate a significant change versus basal (P < 0.005 by ANOVA, post hoc Tukey test) within a group, whereas the P values indicate the significant difference between the two groups by considering both periods together (by ANOVA, either interaction or group effect).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927936&req=5

Figure 4: (Upper panel) NOx FSR, expressed as percent of pool per day, and (bottom panel) NOx ASR (expressed as mol per day), in the type 2 diabetic (black bars, n = 8) and in the control subjects (white bars, n = 10) in the basal and in the clamp periods. Asterisks indicate a significant change versus basal (P < 0.005 by ANOVA, post hoc Tukey test) within a group, whereas the P values indicate the significant difference between the two groups by considering both periods together (by ANOVA, either interaction or group effect).
Mentions: In the fasting state, NOx FSR in the type 2 diabetic patients (19.3 ± 3.9% per day) was ∼15% lower than that in control subjects (22.9 ± 4.5% per day) (Fig. 4). After hyperinsulinemia, NOx FSR did not increase in the patients (to 24.0 ± 5.6% per day, not significant versus baseline), whereas it increased significantly in the control subjects (to 37.9 ± 6.4% per day, P < 0.001 vs. baseline by the paired t test; P < 0.03 by ANOVA between groups, interaction effect). These differences between groups were maintained also when subject #2, who exhibited somehow extreme data, as reported in the lower panel of Fig. 3, was excluded. An inverse relationship between NOx FSR during the clamp and plasma creatinine within the entire subjects' set was found (R = −0.52, P < 0.05).

Bottom Line: A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy.Also the fraction of arginine flux converted to NOx (basal, 0.22 +/- 0.05% vs. 0.65 +/- 0.25%; hyperinsulinemia, 0.32 +/- 0.06% vs. 1.03 +/- 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA).In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Medicine, Metabolism Division, University of Padova, Italy. paolo.tessari@unipd.it

ABSTRACT

Objective: Nitric oxide (NO) is a key metabolic and vascular regulator. Its production is stimulated by insulin. A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy. However, whether the decreased NOx excretion in type 2 diabetes is caused by a defective NOx production from arginine in response to hyperinsulinemia has never been studied.

Research design and methods: We measured NOx fractional (FSR) and absolute (ASR) synthesis rates in type 2 diabetic patients with diabetic nephropathy and in control subjects, after l-[(15)N(2)-guanidino]-arginine infusion, and use of precursor-product relationships. The study was conducted both before and after an euglycemic hyperinsulinemic ( approximately 1,000-1,200 pmol/l) clamp.

Results: In type 2 diabetes, NOx FSR was reduced both under basal (19.3 +/- 3.9% per day, vs. 22.9 +/- 4.5% per day in control subjects) and hyperinsulinemic states (24.0 +/- 5.6% per day, vs. 37.9 +/- 6.4% per day in control subjects; P < 0.03 by ANOVA). Similarly, in type 2 diabetes, NOx ASR was lower than in control subjects under both conditions (basal, 0.32 +/- 0.06 vs. 0.89 +/- 0.34 mol per day; hyperinsulinemia, 0.35 +/- 0.07 vs. 1.15 +/- 0.38 mol per day; P = 0.01 by ANOVA). In type 2 diabetes, the ability of insulin to stimulate both the FSR (4.7 +/- 3.2% per day) and the ASR (0.03 +/- 0.04 mol per day) of NOx was several-fold lower than that in control subjects (15.0 +/- 2.9% per day and 0.25 +/- 0.07 mol per day, P < 0.03 and P < 0.02, respectively). Also the fraction of arginine flux converted to NOx (basal, 0.22 +/- 0.05% vs. 0.65 +/- 0.25%; hyperinsulinemia, 0.32 +/- 0.06% vs. 1.03 +/- 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA).

Conclusions: In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states. This defect extends the concept of insulin resistance to NO metabolism.

Show MeSH
Related in: MedlinePlus