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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

Schematic depiction of the experimental design.
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Figure 1: Schematic depiction of the experimental design.

Mentions: After a baseline blood sample (Figs. 1 and 2), a primed (2.4 μmol/kg), continuous (0.04 μmol/kg · min) infusion of l-[15N2-guanidino]-arginine (15N2-arginine, sterile and pyrogen-free) (MassTrace, Woburn, MA; isotope purity = 99%) was started at ∼07:30 a.m. (defined as −180 min). Blood samples were drawn every 30 min for ∼2 h, to assess the achievement of steady state in blood isotope enrichment (data not shown). In the diabetic group, after 100 min from the start of isotope infusion, five blood samples were collected every 20 min (i.e., between −80 min and 0 min), for measurements of whole-blood isotope enrichments of NOx and arginine, as well as for plasma substrate and hormone concentrations (Figs. 2 and 3, upper panels). In the control group, there were minor changes in blood sampling, which started 120 min after the initiation of isotope infusion (i.e., at −60 min) and was spaced by 15-min intervals (i.e., five samples) for blood isotope enrichments of NOx, and by 30-min intervals (three samples) for blood arginine, plasma substrate, and hormone concentrations (Figs. 2 and 3, lower panels).


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)

Schematic depiction of the experimental design.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: Schematic depiction of the experimental design.
Mentions: After a baseline blood sample (Figs. 1 and 2), a primed (2.4 μmol/kg), continuous (0.04 μmol/kg · min) infusion of l-[15N2-guanidino]-arginine (15N2-arginine, sterile and pyrogen-free) (MassTrace, Woburn, MA; isotope purity = 99%) was started at ∼07:30 a.m. (defined as −180 min). Blood samples were drawn every 30 min for ∼2 h, to assess the achievement of steady state in blood isotope enrichment (data not shown). In the diabetic group, after 100 min from the start of isotope infusion, five blood samples were collected every 20 min (i.e., between −80 min and 0 min), for measurements of whole-blood isotope enrichments of NOx and arginine, as well as for plasma substrate and hormone concentrations (Figs. 2 and 3, upper panels). In the control group, there were minor changes in blood sampling, which started 120 min after the initiation of isotope infusion (i.e., at −60 min) and was spaced by 15-min intervals (i.e., five samples) for blood isotope enrichments of NOx, and by 30-min intervals (three samples) for blood arginine, plasma substrate, and hormone concentrations (Figs. 2 and 3, lower panels).

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