Impairment of the NO/cGMP Pathway in the Fasting and Postprandial State in Type 1 Diabetes Mellitus

Abstract

The assessment of the postprandial state in diabetes mellitus has gained importance due to postprandial hyperglycemia being considered as an independent risk factor for cardiovascular disease. Hyperglycemia may contribute to vascular dysfunction through the alteration of the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway.

The authors assessed the NO/cGMP pathway in the fasting and postprandial state in 20 type 1 diabetic patients (age: 34.1 ± 2.6 years, body mass index (BMI): 24.1 ± 1.3 kg/m², duration of diabetes: 16 ± 2.2 years, HbA_1C: 8.3 ± 0.4 %, [x ± SEM], 10 without, 10 with late complications) and 20 matched control subjects (age: 39.7 ± 1.9 years, BMI: 25.3 ± 1.1 kg/m²).

In the fasting state NO end product (nitrite/nitrate) levels did not differ between the diabetic and control group, cGMP levels were found to be significantly lower in the diabetic group (2.5 ± 0.2 vs. 4.6 ± 0.6 nmol/l, p = 0.01). A higher level of lipid peroxidation end products (TBARS) was found in diabetic subjects (6.7 ± 0.4 vs. 5.0 ± 0.3 µmol/l, p = 0.004). The diabetic subgroup without late complications had significantly higher nitrite/nitrate levels compared to the patients with complications (57.8 ± 6.6 vs. 30.4 ± 4.3 µmol/l, p = 0.006), their TBARS and cGMP levels were similar.

The control subjects responded to the test meal with an increase in the cGMP levels (4.6 ± 0.6 to 5.5 ± 0.6 nmol/l, p = 0.02), while in the diabetic group no change was detected. Postprandial nitrite/nitrate levels decreased in both groups, they were significantly lower in the diabetic group. There was no difference between postprandial nitrite/nitrate, cGMP, or glucose levels in the diabetic subgroups. Postprandial glucose levels showed a significant negative correlation with cGMP levels in the diabetic group (r = - 0.50, p = 0.02).

The results suggest that in subjects with type 1 diabetes mellitus NO might have an impaired ability to induce cGMP production in the fasting state prior to the development of late specific complications or microalbuminuria under hyperglycemic conditions. Postprandial hyperglycemia is suggested to interfere with endothelial NO action, as shown by the decreased nitrite/nitrate and unchanged cGMP plasma levels in the diabetic group. The impairment of the NO/cGMP pathway both in the fasting and postprandial state that was shown in patients without diabetic complications may be an early sign of hyperglycemia induced vascular damage in type 1 diabetes mellitus.

Key words

Type 1 diabetes - postprandial hyperglycemia - endothelial dysfunction - nitric oxide/cyclic guanosine monophosphate - oxidative stress

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