Effect of acute ketosis on the endothelial function of type 1 diabetic patients: the role of nitric oxide.

Abstract

In type 1 diabetic patients, acute loss of metabolic control is associated with increased blood flow, which is believed to favor the development of long-term complications. The mechanisms for inappropriate vasodilation are partially understood, but a role of endothelium-derived nitric oxide (NO) production can be postulated. We assessed, in type 1 diabetic patients, the effect of the acute loss of metabolic control and its restoration on forearm endothelial function in 13 type 1 diabetic patients who were studied under conditions of mild ketosis on two different occasions. In study 1, after basal determination, a rapid amelioration of the metabolic picture was obtained by insulin infusion. In study 2, seven type 1 diabetic patients underwent the same experimental procedure, except that fasting plasma glucose was maintained constant throughout. Basal plasma venous concentrations of nitrites/nitrates (NO2- + NO3-) were determined both before and after intravenous insulin infusion. Endothelium-dependent and -independent vasodilation of the brachial artery was assessed by an intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA) and sodium nitroprusside (SNP), respectively. The same parameters were determined in 13 control subjects at baseline conditions and during a hyperinsulinemic-euglycemic glucose clamp. Baseline forearm blood flow (4.89 +/- 0.86 vs. 3.65 +/- 0.59 ml x (100 ml tissue)(-1) x min(-1)) and NO2- + NO3- concentration (30 +/- 8 vs. 24 +/- 3 micromol/l) were higher in type 1 diabetic patients than in control subjects (P < 0.05). Insulin infusion was associated with lower forearm blood flow and plasma (NO2- + NO3-) concentration (P < 0.05), irrespective of the prevailing glucose levels, as compared with patients under ketotic conditions. The responses to L-NMMA were significantly lower in type 1 diabetic patients during euglycemia and hyperglycemic hyperinsulinemia (-11 +/- 5 and -10 +/- 4%, respectively, of the ratio of the infused arm to the control arm) than in control subjects at baseline (-18 +/- 6%, P < 0.05) and during hyperinsulinemia (-32 +/- 11%, P < 0.01). We conclude that the acute loss of metabolic control is associated with a functional disturbance of the endothelial function characterized by hyperemia and increased NO release during ketosis and blunted NO-mediated vasodilatory response during restoration of metabolic control by intravenous insulin. This functional alteration is unlikely to be explained by hyperglycemia itself.

Diabetic ketosis activates lymphomonocyte‐inducible nitric oxide synthase

“…This experimental model differs from clinical ketoacidosis in the relatively limited rises in glucagon and catecholamine levels as observed in our previous studies [2,10]. Thus caution must be adopted in extrapolating the present findings into a clinical setting.…”

“…At the second appointment, scheduled 7 days later, the patient was admitted to the Metabolic Unit at 6.00 p.m. Before supper, two‐thirds of their usual dose of soluble insulin and no intermediate or long‐acting insulin were given. This was done to induce mild ketosis by the following morning [2,10]. No patient reported hypoglycaemic episodes the day before.…”

Citric acid inhibits development of cataracts, proteinuria and ketosis in streptozotocin (type 1) diabetic rats

“…Under these circumstances, total ketone bodies may exceed 10 mmol/l, while those of normal subjects are less than 0.5 mmol/l [13]. Ketoacidosis is a major complication of Type I diabetes, and also enhances endogenous AGE formation by stimulating nitric oxide (NO) release from vascular endothelial cells [14], oxygen radical formation and lipid peroxidation [15]. Diabetic patients with frequent episodes of ketoacidosis suffer from increased incidences of vascular diseases, morbidity and mortality [16].…”

Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

“…In vitro and in vivo studies demonstrated that the activity of eNOS and generation of nitric oxide (NO) are significantly reduced in endothelial cells exposed to a hyperglycemic environment [7, 9, 23, 41]. It has been demonstrated that mouse microvascular endothelial cells (MMECs) develop oxidative stress after exposure to high glucose [42].…”