title: 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.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Padova, Italy. avogaro@ux1.unipd.it
authors.forename: A
authors.initials: A
authors.lastname: Avogaro
authors.forename: L
authors.initials: L
authors.lastname: Calò
authors.forename: F
authors.initials: F
authors.lastname: Piarulli
authors.forename: M
authors.initials: M
authors.lastname: Miola
authors.forename: S
authors.initials: S
authors.lastname: deKreutzenberg
authors.forename: A
authors.initials: A
authors.lastname: Maran
authors.forename: A
authors.initials: A
authors.lastname: Burlina
authors.forename: R
authors.initials: R
authors.lastname: Mingardi
authors.forename: A
authors.initials: A
authors.lastname: Tiengo
authors.forename: S
authors.initials: S
authors.lastname: Del Prato
mesh_terms: D000208:Acute Disease; D000328:Adult; D001916:Brachial Artery / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006728:Hormones / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007275:Injections, Intravenous; D007328:Insulin / Q000627:therapeutic use; D007662:Ketosis / Q000209:etiology* / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006728:Hormones; D007004:Hypoglycemic Agents; D007328:Insulin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide