Prevention of Type 2 Diabetes Mellitus by L-Arginine in Patients With Metabolic Syndrome

Summary

Aim The principal objective of this project is: • To evaluate the efficacy of long term (18 months) L-Arginine therapy in preventing or delaying clinical onset of type 2 diabetes mellitus in subjects with impaired glucose tolerance (IGT) and Metabolic Syndrome. Secondary end points are: 1. To define if a long term treatment with L-arginine is able to ameliorate insulin sensitivity and endothelial dysfunction in this population. 2. To find new risk profiles and candidate genes able to define the sub-group of patients at higher risk to develop type 2 diabetes mellitus. Methodology This is a double blind, parallel, one centre study to determine if long term oral L-arginine administration is able to delay or prevent type 2 diabetes mellitus in patients with Metabolic Syndrome. Two hundred and ninety four subjects were recruited at the Cardio-Metabolic and Clinical Trials Unit of the San Raffaele Scientific Institute. One hundred and forty two patients were randomized to enter the study and assigned to two arms: oral L-arginine (6.4 g/die) or placebo, in addition to diet and physical exercise. The treatment were maintained for 18 months. Visits were performed every 3 months for clinical evaluation, blood samples, treatment supply and collection of data on adverse events. Furthermore, patients were contacted every month by telephone to evaluate the accurate continuation of the study and they were instructed to phone to the centre in case of possible adverse events. An OGTT were performed before the enter into the study and at the end of the study period. An additional OGTT were performed at an intermediate visit if fasting glucose levels were more than 126 mg/dl. A diabetic response caused the end-point of the patient. Metabolic, hormonal and endothelial activation and inflammation parameters were measured. Evaluation of endothelium-mediated and non-endothelium-mediated vasodilatation were performed by strain gauche plethysmography evaluating forearm blood at the basal state. in post-ischemic conditions and after nitroglycerine administration. Before the enter into the study, an additional blood sample were drawn for DNA extraction and candidate genes variants evaluation. Before the enter into the study and at the end of the study period, gene expression for inflammation were measured on mRNA extraction on endothelial progenitor cells.

Timeline

Start

2005-12

Primary completion

2009-06

Completion

2009-06

Publications

• Monti LD, Galluccio E, Villa V, Fontana B, Spadoni S, Piatti PM. Decreased diabetes risk over 9 year after 18-month oral L-arginine treatment in middle-aged subjects with impaired glucose tolerance and metabolic syndrome (extension evaluation of L-arginine study). Eur J Nutr. 2018 Dec;57(8):2805-2817. doi: 10.1007/s00394-017-1548-2. Epub 2017 Oct 20.
• Monti LD, Galluccio E, Fontana B, Spadoni S, Comola M, Marrocco Trischitta MM, Chiesa R, Comi G, Bosi E, Piatti P. Pharmacogenetic influence of eNOS gene variant on endothelial and glucose metabolism responses to L-arginine supplementation: Post hoc analysis of the L-arginine trial. Metabolism. 2015 Nov;64(11):1582-91. doi: 10.1016/j.metabol.2015.08.015. Epub 2015 Aug 28.

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