Arginine plus proline supplementation elicits metabolic adaptation that favors wound healing in diabetic rats

Abstract

Diabetic patients with wounds are at risk of protein malnutrition, have low arginine plasma levels, and suffer from delayed wound healing. We sought to determine the efficacy of arginine plus proline supplementation on protein and amino acid metabolism and on wound repair in a model of diabetic rats. Eighteen 11-wk-old Zucker diabetic fatty fa/fa male rats underwent a 7-cm abdominal skin incision with implantation of sponges and daily excision of full-thickness round sections of dorsal skin for 5 days. They were randomized to be fed with either a standard formula (S group, Clinutren Iso), a high-protein and arginine (ARG) plus proline (PRO)-enriched formula (ARG+PRO group, Clinutren Repair), or an isonitrogenous isoenergetic control formula (IC group). Nitrogen balance was calculated daily. The rats were euthanized on day 5, and plasma glucose, insulin, amino acids, skin epithelialization, and angiogenesis were measured. In macrophages, we assessed inducible nitric oxide synthase (iNOS) and arginase expression, production of nitric oxide (NO) and amino acid metabolism. Both the ARG+PRO and IC groups showed improved nitrogen balance. ARG plus PRO supplementation increased proline and branched-chain amino acid plasma concentrations and improved angiogenesis. Arginase and iNOS expressions in macrophages were reduced, together with NO and citrulline production. In diabetic rats, ARG plus PRO supplementation improves wound angiogenesis and favors whole body protein metabolism. Low macrophage iNOS expression at day 5 may reflect a low inflammatory state in the wounds, favoring wound closure.