Syngeneic Pancreatic Islet Transplantation Reverses Endothelial Dysfunction in Experimental Diabetes

Abstract

Diabetes is known to cause impaired endothelium-dependent relaxation of blood vessels. The purpose of this study was to determine whether this endothelial dysfunction is a permanent defect or is reversible after acute arginine supplementation in vitro or by surgical intervention in vivo using syngeneic pancreatic islet transplantation. Lewis rats were injected with streptozotocin to induce diabetes and were studied either 8 or 12 weeks later. Another group received syngeneic islets via intraportal injection at 8 weeks of diabetes and were allowed to become euglycemic for 4 weeks before study. Thoracic aortic rings were tethered in isolated muscle baths, contracted with a submaximal concentration of norepinephrine, and challenged with either the endothelium-dependent vasodilator acetylcholine or the endothelium-independent vasodilator nitroglycerin. Relaxation to acetylcholine (but not nitroglycerin) was reduced in both 8- and 12-week diabetic rings compared with age-matched control rings. Preincubation of diabetic rings in vitro with L-arginine (but not D-arginine) restored relaxation to acetylcholine to normal to rings from 8-week but not 12-week diabetic animals. Plasma basic amino acids (arginine, lysine, and histidine) were reduced by diabetes, whereas other neutral or acidic amino acids were unchanged (phenylalanine, proline, and glutamate), reduced (serine, cysteine, threonine, tyrosine, tryptophan, and aspartate), or elevated (isoleucine, leucine, and valine). Islet transplantation restored to normal the changes in plasma amino acids. Elevation in blood glucose and total glycosylated hemoglobin in diabetic animals was normalized after islet transplantation. Furthermore, islet transplantation completely restored the defective endothelium-dependent relaxation to acetylcholine in diabetic rings.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal by L-arginine of a dysfunctional arginine/nitric oxide pathway in the endothelium of the genetic diabetic BB rat

“…Our observation showing improvement in endothelium-dependent relaxation of diabetic BB rat aorta by l -ARG is consistent with previous studies conducted in our laboratory in which acute administration of l -ARG in vitro normalized the defective relaxation to ACH in aorta taken from STZ-induced diabetic Sprague-Dawley and Lewis strain rats [8,9]. The observation that l -ARG did not enhance relaxation in aorta of rats of longer diabetes duration [9] suggests that the mechanism of dysfunction might vary with duration of disease.…”

“…The extracellular concentration of ARG used in the mesenteric study was 10 m mol/l (i. e. 300 times lower than that used in our study). This low concentration is nearly 20 times lower than the physiological plasma ARG concentration of approximately 200 m mol/l reported in our laboratory [8,9,15] and elsewhere [16] in different strains of rats and from 7-to 10-times lower than the plasma ARG concentration in STZ-induced diabetic rats. Furthermore, ARG transport into tissue would not be expected to be anywhere near saturation since 10 m mol/l ARG is approximately 10 times lower than the K m for transport by endothelial cells reported to be near 100 m mol/l [17].…”

“…The observation that l -ARG did not enhance relaxation in aorta of rats of longer diabetes duration [9] suggests that the mechanism of dysfunction might vary with duration of disease. The salient effect of l -ARG has also been recently shown in coronary arteries of the alloxan-induced diabetic dog evaluated in vivo [10] and in normal mesenteric arteries exposed in vitroto elevated glucose concentrations [11].…”

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

“…The vascular endothelial dysfunction developed in streptozotocin-induced diabetic rats can be recovered after 8 to 12 weeks of treatment with insulin [51], or with a pancreatic islet transplantation [52]. In these studies, the improvement of endothelial function was accompanied by a parallel improvement in metabolic control, estimated by HbA 1c values [52] or by the extinction of glycosuria or ketonuria [51].…”

“…In these studies, the improvement of endothelial function was accompanied by a parallel improvement in metabolic control, estimated by HbA 1c values [52] or by the extinction of glycosuria or ketonuria [51]. In our laboratory, we have shown a close relation between the presence of endothelial dysfunction and the metabolic control of the disease [36,37].…”