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Mechanisms of Organ Specificity in Diabetic Microvasculopathy

Author: WangHui
Tutor: LouJinNing
School: Beijing Union Medical College
Course: Pathology and Pathophysiology
Keywords: diabetic microvasculopathy advanced glycation end products proteinkinase C protein kinase Aislet transplantation islet isolation alpha cell beta cell glucagon insulin glucose diabetes
CLC: R587.2
Type: PhD thesis
Year: 2010
Downloads: 227
Quote: 0
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Abstract


Diabetic microvasculopathy is a major complication of diabetes. Diabetic microvasculopathy is characterized with organ specificity, which mainly affect retinal, glomerular and peripheral capillary. It is the leading cause of blindness, renal failure and limb amputation in patients with diabetes. However, mechanisms of organ-specific diabetic microvasculopathy have not been well elucidated. Therefore, it is necessary to further investigate mechanisms of organ specificity in diabetic microvasculopathy for prevention and treatment of diabetic microvasculopathy. It has been recognized that the increased formation of advanced glycation end products, activation of protein kinase C isoforms, oxidative stress are implicated in the mechanisms of diabetes-induced microvasculopathy. However, it is unclear whether these factors are involved in the course of different susceptibility of organs in diabetic microvasculopathy under diabetic conditions.Objectives:To investigate the effect of protein kinase C and protein kinase A on organ-specific diabetic microvasculopathy by comparative research on kidney, liver and brain of diabetic rat and exploring the effect of advanced glycation end products on retinal microvascular endothelial cell.Methods:Streptozotocin was injected intraperitoneally to establish rat model of type1diabetes, spontaneous diabetic GK rats were used as model of type2diabetes. Renal microvasculopathy in diabetic rats was detected by quantitative assay of urine albumin and histopathologic staining. Serum levels of advanced glycation end products in diabetic rats were assayed by ELISA. The expression of receptor for advanced glycation end products, protein kinase C and protein kinase A in glomeruli, liver and brain of diabetic rats were assayed by real-time quantitative PCR, western blotting and immunohistochemistry. In addition, we further investigated the effect of advanced glycation end products on the expression of receptor for advanced glycation end products, inducible nitric oxide synthase and manganese superoxide dismutase in retinal microvascular endothelial cells in vitro. The effect of advanced glycation end products on reactive oxygen species and nitric oxide production of retinal microvascular endothelial cells were also analyzed. At last, we studied the effect of PKC inhibitor and PKA activator on these phenotypic and functional changes of endothelial cells induced by advanced glycation end products.Results:Urinary albumin excretion rate, mean volume of kidney and kidney hypertrophy index of STZ-induced diabetic rats and spontaneously diabetic GK rats were significantly increased as compared with normal control group. In diabetic rats, increased glomerular basement membrane thickness and decreased interspace in glomerular capsule were observed. But there is no change with cerebral capillary or sinusoidal microvascular endothelial cells of diabetic rats.The level of serum AGEs in diabetic rats is gradually increased under diabetic condition. The expression of RAGE and PKC were increased in glomeruli of diabetic rats, but not in liver or brain. The expression of PKA were decreased in glomerule of diabetic rats, but increased in brain and liver.Increased expression of inducible nitric oxide synthase, production of reactive oxygen species and nitric oxide in endothelial cells, but decreased the expression of superoxide dismutase2in endothelial cells were found in the retinal endothelial cells treated with advanced glycation end products. We also found that these effects of advanced glycation end products were inhibited by PKC-β inhibitor and PKA activator.Conclusions:PKC and PKA may be the crucial cause of organ specificity in diabetic microvasculopathy. The transplantation of islets of Langerhans is an effective method for treatment of type I diabetes. After islet transplantation, an early loss of islet mass and the progressive deterioration of the graft were found in some recipients for obscure reasons.Pancreatic islets are composed of several different cell types including beta (β), alpha (α), delta (δ) and polypeptide (PP) cells, α,δ and PP cells are all located at the periphery of islets. The loss of alpha cell was found in islet isolation. It is important for treatment of type1diabetes to further investigate the effect of alpha cell loss from human islets on their function.Objectives:To investigate whether alpha-cell cell loss could impair the function of islets in vitro and in vivo.Methods:Human islets with alpha cell deficiency were prepared by prolonged enzyme digestion, as confirmed by immunocytochemistry and islet insulin/glucagon content analysis. The function of islets with alpha cell deficiency was evaluated by insulin release in vitro in response to glucose stimulation and in vivo by glycemia levels in diabetic mice after islet transplantation.Results:In vitro, human islets with alpha cell deficiency exhibited low glucose-induced insulin release compared with intact islets. In islets deficient in alpha cells, exogenous glucagon did not alone stimulate insulin release in the absence of glucose, but increased the glucose-induced insulin release in a dose-dependent manner. In intact islets, glucagon did not significantly change the glucose-stimulated insulin secretion. In vivo, transplantation of human islets with alpha cell deficiency did not effectively correct hyperglycemia in diabetic C57BL/6mice. In diabetic nude mice transplanted with islets deficient in alpha cells, administration of exogenous glucagon significantly decreased glycemia, while withdrawing glucagon increased glycemic levels as compared with relevant controls. In addition, the survival of diabetic nude mice grafted with islets deficient in alpha cells was significantly shorter than the survival of nude mice grafted with intact islets.Conclusion:These results indicate that glucagon-secreting alpha cells have an important role in maintaining stimulated insulin release from beta cells, and that alpha cell loss from islets during isolation has a deleterious effect on islet function.

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CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetic coma and other complications
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