The pathogenesis of brain disorders in type 1 diabetes (T1D) is multifactorial and involves the adverse effects of chronic hyperglycemia and of recurrent hypoglycemia. Kidney-pancreas (KP), but not kidney alone (KD), transplantation is associated with sustained normoglycemia, improvement in quality of life, and reduction of morbidity/mortality in diabetic patients with end-stage renal disease (ESRD).
RESEARCH DESIGN AND METHODS
The aim of our study was to evaluate with magnetic resonance imaging and nuclear magnetic resonance spectroscopy (1H MRS) the cerebral morphology and metabolism of 15 ESRD plus T1D patients, 23 patients with ESRD plus T1D after KD (n = 9) and KP (n = 14) transplantation, and 8 age-matched control subjects.
Magnetic resonance imaging showed a higher prevalence of cerebrovascular disease in ESRD plus T1D patients (53% [95% CI 36–69]) compared with healthy subjects (25% [3–6], P = 0.04). Brain 1H MRS showed lower levels of N-acetyl aspartate (NAA)-to-choline ratio in ESRD plus T1D, KD, and KP patients compared with control subjects (control subjects vs. all, P < 0.05) and of NAA-to-creatine ratio in ESRD plus T1D compared with KP and control subjects (ESRD plus T1D vs. control and KP subjects, P ≤ 0.01). The evaluation of the most common scores of psychological and neuropsychological function showed a generally better intellectual profile in control and KP subjects compared with ESRD plus T1D and KD patients.
Diabetes and ESRD are associated with a precocious form of brain impairment, chronic cerebrovascular disease, and cognitive decline. In KP-transplanted patients, most of these features appeared to be near normalized after a 5-year follow-up period of sustained normoglycemia.
Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.
peroxynitrite; nitric oxide; superoxide; nitrotyrosine; diabetes; vascular; cardiomyopathy; nephropathy; neuropathy; retinopathy
The hyperglycemia triggers several chronic diabetic complications mediated by increased oxidative stress that eventually causes diabetic nephropathy. The aim of this study was to examine if the sodium-glucose cotransporter (SGLT2) inhibition prevents the oxidative stress in the kidney of diabetic rats. Methods. The diabetic rat model was established by intraperitoneal injection of streptozotocin (50 mg/kg). The inhibition of SGLT2 was induced by daily subcutaneous administration of phlorizin (0.4 g/kg). Oxidative stress was assessed by catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities and by immunohistochemical analysis of 3-nitrotyrosine (3-NT). Results. Streptozotocin-induced diabetes caused hyperglycemia and lower body weight. The CAT activity decreased in cortex and medulla from diabetic rats; in contrast, the GPx activity increased. Furthermore the 3-NT staining of kidney from diabetic rats increased compared to control rats. The inhibition of SGLT2 decreased hyperglycemia. However, significant diuresis and glucosuria remain in diabetic rats. The phlorizin treatment restores the CAT and GPX activities and decreases 3-NT staining. Conclusion. The inhibition of SGLT2 by phlorizin prevents the hyperglycemia and oxidative stress in kidney of diabetic rats, suggesting a prooxidative mechanism related to SGLT2 activity.
In islet transplantation, nonimmunological factors such as limited growth capacity or increased death rate could reduce the beta cell mass in the graft and lead to failure of the transplant. We studied the evolution of beta cell replication and mass after transplantation of insufficient, minimally sufficient, or excessive islet tissue. Streptozocin diabetic C57BL/6 mice received 150 or 300 syngeneic islets under the kidney capsule and normal mice received 300 islets. In streptozocin diabetic mice 300 islets restored normoglycemia; beta cell replication in transplanted islets was similar to replication in normal pancreas and beta cell mass in the graft remained constant. In contrast, 150 islets were insufficient to achieve normoglycemia; beta cell replication was increased initially but not by 18 or 30 d despite persistent hyperglycemia, and beta cell mass fell progressively. When islets were transplanted into normal recipients, beta cell replication remained normal but beta cells underwent atrophy and mass in the graft was substantially reduced. Therefore, with a successful islet transplant, in diabetic mice beta cell replication and mass remain constant. In contrast, when insufficient islet tissue is transplanted an initial increase in beta cell replication can not compensate for a decline in beta cell mass. When excessive islet tissue is transplanted, beta cell mass is reduced despite normal beta cell replication.
The expanding impact of chronic kidney disease (CKD) due to pandemic diabetes mellitus is recounted emphasizing its epidemiology that has induced global socioeconomic stress on health care systems in industrialized nations now attempting to proffer optimal therapy for end stage renal disease (ESRD). Strategies to delay and perhaps prevent progression of diabetic nephropathy from minimal proteinuria through nephrotic range proteinuria and azotemia to ESRD appear to have decreased the rate of persons with diabetes who develop ESRD. For those with ESRD attributed to diabetes, kidney transplantation affords better survival and rehabilitation than either hemodialysis or peritoneal dialysis. It is likely that advances in genetics and molecular biology will suggest early interventions that will preempt diabetic complications including renal failure.
diabetic nephropathy; chronic kidney disease; glycation; renal failure; renoprotection
Marfan's syndrome is a systemic disorder of the connective tissue caused by mutations in the extracellular matrix protein fibrillin-1, with aortic dissection and aneurysm being its most life-threatening manifestations. Kidney transplantation for end-stage renal disease (ESRD) in patients with Marfan's syndrome has not been reported in the literature, and the rate of the incidence of dissection or aneurysm in the iliac artery is unknown. Here, we present a patient with Marfan's syndrome with ESRD due to severe renal ischemia caused by massive bleeding from thoracoabdominal aortic dissection leading to transplant surgery of a living kidney procured from the patient's mother. After kidney transplantation, the renal function normalized without vascular complications, and stable graft function along with negative results for both microhematuria and proteinuria continued for two years. Also, vascular complication such as aneurysm or dissection of the iliac artery was not observed using ultrasonography during the follow-up period. ESRD patients with Marfan's syndrome might be suitable for kidney transplantation, but long-term and careful observations are needed.
Macrovascular and microvascular diseases are currently the principal causes of morbidity and mortality in subjects with diabetes. Disorders of the physiological signaling functions of reactive oxygen species (superoxide and hydrogen peroxide) and reactive nitrogen species (nitric oxide and peroxynitrite) are important features of diabetes. In the absence of an appropriate compensation by the endogenous antioxidant defense network, increased oxidative stress leads to the activation of stress-sensitive intracellular signaling pathways and the formation of gene products that cause cellular damage and contribute to the vascular complications of diabetes. It has recently been suggested that diabetic subjects with vascular complications may have a defective cellular antioxidant response against the oxidative stress generated by hyperglycemia. This raises the concept that antioxidant therapy may be of great benefit to these subjects. Although our understanding of how hyperglycemia-induced oxidative stress ultimately leads to tissue damage has advanced considerably in recent years, effective therapeutic strategies to prevent or delay the development of this damage remain limited. Thus, further investigation of therapeutic interventions to prevent or delay the progression of diabetic vascular complications is needed.
Diabetic vascular complications; Reactive nitrogen species; Reactive oxygen species
Numerous studies have documented the presence of racial disparities among Americans in health outcomes with respect to cardiovascular disease, infant mortality, cancer, and kidney disease. With regard to kidney diseases, these disparities are more dramatic. African, Hispanic, and Native Americans have the highest risks of end-stage renal disease (ESRD). The incidence of ESRD is four times higher in African Americans than in whites. Diseases causing chronic kidney failure, such as diabetes mellitus, hypertension, systemic lupus erythematosus, and human immunodeficiency virus-associated nephropathy, are particularly prevalent among African-American patients. In addition to the higher prevalence, the morbidity associated with kidney complications of these diseases appears worse in African-American patients. African Americans also have worse outcomes and a relatively reduced access to kidney transplantation--the best therapy for ESRD. It is highly likely that social and environmental factors play a very significant role in the persistence of these disparities. A detailed understanding of these socioeconomic and environmental factors will be critical in formulating rational public health strategies to redress these disparities. This paper reviews the social, economic and environmental factors that impact on the incidence of ESRD in minority groups.
In all diabetic animal models studied to date, microangiopathic complications develop which can be prevented by tight control and reversed by either islet cell transplantation or transplanting the diabetic kidney into a nondiabetic environment. In humans the prevalence of these complications in secondary diabetes mellitus is similar to the prevalence in genetic diabetes. Furthermore, mesangial basement membrane thickness is normal at the onset of the disease and increases shortly thereafter. These two facts strongly suggest that the microangiopathic complications are not an independent genetic component but rather are secondary to the metabolic derangements of uncontrolled diabetes. Normal kidneys transplanted into diabetic recipients developed the vascular lesions of diabetes. Conversely, two diabetic kidneys inadvertently transplanted into nondiabetic recipients showed clearing of the vascular lesions.
Most retrospective studies support the conclusion that control is associated with lessened complications. The three prospective studies published to date also support this hypothesis. Because glucose concentrations cannot be brought to normal levels by present methods, the critical question is whether a major emphasis on restoring metabolism to as nearly normal as possible will help ameliorate the microangiopathic complications in our patients. The accumulated evidence would strongly favor an affirmative answer. Two daily injections of intermediate-acting insulin supplemented with small amounts of short-acting insulin as needed is one method to approach this goal.
Diabetes is characterized by chronic hyperglycemia, which can increase reactive oxygen species (ROS) production by the mitochondrial electron transport chain. The formation of ROS induces oxidative stress and activates oxidative damage-inducing genes in cells. No research has been published on oxidative damage-related extracellular superoxide dismutase (EC-SOD) protein levels in human diabetic skin. We investigated the expression of EC-SOD in diabetic skin compared with normal skin tissue in vivo.
The expression of EC-SOD protein was evaluated by western blotting in 6 diabetic skin tissue samples and 6 normal skin samples. Immunohistochemical staining was also carried out to confirm the EC-SOD expression level in the 6 diabetic skin tissue samples.
The western blotting showed significantly lower EC-SOD protein expression in the diabetic skin tissue than in the normal tissue. Immunohistochemical examination of EC-SOD protein expression supported the western blotting analysis.
Diabetic skin tissues express a relatively small amount of EC-SOD protein and may not be protected against oxidative stress. We believe that EC-SOD is related to the altered metabolic state in diabetic skin, which elevates ROS production.
Skin; Diabetes mellitus; Superoxide dismutase
For patients with type 1 diabetes, innovations in insulin formulations and delivery have improved the ability to achieve excellent blood glucose control. However, it is uncommon to achieve euglycemia, particularly while avoiding complications arising from hypoglycemia. Pancreas transplantation remains the only broadly applied treatment strategy that can result in normalization of blood glucose, but this must be weighed against the risks of a surgical procedure and subsequent immunosuppression. To improve this risk/benefit ratio, pancreas transplantation is typically performed in patients with kidney failure who are to undergo kidney transplantation and immunosuppression (simultaneous pancreas-kidney transplant) or who have undergone kidney transplant and are obligated to the use of immunosuppressive medications (pancreas after kidney transplant). The purpose of this review is to clarify the benefit of an added pancreas transplant in these clinical settings and formulate an approach to the patient with type 1 diabetes as they approach kidney failure.
Pancreas transplantation; Type 1 diabetes; Chronic kidney disease
Diabetes mellitus (DM) causes not only hyperglycemia but oxidative stress, resulting mainly enhanced production of mitochondrial reactive oxygen species (ROS). Hyperbaric oxygen (HBO) treatments are applied various diseases including diabetic patients with unhealing foot ulcers, however, and also increases the formation of ROS. Recently, it has been reported that oxidative stress worsens many pathological conditions including DM and obesity suggesting possible changes in regulation of genes associated with the oxidative stress, however, effects of HBO which could induce ROS on the gene expressions of oxidative stress parameters in DM animals are unknown. The purpose of this study is to investigate the effect of HBO exposure on the gene expression of three important antioxidant enzymes, cytosolic superoxide dismutase (Cu-Zn SOD), cytosolic glutathione peroxidase (GPx-1), and catalase (CAT) in DM rats, respectively. We used streptozotocin-induced DM model rats and examined both mRNA expressions and the activities of these antioxidant enzymes in the liver, skeletal muscle, and pancreas. The mRNA expressions of Cu-Zn SOD and CAT decreased significantly (p < 0.001), and GPx increased significantly (p < 0.001) in all the studied organs of DM rats under HBO exposure compared to those from DM-induced rats not exposed to HBO. Similarly, activities of these three enzymes changed in accordance with the mRNA levels. These results suggested that DM induction and HBO exposure might synergistically affect antioxidant enzymes, resulting increase of oxidative stress state. Thus, HBO exposure seems to be an excellent model system for investigating oxidative stress.
Diabetes mellitus; hyperbaric oxygen; oxidative stress; superoxide dismutase; glutathione peroxidase; catalase
There are several surgical complications which can occur following simultaneous pancreas-kidney transplantation (SPKT). Although intestinal obstruction is known to be a common complication after any type of abdominal surgery, the occurrence of small bowel volvulus, which is one of the rare causes of intestinal obstruction, following SPKT has not been published before. A 24-year-old woman suffering from type I diabetes mellitus with complications of nephropathy resulting in end stage renal disease (ESRD), neuropathy and retinopathy underwent SPKT. On the postoperative month 5, she was brought to the emergency service due to abdominal distention with mild abdominal pain. After laboratory research and diagnostic radiological tests had been carried out, she underwent exploratory laparotomy to determine the pathology for acute abdominal symptoms. Intra-operative observation revealed the presence of an almost totally ischemic small bowel which had occurred due to clockwise rotation of the mesentery. Initially, simple derotation was performed to avoid intestinal resection because of her risky condition, particularly for short bowel syndrome, and subsequent intestinal response was favorable. Thus, surgical treatment was successfully employed to solve the problem without any resection procedure. The patient's postoperative follow-up was uneventful and she was discharged from hospital on postoperative day 7. According to our clinical viewpoint, this study emphasizes that if there is even just a suspicion of acute abdominal problem in a patient with SPKT, surgical intervention should be promptly performed to avoid any irreversible result and to achieve a positive outcome.
A pancreas transplant is a surgical procedure to place a healthy pancreas from a donor into a patient whose pancreas no longer functions properly. Exocrine pancreas transplantation remains the standard treatment of choice for patients with diabetes mellitus complicated by end-stage renal disease. The use of pancreas transplantation for type 2 diabetes mellitus is an emerging concept. A pancreas transplant is often done in conjunction with a kidney transplant. Even if pancreas transplantation provides the best glycemic control option for diabetes mellitus, it is associated with significant morbidities related to infectious disease. The present article provides with a review of pancreatic transplantation.
Graft survival; pancreas transplantation; histopathology; diabetes; pancreas-kidney; infectious disease
Oxidative stress promotes endothelial dysfunction and atherosclerosis in chronic renal disease.
This study investigated the impact of Hatha yoga on oxidative stress indicators and oxidant status, in patients with end-stage renal disease (ESRD) on hemodialysis.
This prospective randomized study consisted of 33 ESRD patients in the Hatha yoga exercise group who were matched with 35 ESRD patients in the control group.
The oxidative stress indicators (malondialdehyde - MDA, protein oxidation - POX, phospholipase A2 - PLA2 activity) and the oxidative status (superoxide dismutase (SOD) and catalase activities) were determined in the blood samples taken at the pre-hemodialysis treatment, at baseline (0 months) and after four months.
In patients in the Hatha yoga exercise group, lipid peroxidation, as indicated by MDA decreased by 4.0% after four months (P = 0.096). There was also a significant reduction in the activity of PLA from 2.68 ± 0.02 IU / L to 2.34 IU / L (− 12.7%; P = 0.010) and POX from 2.28 ± 0.02 nmol / mg to 2.22 ± 0.01 nmol / mg (− 22.6%; P = 0.0001). The activity of SOD significantly increased from 12.91 ± 0.17 U / L to 13.54 ± 0.15 U / L (4.65%; P = 0.0001) and catalase from 79.83 ± 0.63 U / L to 80.54 ± 0.80 U / L (0.90%; P = 0.0001). There was a significant correlation between the pre-hemodialysis oxidative stress parameters at the zero month and after four months for the activities of PLA (r = 0.440), catalase (r = 0.872), and SOD (r = 0.775).
These findings suggest that the Hatha yoga exercise has therapeutic, preventative, and protective effects in ESRD subjects, by decreasing oxidative stress.
Antioxidant enzymes; end-stage renal disease; Hatha yoga exercise; lipid peroxidation; oxidative stress
Kidney disease in type 1 diabetes has been historically thought to be more prevalent in men. As recent data do not reflect this pattern, we evaluated whether a sex difference persists.
Prospective cohort study.
Setting and participants
We used 18-year follow-up data from the Pittsburgh Epidemiology of Diabetes Complications study (n=788; baseline mean age 27 and diabetes duration 19 years).
Predictor or factor
Sex and diagnosis interval (1950–64 or 1965–80).
The cumulative incidences of macroalbuminuria (albumin excretion rate >200 μg/min) and end-stage renal disease (ESRD, kidney failure, dialysis or transplant) were evaluated at 20, 25, and 30 years of diabetes duration. To address potential survival bias, death certificate information was included in determining ESRD for those who died before baseline (n=145). Analyses were stratified by diagnosis year (1950–64 or 1965–80).
Kidney disease risk factor information was available.
A significant interaction was noted between sex and diagnosis cohort for ESRD incidence by 25 (p=0.002) and 30 (p<0.001) years’ duration. Thus, within the 1950–64 cohort (210 men, 180 women), ESRD was higher in men compared to women by 25 (30.6% vs. 18.0%, respectively) and 30 (43.4% vs. 24.6%, respectively) years duration. However, within the 1965–80 cohort (260 men, 283 women), incidence was higher in women (7.6% vs. 13.8% by 25 yrs [p=0.04] and 13.7% vs. 21.0% by 30 yrs [p=0.09] in men vs. women, respectively). Results were similar for macroalbuminuria.
Study participants were not followed from the onset of diabetes and thus, risk factor data from that period are lacking.
Our data suggest that the male excess of type 1 diabetic kidney disease cases observed in the earlier cohort has been eliminated in the younger cohort. The reason for this dramatic change is currently unclear but should be addressed in subsequent studies.
Hyperglycemia exerts toxic effects on the pancreatic β-cells. This study investigated the hypothesis that the common antidiabetic drugs glibenclamide and metformin, in combination with tualang honey, offer additional protection for the pancreas of streptozotocin (STZ)-induced diabetic rats against oxidative stress and damage. Diabetes was induced in male Sprague Dawley rats by a single dose of STZ (60 mg/kg; ip). Diabetic rats had significantly elevated levels of lipid peroxidation (TBARS), up-regulated activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) while catalase (CAT) activity was significantly reduced. Glibenclamide and metformin produced no significant effects on TBARS and antioxidant enzymes except GPx in diabetic rats. In contrast, the combination of glibenclamide, metformin and honey significantly up-regulated CAT activity and down-regulated GPx activity while TBARS levels were significantly reduced. These findings suggest that tualang honey potentiates the effect of glibenclamide and metformin to protect diabetic rat pancreas against oxidative stress and damage.
diabetes mellitus; streptozotocin; oxidative stress; pancreas; tualang honey; glibenclamide; metformin
Diabetes is associated with significantly increased rates of kidney disease or diabetic nephropathy (DN), a severe microvascular complication that can lead to End-stage renal disease (ESRD). ESRD needs to be treated by dialysis or kidney transplantation and is also associated with cardiovascular disease and macrovascular complications. Therefore, effective renal protection is critical to reduce the rates of mortality associated with diabetes. Although key signal transduction and gene regulation mechanisms have been identified and several drugs are currently in clinical use, the rates of DN are still escalating, suggesting the imperative need to identify new biomarkers and drug targets. The recent discovery of microRNAs (miRNAs) and their cellular functions provide an opportunity to fill these critical gaps. Since miRNAs can modulate the actions of key factors involved in DN such as transforming growth factor-beta (TGF-β), they could be novel targets for the treatment of DN. This review covers the recent studies on the roles of miRNAs and miRNA circuits in TGF-β actions and in DN.
microRNAs; TGF-β; Diabetic Nephropathy; Fibrosis; Hypertrophy
The incidence of end-stage renal disease (ESRD) in the US is rising at an alarming rate, with the largest increase among African-American populations. The key risk factors for kidney disease are hypertension and diabetes, which are both becoming more prevalent in the US, and particularly in African Americans. Although African Americans make up 12.6% of the US population, the incidence of diabetes-related ESRD is four times higher than for whites, and the prevalence of ESRD due to hypertension is twice that of white patients. Approximately 30 to 40% of all patients with diabetes will develop nephropathy and many will progress to ESRD, necessitating dialysis or kidney transplantation. Recent studies in patients with type 2 diabetes indicate a significant delay in progression or development of diabetic nephropathy following blockade of the renin-angiotensin-aldosterone system with the use of angiotensin receptor antagonists. Early intervention in patients with hypertension is necessary to prevent kidney damage, and data from the African American Study of Kidney Disease and Hypertension suggest that angiotensin-converting enzyme inhibitors are effective in this population. Although African-American patients receiving hemodialysis appear to have increased survival compared with whites, racial factors and poor access to medical care contribute to the increased risk of kidney disease in minorities. A concerted effort is necessary to raise awareness in minority populations and provide strategies for prevention and early treatment thereby attenuating the increasing prevalence of kidney failure in these groups.
Prior studies reporting outcomes after pancreas transplant have included a combination of C-peptide cutoffs and clinical criteria to classify type 2 diabetes mellitus (T2DM). However, since the kidney is the major site for C-peptide catabolism, C-peptide is unreliable to discriminate type of diabetes in patients with kidney disease.
To improve the discriminating power and better classify type of diabetes we used a composite definition to identify T2DM: Presence of C-peptide, negative GAD65 antibody, absence of diabetic ketoacidosis and use of oral hypoglycemics. Additionally, BMI <30 kg/m2 and use of < than 1 unit/kg of insulin/day are selection criteria among T2DM patients with ESRD deemed suitable for SPKTx. We compared graft and patient survival between T1DM and T2DM after SPKTx.
Our study cohort consisted of 80 patients, 10 of whom were assigned as T2DM based on our study criteria. Approximately 15% of patients with T1DM had detectable C-peptide. Cox regression survival analyses found no significant differences in allograft (pancreas and kidney) and patient survival in the 2 groups. The mean creatinine clearance at 1 year by MDRD equation was not significantly different between the 2 groups. Among those with 1 year follow up, all patients with T2DM had HbA1C < 6.0 at 1 year vs. 92% of those with T1DM.
SPKTx needs to be considered in the therapeutic armamentarium for renal replacement in selected patients with T2DM and ESRD. Utilization of C-peptide in patients with ESRD as sole criteria to phenotype type of diabetes can be misleading.
Chronic hyperglycemia increases oxidative stress status and has been associated with neurological complications in diabetic individuals. This study compared the antioxidant properties of red wine or resveratrol in different brain areas of diabetic and non-diabetic rats, and investigated the effect of them on hippocampal cell proliferation in hippocampal dentate gyrus of diabetic rats. Streptozotocin-induced diabetic and control rats were treated with red wine (4 mL/kg), resveratrol (20 mg/kg) or saline, by oral gavage, for 21 days. Lipid peroxidation (TBARS), catalase and superoxide dismutase were measured to evaluate the oxidative stress and the BrdU-positive cells were assessed to measure changes in cellular proliferation. In diabetic animals, resveratrol showed antioxidant property in the hippocampus and in the striatum, while red wine had an antioxidant effect only in the hippocampus. Neither red wine nor resveratrol reversed the lower hippocampal cell proliferation in diabetic rats. Daily doses of red wine or resveratrol have an antioxidant effect in rats depending on the brain area and the glycemic status.
The exploration of coronary microcirculatory dysfunction in diabetes has accelerated in recent years. Cardiac function is compromised in diabetes. Diabetic patients manifest accelerated atherosclerosis in coronary arteries. These data are confirmed in diabetic animal models, where lesions of small coronary arteries have been described. These concepts are epitomized in the classic microvascular complications of diabetes, i.e. blindness, kidney failure and distal dry gangrene. Most importantly, accumulating data indicate that insights gained from the link between inflammation and diabetes can yield predictive and prognostic information of considerable clinical utility. This review summarizes the evidence for the predisposing factors and the mechanisms involved in diabetes, and assesses the current state of knowledge regarding the triggers for inflammation in this disease. We evaluate the roles of hyperglycemia, oxidative stress, polyol pathway, protein kinase C, advanced glycation end products, insulin resistance, peroxisome proliferator-activated receptor-γ, inflammation, and diabetic cardiomyopathy as a “stem cell disease”. Furthermore, we discuss the mechanisms responsible for impaired coronary arteriole function. Finally, we consider how new insights in diabetes may provide innovative therapeutic strategies.
Coronary artery; Diabetes; Endothelial dysfunction; Hyperglycemia; Inflammation; Insulin; Microcirculation; Nitric oxide; Oxidative stress
This study investigates whether end-stage renal disease (ESRD) patients with amputation secondary to peripheral vascular disease (PVD) or diabetes mellitus (DM) are appropriate candidates for renal transplant.
Limb- or digit- amputees with ESRD on the renal transplant list from 1993–2008 were included. Comorbidities, amputation type, duration on the waitlist, and current transplant status were analyzed. Additionally, US renal transplant centers were surveyed regarding their views about amputees' transplant candidacy.
Thirty-eight ESRD patients with amputations were identified; 3 patients underwent renal transplant, 14 expired on the waitlist, and 14 were removed for medical reasons. The survey indicated that centers generally don't consider amputation a contraindication to transplant listing.
Few ESRD patients with amputations who are placed on the transplant list undergo renal transplant; most die or are removed for medical reasons. Amputation should be considered an indicator of severe PVD and possibly a relative contraindication to listing for renal transplant.
amputation; diabetes; kidney; peripheral vascular disease; transplant
BACKGROUND/AIMS—Simultaneous pancreas and kidney transplantation (SPK) has become an important option in selected IDDM patients with end stage renal disease (ESRD). Successful SPK transplants are associated with long term normoglycaemic control and improved quality of life. However, debate still continues on the benefit to patients in terms of stabilisation or amelioration of diabetic retinopathy. The progression of diabetic retinopathy (DR) in a cohort of 20 SPK transplant patients is reported.
METHODS—All patients were reviewed postoperatively with corrected visual acuity, slit lamp examination, and fundal biomicroscopy. Preoperative data were collected retrospectively and DR was considered unstable if there had been a drop in Snellen acuity greater than three lines or a need for laser photocoagulation or vitrectomy in the 2 years preoperatively.
RESULTS—20 patients who received SPK transplants between March 1983 and April 1994 were reviewed (mean age 35.1 years; mean duration of IDDM = 24.6 years). 17 patients still had functioning grafts at a mean follow up of 5.1 years. Nine of these patients had unstable DR before transplantation. Of these, 89% (8/9) had stabilised DR following transplantation with only a single case requiring laser photocoagulation. Of the eight patients that had stable DR before transplantation all had stable DR following transplantation. 41% of cases (7/17) required cataract surgery during the follow up period.
CONCLUSIONS—Advanced diabetic retinopathy is present in a high proportion of cases managed with SPK transplant as a consequence of the duration of IDDM and the presence of ESRD. More than 90% of cases have stable DR following transplant.
Hyperglycemia can promote vascular complications by multiple mechanisms, with formation of advanced glycation endproducts (AGEs) and increased oxidative stress proposed to contribute to both macrovascular and microvascular complications. Many of the earliest pathologic responses to hyperglycemia are manifest in the vascular cells that directly encounter elevated blood glucose levels. In the macrovasculature, these include endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). In the microvasculature, these include ECs, pericytes (in retinopathy), and podocytes (in renal disease). Additionally, neovascularization arising from the vasa vasorum may promote atherosclerotic plaque progression and contribute to plaque rupture, thereby interconnecting macro- and microangiopathy.
glucose; atherosclerosis; advanced glycation endproducts; oxidative stress; inflammation