Impairment of neurovascular coupling in the hippocampus due to decreased nitric oxide bioavailability supports early cognitive dysfunction in type 2 diabetic rats.

Numerous epidemiological and preclinical studies have established a strong correlation between type 2 diabetes (T2DM) and cognitive impairment and T2DM is now established as an undisputable risk factor in different forms of dementia. However, the mechanisms underlying cognitive impairment in T2DM are still not fully understood. The temporal and spatial coupling between neuronal activity and cerebral blood flow (CBF) - neurovascular coupling (NVC) - is essential for normal brain function. Neuronal-derived nitric oxide (⦁NO) produced through the nNOS-NMDAr pathway, is recognized as a key messenger in NVC, especially in the hippocampus. Of note, impaired hippocampal perfusion in T2DM patients has been closely linked to learning and memory dysfunction. In this study, we aimed to investigate the functionality of NVC, in terms of neuronal-•NO signaling and spatial memory performance, in young Goto-Kakizaki (GK) rats, a non-obese model of T2DM. For that, we performed direct and simultaneous measurements of •NO concentration dynamics and microvascular CBF changes in the hippocampus upon glutamatergic activation. We found that limited •NO bioavailability, connected to shorter and faster •NO transients in response to glutamatergic neuronal activation, is associated with decreased hemodynamic responses and a decline in spatial memory performance. This evidence supports a close mechanistic association between neuronal-triggered •NO concentration dynamics in the hippocampus, local microvascular responses, and cognitive performance in young diabetic animals, establishing the functionality of NVC as a critical early factor to consider in the cascade of events leading to cognitive decline in T2DM. These results suggest that strategies capable to overcome the limited •NO bioavailability in early stages of T2DM and maintaining a functional NVC pathway may configure pertinent therapeutic approaches to mitigate the risk for cognitive impairment in T2DM.

Cinnamaldehyde Supplementation Reverts Endothelial Dysfunction in Rat Models of Diet-Induced Obesity: Role of NF-E2-Related Factor-2.

Cinnamaldehyde (CN) is an activator of NF-E2-related factor 2 (Nrf2), which has the potential to reduce endothelial dysfunction, oxidative stress and inflammation in metabolic disorders. Our main purpose was to evaluate the effects of CN on vascular dysfunction in metabolic syndrome rats. Normal Wistar (W) rats were divided into eight groups: (1) Wistar (W) rats; (2) W rats fed with a high-fat diet (WHFD); (3) W rats fed with a sucrose diet (WS); (4) WHFD fed with a sucrose diet (WHFDS); (5) W treated with CN (WCn); (6) WS treated with CN (WSCn); (7) WHFD treated with CN (WHFDCn); (8) WHFDS treated with CN (WHFDSCn). CN treatment with 20 mg/kg/day was administered for 8 weeks. Evaluation of metabolic profile, inflammation, endothelial function, oxidative stress, eNOS expression levels and Nrf2 activation was performed. The metabolic dysfunction was greatly exacerbated in the WHFDS rats, accompanied by significantly higher levels of vascular oxidative stress, inflammation, and endothelial dysfunction. In addition, the WHFDS rats displayed significantly reduced activity of Nrf2 at the vascular level. CN significantly reverted endothelial dysfunction in the aortas and the mesenteric arteries. In addition, CN significantly decreased vascular oxidative damage, inflammation at vascular and perivascular level and up-regulated Nrf2 activity in the arteries of WHFDS rats. Cinnamaldehyde, an activator of Nrf2, can be used to improve metabolic profile, and to revert endothelial dysfunction in obesity and metabolic syndrome.

Evaluating the Impact of Different Hypercaloric Diets on Weight Gain, Insulin Resistance, Glucose Intolerance, and its Comorbidities in Rats.

Animal experimentation has a long history in the study of metabolic syndrome-related disorders. However, no consensus exists on the best models to study these syndromes. Knowing that different diets can precipitate different metabolic disease phenotypes, herein we characterized several hypercaloric rat models of obesity and type 2 diabetes, comparing each with a genetic model, with the aim of identifying the most appropriate model of metabolic disease. The effect of hypercaloric diets (high fat (HF), high sucrose (HSu), high fat plus high sucrose (HFHSu) and high fat plus streptozotocin (HF+STZ) during different exposure times (HF 3 weeks, HF 19 weeks, HSu 4 weeks, HSu 16 weeks, HFHSu 25 weeks, HF3 weeks + STZ) were compared with the Zucker fatty rat. Each model was evaluated for weight gain, fat mass, fasting plasma glucose, insulin and C-peptide, insulin sensitivity, glucose tolerance, lipid profile and liver lipid deposition, blood pressure, and autonomic nervous system function. All animal models presented with insulin resistance and dyslipidemia except the HF+STZ and HSu 4 weeks, which argues against the use of these models as metabolic syndrome models. Of the remaining animal models, a higher weight gain was exhibited by the Zucker fatty rat and wild type rats submitted to a HF diet for 19 weeks. We conclude that the latter model presents a phenotype most consistent with that observed in humans with metabolic disease, exhibiting the majority of the phenotypic features and comorbidities associated with type 2 diabetes in humans.

Uncoupling Protein 2 Inhibition Exacerbates Glucose Fluctuation-Mediated Neuronal Effects.

Though glucose fluctuations have been considered as an adverse factor for the development of several diabetes-related complications, their impact in the central nervous system is still not fully elucidated. This study was conducted to evaluate the responses of neuronal cells to different glycemic exposures alongside to elucidate the role of uncoupling protein 2 (UCP2) in regulating such responses. To achieve our goals, primary cortical neurons were submitted to constant high (HG)/low (LG) or glucose level variations (GVs), and the pharmacological inhibition of UCP2 activity was performed using genipin. Results obtained show that GV decreased neuronal cells' viability, mitochondrial membrane potential, and manganese superoxide dismutase activity and increased reactive oxygen species (ROS) production. GV also caused an increase in the glutathione/glutathione disulfide ratio and in the protein expression levels of nuclear factor E2-related factor 2 (NRF2), UCP2, NADH-ubiquinone oxidoreductase chain 1 (ND1), and mitochondrially encoded cytochrome c oxidase I (MTCO1), both mitochondrial DNA encoded subunits of the electron transport chain. Contrariwise, genipin abrogated all those compensations and increased the levels of caspase 3-like activity, potentiated mitochondrial ROS levels, and the loss of neuronal synaptic integrity, decreased the protein expression levels of NRF1, and increased the protein expression levels of UCP5. Further, in the control and LG conditions, genipin increased mitochondrial ROS and the protein expression levels of UCP4, postsynaptic density protein 95 (PSD95), ND1, and MTCO1. Overall, these observations suggest that UCP2 is in the core of neuronal cell protection and/or adaptation against GV-mediated effects and that other isoforms of neuronal UCPs can be upregulated to compensate the inhibition of UCP2 activity.

The Sulforaphane and pyridoxamine supplementation normalize endothelial dysfunction associated with type 2 diabetes.

In this study we investigate pyridoxamine (PM) and/or sulforaphane (SFN) as therapeutic interventions to determine whether activators of NFE2-related factor 2 (Nrf2) can be used in addition with inhibitors of advanced glycation end products (AGE) formation to attenuate oxidative stress and improve endothelial dysfunction in type 2 diabetes. Goto-kakizaki (GK) rats, an animal model of non-obese type 2 diabetes, were treated with or without PM and/or SFN during 8 weeks and compared with age-matched Wistar rats. At the end of the treatment, nitric oxide (NO)-dependent and independent vasorelaxation in isolated aorta and mesenteric arteries were evaluated. Metabolic profile, NO bioavailability and vascular oxidative stress, AGE and Nrf2 levels were also assessed. Diabetic GK rats presented significantly lower levels of Nrf2 and concomitantly exhibited higher levels of oxidative stress and endothelial dysfunction. PM and SFN as monotherapy were capable of significantly improving endothelial dysfunction in aorta and mesenteric arteries decreasing vascular oxidative damage, AGE and HbA1c levels. Furthermore, SFN + PM proved more effective reducing systemic free fatty acids levels, normalizing endothelial function, NO bioavailability and glycation in GK rats. Activators of Nrf2 can be used therapeutically in association with inhibitors of AGE and cross-linking formation to normalize endothelial dysfunction in type 2 diabetes.

Adiponectin improves endothelial function in mesenteric arteries of rats fed a high-fat diet: role of perivascular adipose tissue.

BACKGROUND AND PURPOSE: Adiponectin, the most abundant peptide secreted by adipocytes, is involved in the regulation of energy metabolism and vascular physiology. Here, we have investigated the effects of exogenous administration of adiponectin on metabolism, vascular reactivity and perivascular adipose tissue (PVAT) of mesenteric arteries in Wistar rats fed a high-fat diet. EXPERIMENTAL APPROACH: The effects of adiponectin on NO-dependent and independent vasorelaxation were investigated in isolated mesenteric arteries from 12-month-old male Wistar rats (W12m) fed a high-fat diet (HFD) for 4 months and compared with those from age-matched rats given a control diet. Adiponectin ((96 µg·day-1 ) was administered by continuous infusion with a minipump, implanted subcutaneously, for 28 days. KEY RESULTS: Chronic adiponectin treatment reduced body weight, total cholesterol, free fatty acids, fasting glucose and area under the curve of intraperitoneal glucose tolerance test, compared with HFD rats. It also normalized NO-dependent vasorelaxation increasing endothelial NO synthase (eNOS) phosphorylation in mesenteric arteries of HFD rats. In PVAT from aged (W12m) and HFD rats there was increased expression of chemokines and pro-inflammatory adipokines, the latter being important contributors to endothelial dysfunction. Infusion of adiponectin reduced these changes. CONCLUSIONS AND IMPLICATIONS: Adiponectin normalized endothelial cell function by a mechanism that involved increased eNOS phoshorylation and decreased PVAT inflammation. Detailed characterization of the adiponectin signalling pathway in the vasculature and perivascular fat is likely to provide novel approaches to the management of atherosclerosis and metabolic disease. LINKED ARTICLES: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.

Mitochondria as a target for neuroprotection: implications for Alzheimer´s disease.

INTRODUCTION: Alzheimer's disease (AD), the most common form of dementia, is marked by progressive loss of memory and impairment of cognitive ability. Despite decades of intensive research and scientific advances, the intricate pathogenic mechanisms of AD are still not fully understood and, consequently, an effective treatment is yet to be developed. As widely accepted, the alterations of mitochondrial function are actively engaged in a plethora of neurodegenerative diseases, including AD. With growing interest in the mitochondria as a potential target for understanding AD, it has even been hypothesized that deficits in these organelles may be at the heart of the progression of AD itself. Areas covered: The purpose of this review is to summarize relevant studies that suggest a role for mitochondrial (dys)function in AD and to provide a survey on latest developments regarding AD-related mitochondrial therapeutics. Expert commentary: As outlined in a plethora of studies, there is no doubt that mitochondria play a major role in several stages of AD progression. Even though more in-depth studies are needed before pharmaceutical industry can apply such knowledge to human medicine, the continuous advances in AD research field will certainly facilitate and accelerate the development of more effective preventive or therapeutic strategies to fight this devastating disease.

Alzheimer's Disease: From Mitochondrial Perturbations to Mitochondrial Medicine.

Age-related neurodegenerative diseases such as Alzheimer's disease (AD) are distressing conditions causing countless levels of suffering for which treatment is often insufficient or inexistent. Considered to be the most common cause of dementia and an incurable, progressive neurodegenerative disorder, the intricate pathogenic mechanisms of AD continue to be revealed and, consequently, an effective treatment needs to be developed. Among the diverse hypothesis that have been proposed to explain AD pathogenesis, the one concerning mitochondrial dysfunction has raised as one of the most discussed with an actual acceptance in the field. It posits that manipulating mitochondrial function and understanding the deficits that result in mitochondrial injury may help to control and/or limit the development of AD. To achieve such goal, the concept of mitochondrial medicine places itself as a promising gathering of strategies to directly manage the major insidious disturbances of mitochondrial homeostasis as well as attempts to directly or indirectly manage its consequences in the context of AD. The aim of this review is to summarize the evolution that occurred from the establishment of mitochondrial homeostasis perturbation as masterpieces in AD pathogenesis up until the development of mitochondrial medicine. Following a brief glimpse in the past and current hypothesis regarding the triad of aging, mitochondria and AD, this manuscript will address the major mechanisms currently believed to participate in above mentioned events. Both pharmacological and lifestyle interventions will also be reviewed as AD-related mitochondrial therapeutics.

Perspectives on mitochondrial uncoupling proteins-mediated neuroprotection.

The integrity of mitochondrial function is essential to cell life. It follows that disturbances of mitochondrial function will lead to disruption of cell function, expressed as disease or even death. Considering that neuronal uncoupling proteins (UCPs) decrease reactive oxygen species (ROS) production at the expense of energy production, it is important to understand the underlying mechanisms by which UCPs control the balance between the production of adenosine triphosphate (ATP) and ROS in the context of normal physiological activity and in pathological conditions. Here we review the current understanding of neuronal UCPs-mediated respiratory uncoupling process by performing a survey in their physiology and regulation. The latest findings regarding neuronal UCPs physiological roles and their involvement and interest as potential targets for therapeutic intervention in brain diseases will also be exploited.

Amelioration of glycemic control by sleeve gastrectomy and gastric bypass in a lean animal model of type 2 diabetes: restoration of gut hormone profile.

BACKGROUND: In obese diabetic patients, bariatric surgery has been shown to induce remission of type 2 diabetes. Along with weight loss itself, changes in gut hormone profiles after surgery play an important role in the amelioration of glycemic control. However, the potential of gastrointestinal surgery regarding diabetes remission in non-severely obese diabetic patients has yet to be defined. In the present experimental study, we explored the effect of established bariatric procedures with and without duodenal exclusion on glycemic control and gut hormone profile in a lean animal model of type 2 diabetes. METHODS: Forty 12- to 14-week-old non-obese diabetic Goto-Kakizaki (GK) rats were randomly assigned to four groups: control group (GKC), sham surgery (GKSS), sleeve gastrectomy (GKSG), and gastric bypass (GKGB). Age-matched Wistar rats served as a non-diabetic control group (WIC). Glycemic control and plasma lipids were assessed at the beginning of the observation period and 4 weeks after surgery. Fasting and mixed meal-induced plasma levels of ghrelin, glucagon-like peptide-17-36 (GLP-1), and peptide tyrosine-tyrosine (PYY) were measured. RESULTS: In GK rats, glycemic control improved after sleeve gastrectomy (SG) and gastric bypass (GB). Mixed meal-induced gut hormone profiles in Wistar rats (WIC) were significantly different from those of sham-operated or control group GK rats. After SG and GB, GK rats showed a similar postprandial decrease in ghrelin as observed in non-diabetic WIC. Following both surgical procedures, a significant meal-induced increase in PYY and GLP-1 could be demonstrated. CONCLUSIONS: SG and GB induce a similar improvement in overall glycemic control in lean diabetic rodents. Meal-induced profiles of ghrelin, GLP-1, and PYY in GK rats are significantly modified by SG and GB and become similar to those of non-diabetic Wistar rats. Our data do not support the hypothesis that duodenal exclusion and early contact of food with the ileal mucosa alone explain changes in gut hormone profile in GK rats after gastrointestinal surgery.

Insulin resistance and beta cell function before and after sleeve gastrectomy in obese patients with impaired fasting glucose or type 2 diabetes.

BACKGROUND: Pathophysiology of type 2 diabetes (T2D) includes insulin resistance (IR) and insufficient insulin secretion. Remission in obese patients can be achieved through surgically induced weight loss. Sleeve gastrectomy is a novel technique for the treatment of morbid obesity, and its effects on the metabolic syndrome and T2D have not yet been fully understood. METHODS: From February 2008 to July 2010, sleeve gastrectomy as stand-alone treatment for severe or morbid obesity was performed in 23 patients with T2D or impaired fasting glucose (IFG). No postoperative complications occurred and patients were dismissed from hospital on day 2 after surgery. Body mass index (BMI), fasting blood glucose (FBG) and fasting insulin were determined before and up to 24 months after surgery. IR and beta cell function were calculated using the modified homeostasis model assessment (HOMA2). RESULTS: BMI, FBG and fasting insulin improved significantly as early as 3 months after surgery. Threefold increased preoperative insulin resistance (3.05) decreased to near-normal values (1.14) during the same period. Interestingly, overall beta cell function diminished at 12 months of follow-up (79.6 %), in comparison with preoperative values (117.8 %). Patients with a markedly reduced preoperative beta cell function (<40 %) did not achieve a complete remission after surgery. CONCLUSIONS: In obese patients with T2D and IFG, commonly characterized by an augmented beta cell function and an increased insulin resistance, sleeve gastrectomy induces remission through reduction of insulin resistance. Preoperative IR and beta cell function calculated by HOMA2 deserve further studies in patients undergoing metabolic surgery.

Type 2 diabetes aggravates Alzheimer's disease-associated vascular alterations of the aorta in mice.

Vascular risk factors are associated with a higher incidence of dementia. In fact, diabetes mellitus is considered a main risk factor for Alzheimer's disease (AD) and both diseases are characterized by vascular dysfunction. However, the underlying mechanisms remain largely unknown. Here, the effects of high-sucrose-induced type 2 diabetes (T2D) in the aorta of wild type (WT) and triple-transgenic AD (3xTg-AD) mice were investigated. 3xTg-AD mice showed a significant decrease in body weight and an increase in postprandial glycemia, glycated hemoglobin (HbA1c), and vascular nitrotyrosine, superoxide anion (O2•-), receptor for the advanced glycation end products (RAGE) protein, and monocyte chemoattractant protein-1 (MCP-1) levels when compared to WT mice. High-sucrose intake caused a significant increase in body weight, postprandial glycemia, HbA1c, triglycerides, plasma vascular cell adhesion molecule 1 (VCAM-1), and vascular nitrotyrosine, O2•-, RAGE, and MCP-1 levels in both WT and 3xTg-AD mice when compared to the respective control group. Also, a significant decrease in nitric oxide-dependent vasorelaxation was observed in 3xTg-AD and sucrose-treated WT mice. In conclusion, AD and T2D promote similar vascular dysfunction of the aorta, this effect being associated with elevated oxidative and nitrosative stress and inflammation. Also, AD-associated vascular alterations are potentiated by T2D. These findings support the idea that metabolic alterations predispose to the onset and progression of dementia.

Atorvastatin-mediated protection of the retina in a model of diabetes with hyperlipidemia.

Insulin resistance, a key feature of obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), results in a variety of metabolic and vascular abnormalities. Metabolic disturbances associated with diabetes could contribute to disrupting the structural and (or) functional integrity of the retina. The effects of atorvastatin on retinal cells in hyperlipidemic T2DM rats have not yet been investigated. We used Goto-Kakizaki (GK) rats fed with an atherogenic diet (AD) for 4 months to investigate whether atorvastatin (administered for 1 month) would slow-down or reverse the progression of lesions in the diabetic retina. Fluorogenic substrates were used to measure the proteasome activities in retinal cells. The production of reactive oxygen species was determined by immunofluorescence in frozen retina sections, using dihydroethydium. Nitrotyrosine levels were assessed using immunohistochemistry. Protein levels of ubiquitin conjugates, free ubiquitin, and ubiquitin activating enzyme E1 were determined with Western blotting. Atorvastatin significantly reduced the levels of oxidative stress that were induced by the AD and restored the proteasome activities in the diabetic GK rats. Atorvastatin therapy significantly improved local oxidative stress levels in GK rats fed with AD. Atorvastatin can, at least in part, restore the ubiquitin proteasome system, and may represent a pharmacological approach to prevent some of the complications associated with diabetic retinopathy.

Effects of methylglyoxal and pyridoxamine in rat brain mitochondria bioenergetics and oxidative status.

Advanced glycation end products (AGEs) and methylglyoxal (MG), an important intermediate in AGEs synthesis, are thought to contribute to protein aging and to the pathogenesis of age-and diabetes-associated complications. This study was intended to investigate brain mitochondria bioenergetics and oxidative status of rats previously exposed to chronic treatment with MG and/or with pyridoxamine (PM), a glycation inhibitor. Brain mitochondrial fractions were obtained and several parameters were analyzed: respiratory chain [states 3 and 4 of respiration, respiratory control ratio (RCR), and ADP/O index] and phosphorylation system [transmembrane potential (ΔΨm), ADP-induced depolarization, repolarization lag phase, and ATP levels]; hydrogen peroxide (H2O2) production levels, mitochondrial aconitase activity, and malondialdehyde levels as well as non-enzymatic antioxidant defenses (vitamin E and glutathione levels) and enzymatic antioxidant defenses (glutathione disulfide reductase (GR), glutathione peroxidase (GPx), and manganese superoxide dismutase (MnSOD) activities). MG treatment induced a statistical significant decrease in RCR, aconitase and GR activities, and an increase in H2O2 production levels. The administration of PM did not counteract MG-induced effects and caused a significant decrease in ΔΨm. In mitochondria from control animals, PM caused an adaptive mechanism characterized by a decrease in aconitase and GR activities as well as an increase in both α-tocopherol levels and GPx and MnSOD activities. Altogether our results show that high levels of MG promote brain mitochondrial impairment and PM is not able to reverse MG-induced effects.

Methylglyoxal promotes oxidative stress and endothelial dysfunction.

Modern diets can cause modern diseases. Research has linked a metabolite of sugar, methylglyoxal (MG), to the development of diabetic complications, but the exact mechanism has not been fully elucidated. The present study was designed to investigate whether MG could directly influence endothelial function, oxidative stress and inflammation in Wistar and Goto-Kakizaki (GK) rats, an animal model of type 2 diabetes. Wistar and GK rats treated with MG in the drinking water for 3 months were compared with the respective control rats. The effects of MG were investigated on NO-dependent vasorelaxation in isolated rat aortic arteries from the different groups. Insulin resistance, NO bioavailability, glycation, a pro-inflammatory biomarker monocyte chemoattractant protein-1 (MCP-1) and vascular oxidative stress were also evaluated. Methylglyoxal treated Wistar rats significantly reduced the efficacy of NO-dependent vasorelaxation (p<0.001). This impairment was accompanied by a three fold increase in the oxidative stress marker nitrotyrosine. Advanced glycation endproducts (AGEs) formation was significantly increased as well as MCP-1 and the expression of the receptor for AGEs (RAGE). NO bioavailability was significantly attenuated and accompanied by an increase in superoxide anion immunofluorescence. Methylglyoxal treated GK rats significantly aggravated endothelial dysfunction, oxidative stress, AGEs accumulation and diminished NO bioavailability when compared with control GK rats. These results indicate that methylglyoxal induced endothelial dysfunction in normal Wistar rats and aggravated the endothelial dysfunction present in GK rats. The mechanism is at least in part by increasing oxidative stress and/or AGEs formation with a concomitant increment of inflammation and a decrement in NO bioavailability. The present study provides further evidence for methylglyoxal as one of the causative factors in the pathogenesis of atherosclerosis and development of macrovascular diabetic complication.

Metformin restores endothelial function in aorta of diabetic rats.

BACKGROUND AND PURPOSE: The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been fully elucidated. This study was designed to assess the effect of metformin on impaired endothelial function, oxidative stress, inflammation and advanced glycation end products formation in type 2 diabetes mellitus. EXPERIMENTAL APPROACH: Goto-Kakizaki (GK) rats, an animal model of nonobese type 2 diabetes, fed with normal and high-fat diet during 4 months were treated with metformin for 4 weeks before evaluation. Systemic oxidative stress, endothelial function, insulin resistance, nitric oxide (NO) bioavailability, glycation and vascular oxidative stress were determined in the aortic rings of the different groups. A pro-inflammatory biomarker the chemokine CCL2 (monocyte chemoattractant protein-1) was also evaluated. KEY RESULTS: High-fat fed GK rats with hyperlipidaemia showed increased vascular and systemic oxidative stress and impaired endothelial-dependent vasodilatation. Metformin treatment significantly improved glycation, oxidative stress, CCL2 levels, NO bioavailability and insulin resistance and normalized endothelial function in aorta. CONCLUSION AND IMPLICATIONS: Metformin restores endothelial function and significantly improves NO bioavailability, glycation and oxidative stress in normal and high-fat fed GK rats. This supports the concept of the central role of metformin as a first-line therapeutic to treat diabetic patients in order to protect against endothelial dysfunction associated with type 2 diabetes mellitus.

Insulin and metformin may prevent renal injury in young type 2 diabetic Goto-Kakizaki rats.

Type 2 diabetes is increasing at epidemic proportions throughout the world, and diabetic nephropathy is the principal cause of end stage renal failure. Approximately 40% of patients with type 2 diabetes may progress to nephropathy and a good metabolic control can prevent the development of diabetic renal injury. The aim of our study was to evaluate, in young type 2 diabetic Goto-Kakizaki (GK) rats fed with atherogenic diet, the effects of the anti-diabetic compounds insulin, metformin and gliclazide on renal damage. GK rats fed with atherogenic diet showed increased body weight and fasting blood glucose, total cholesterol, triglycerides, C-reactive protein and protein carbonyl levels and lower HDL-cholesterol concentration; renal markers of inflammation and fibrosis were also elevated. All the anti-diabetic agents ameliorated fasting glycaemia and insulin resistance but only insulin and metformin were able to improve glycoxidation, fibrosis and inflammation kidney parameters. Our data suggest that insulin and metformin treatments, improving glicoxidative, inflammatory and fibrotic renal damage markers, play a key role in the prevention of diabetic nephropathy.

Supplementation of coenzyme Q10 and alpha-tocopherol lowers glycated hemoglobin level and lipid peroxidation in pancreas of diabetic rats.

The importance of nutritional supplementation in diabetes remains an unresolved issue. The present study was undertaken to examine the effects of alpha-tocopherol and CoQ(10), powerful antioxidants, on metabolic control and on the pancreatic mitochondria of GK rats, a model of type 2 diabetes. We also evaluated the efficacy of these nutrients in preventing the diabetic pancreatic lesions observed in GK rats. Rats were divided into 4 groups, a control group of diabetic GK rats and 3 groups of GK rats administered with alpha-tocopherol and CoQ(10) alone or both in association, during 8 weeks. Fasting blood glucose levels were not significantly different between the groups, nor were blood glucose levels at 2 hours after a glucose load. HbA1c level was significantly reduced in the group supplemented with both antioxidants. Diabetes induced a decrease in coenzyme Q plasma levels that prevailed after treatment with antioxidants. In addition, the plasma alpha-tocopherol levels were higher after treatment with the antioxidants. An increment in some components of the antioxidant defense system was observed in pancreatic mitochondria of treated GK rats. Moreover, the antioxidants tested either alone or in association failed to prevent the pancreatic lesions in this animal model of type 2 diabetes. In conclusion, our results indicate that CoQ(10) and alpha-tocopherol decrease glycated HbA1c and pancreatic lipid peroxidation. These antioxidants increase some components of the antioxidant defense system but do not prevent pancreatic lesions. Thus, we cannot rule out the potential benefit of antioxidant treatments in type 2 diabetes in the prevention of their complications.

The effect of soybean oil on glycaemic control in Goto-kakizaki rats, an animal model of type 2 diabetes.

UNLABELLED: Several studies in humans and laboratory animals with type 2 diabetes indicate that antioxidant supplements lessen the impact of oxidative damage caused by dysregulation of glucose metabolism. The present study was undertaken to examine the effect of soybean oil on glycaemic control and lipid metabolism in Goto-kakizaki (GK) rats, a model of type 2 diabetes. Rats were divided into three groups, a control group of non-diabetic (Wistar) rats, a group of diabetic GK rats and a group of GK rats treated with soybean oil. Plasma samples from the different groups were analysed for total alpha-tocopherol, coenzyme Q and glucose levels. Glycated haemoglobin was also compared between the different groups. Fasting and non-fasting blood glucose levels were significantly decreased in soybean oil group compared with GK group. There was also a 14 % reduction in the levels of HbA(1c) in SO-treated GK when compared with the diabetic control group. Diabetes induced a decrease in coenzyme Q plasma levels that prevailed after treatment with soybean oil. Moreover, the plasma alpha-tocopherol levels were higher after treatment with soybean oil. CONCLUSIONS: Our observations suggest that soybean oil treatment may be beneficial in type 2 diabetes. Since soybean oil has very high amounts of coenzyme Q and other antioxidants one possible mechanism of action could be as an antioxidant.

Endothelial dysfunction in type 2 diabetes: effect of antioxidants.

Individuals with insulin resistance and diabetes mellitus have increased cardiovascular morbidity and mortality, caused in part by vascular complications. Endothelial dysfunction has been implicated in the pathogenesis of vascular diabetic disease. This abnormal function of the vasculature precedes cardiovascular disease and is associated with impaired endothelium-dependent vasorelaxation. The main etiology of the increased mortality and morbidity of type 2 diabetic patients is atherosclerosis. Increased production of free radicals is associated with the pathophysiology of diabetes, resulting in oxidative damage to lipids and proteins. Reduction of oxidative stress in diabetic patients may delay the onset of atherogenesis and the appearance of micro- and macrovascular complications. Alpha-lipoic acid (LA) is a multifunctional antioxidant that has been shown to have beneficial effects on polyneuropathy and on markers of oxidative stress in various tissues. This study was conducted to investigate the effects of LA on endothelial function in diabetic and hyperlipidemic animal models. Carbohydrate and lipid metabolism, endothelial function, plasma malondialdehyde (MDA) and urinary 8-hydroxydeoxyguanosine (8-OHdG) were assessed in non-diabetic controls (Wistar rats), untreated diabetic Goto-Kakizaki (GK) rats and, atherogenic diet (AD)-fed GK rats (fed with atherogenic diet only, treated with alpha-lipoic acid and treated with vehicle, for 3 months). AD resulted in a 3-fold increase in both total and non-HDL serum cholesterol levels and in a 2-fold increase triglyceride levels while endothelial function was significantly reduce MDA and 8-OHdG levels were higher in the GK and GK hyperlipidemic groups and were completely reversed by the antioxidant. Hyperlipidemic GK diabetic rats showed significantly reduced endothelial function that was partially improved with LA. Furthermore, lipoic acid significantly reduced serum cholesterol levels, without lowering HDL cholesterol. Alpha-lipoic acid supplementation represents an achievable adjunct therapy to improve endothelial function and reduce oxidative stress, factors that are implicated in the pathogenesis of atherosclerosis in diabetes.