Endothelial Dysfunction in Type 2 Diabetes: Targeting Inflammation

Several experimental and clinical studies have indicated a prominent role of vascular inflammation in the development of endothelial dysfunction. In endothelial dysfunction, the endothelium loses its physiological features, decrements nitric oxide bioavailability, and shifts towards a vasoconstrictor, pro-thrombotic and pro-inflammatory state. Within arterial wall, the interplay between the pro-inflammatory and pro-oxidant milieus promotes vascular dysfunction, and perivascular adipose tissue seems to play an important role. Inflammation is now considered a key event in vascular dysfunction and the development of vascular disease associated with obesity and type 2 diabetes. This concept is supported by the fact that anti-inflammatory adipokines such as adiponectin protect endothelial function, and interventions resulting in reduced inflammation such as the administration of salicylates prevent vascular dysfunction and cardiovascular events. Thus, the aim of this review is to address the role of inflammation and its mechanisms in endothelial dysfunction associated with diabetes, describing the impact of these conditions on vascular function

Enhanced mitochondrial testicular antioxidant capacity in Goto-Kakizaki diabetic rats: role of coenzyme Q

Because diabetes mellitus is associated with impairment of testicular function, ultimately leading to reduced fertility, this study was conducted to evaluate the existence of a cause-effect relationship between increased oxidative stress in diabetes and reduced mitochondrial antioxidant capacity. The susceptibility to oxidative stress and antioxidant capacity (in terms of glutathione, coenzyme Q, and vitamin E content) of testis mitochondrial preparations isolated from Goto-Kakizaki (GK) non-insulin-dependent diabetic rats and from Wistar control rats, 1 yr of age, was evaluated. It was found that GK mitochondrial preparations showed a lower susceptibility to lipid peroxidation induced by ADP/Fe(2+), as evaluated by oxygen consumption and reactive oxygen species generation. The decreased susceptibility to oxidative stress in diabetic rats was associated with an increase in mitochondrial glutathione and coenzyme Q9 contents, whereas vitamin E was not changed. These results demonstrate a higher antioxidant capacity in diabetic GK rats. We suggest this is an adaptive response of testis mitochondria to the increased oxidative damage in diabetes mellitu

Calcium-dependent mitochondrial permeability transition is augmented in the kidney of Goto-Kakizaki diabetic rat

Renal disease associated with diabetes mellitus is a major problem among diabetic patients. The role of mitochondria in the pathogenesis of diabetes has received a large amount of attention in the last years, but many aspects of this subject are still poorly understood. In the present study, we studied the susceptibility of the mitochondrial permeability transition (MPT) on kidney mitochondria from the Goto-Kakizaki (GK) rat, an animal model featuring physiological and pathological alterations characteristic of type 2 diabetes.Kidney mitochondria were isolated by differential centrifugations; mitochondrial electric transmembrane potential and calcium loading capacity were evaluated with a TPP+-selective electrode and with a calcium-sensitive fluorescent probe. Coenzyme Q9, Q10 and vitamin E were evaluated by high-performance liquid chromatography (HPLC).Kidney mitochondria from the diabetic animals had an increased susceptibility to the induction of the MPT by calcium. We observed a loss of calcium-loading capacity and a higher calcium-induced mitochondrial depolarization. Vitamin E and coenzyme Q9 were also increased in kidney mitochondria from GK rats.The results show an enhanced MPT activation in kidney mitochondria from GK rats, which lead us to suggest that this condition may be one major alteration triggered by chronic diabetes in kidney cells, ultimately leading to cell dysfunction. Copyright © 2004 John Wiley & Sons, Ltd

Brain and liver mitochondria isolated from diabeticGoto-Kakizaki rats show different susceptibility to induced oxidative stress

Increased oxidative stress and changes in antioxidant capacity observed in both clinical and experimental diabetes mellitus have been implicated in the etiology of chronic diabetic complications. Many authors have shown that hyperglycemia leads to an increase in lipid peroxidation in diabetic patients and animals reflecting a rise in reactive oxygen species production. The aim of the study was to compare the susceptibility of mitochondria from brain and liver of Goto-Kakizaki (12-month-old diabetic) rats (GK rats), a model of non-insulin dependent diabetes mellitus, to oxidative stress and antioxidant defenses.Brain and liver mitochondrial preparations were obtained by differential centrifugation. Oxidative damage injury was induced in vitro by the oxidant pair ADP/Fe2+ and the extent of membrane oxidation was assessed by oxygen consumption, malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS) formation. Coenzyme Q and alpha-tocopherol contents were measured by high-performance liquid chromatography (HPLC).Brain mitochondria isolated from 12-month-old control rats displayed a higher susceptibility to lipid peroxidation, as assessed by oxygen consumption and formation of MDA and TBARS, compared to liver mitochondria. In GK rats, mitochondria isolated from brain were more susceptible to invitro oxidative damage than brain mitochondria from normal rats. In contrast, liver mitochondria from diabetic rats were less susceptible to oxidative damage than mitochondria from normal rats. This decreased susceptibility was inversely related to their alpha-tocopherol and coenzyme Q (CoQ) content.The present results indicate that the diabetic state can result in an elevation of both alpha-tocopherol and CoQ content in liver, which may be involved in the elimination of mitochondrially generated reactive oxygen species. The difference in the antioxidant defense mechanisms in the brain and liver mitochondrial preparations of moderately hyperglycemic diabetic GK rats may correspond to a different adaptive response of the cells to the increased oxidative damage in diabetes. Copyright © 2001 John Wiley & Sons, Ltd

Vascular Oxidative Stress: Impact and Therapeutic Approaches

Oxidative stress has been defined as an imbalance between oxidants and antioxidants and more recently as a disruption of redox signaling and control. It is generally accepted that oxidative stress can lead to cell and tissue injury having a fundamental role in vascular dysfunction. Physiologically, reactive oxygen species (ROS) control vascular function by modulating various redox-sensitive signaling pathways. In vascular disorders, oxidative stress instigates endothelial dysfunction and inflammation, affecting several cells in the vascular wall. Vascular ROS are derived from multiple sources herein discussed, which are prime targets for therapeutic development. This review focuses on oxidative stress in vascular physiopathology and highlights different strategies to inhibit ROS production

Circulating Dopamine Is Regulated by Dietary Glucose and Controls Glucagon-like 1 Peptide Action in White Adipose Tissue

Funding: This work was supported by a grant from GIFT (Grupo de Investigação Fundamental e Translational) from the Portugal Society of Diabetes and Portugal Foundation for Science and Technology (PEst UID/NEU/04539/2013 and UID/NEU/04539/2019: CNC.IBILI; PEst UIDB/04539/2020 and UIDP/04539/2020: CIBB). G.T. and D.R.S. were supported by Ph.D. Grants from the Portuguese Foundation for Science and Technology (PD/BD/127822/2016 and 2021.08160.BD respectively). J.F.S. is supported by a contract from the Portuguese Foundation for Science and Technology (CEEC IND/02428/2018).Dopamine directly acts in the liver and white adipose tissue (WAT) to regulate insulin signaling, glucose uptake, and catabolic activity. Given that dopamine is secreted by the gut and regulates insulin secretion in the pancreas, we aimed to determine its regulation by nutritional cues and its role in regulating glucagon-like peptide 1 (GLP-1) action in WAT. Solutions with different nutrients were administered to Wistar rats and postprandial dopamine levels showed elevations following a mixed meal and glucose intake. In high-fat diet-fed diabetic Goto-Kakizaki rats, sleeve gastrectomy upregulated dopaminergic machinery, showing the role of the gut in dopamine signaling in WAT. Bromocriptine treatment in the same model increased GLP-1R in WAT, showing the role of dopamine in regulating GLP-1R. By contrast, treatment with the GLP-1 receptor agonist Liraglutide had no impact on dopamine receptors. GLP-1 and dopamine crosstalk was shown in rat WAT explants, since dopamine upregulated GLP-1-induced AMPK activity in mesenteric WAT in the presence of the D2R and D3R inhibitor Domperidone. In human WAT, dopamine receptor 1 (D1DR) and GLP-1R expression were correlated. Our results point out a dietary and gut regulation of plasma dopamine, acting in the WAT to regulate GLP-1 action. Together with the known dopamine action in the pancreas, such results may identify new therapeutic opportunities to improve metabolic control in metabolic disorders.publishersversionpublishe

Impaired Insulin Secretion In Isolated Islets Of Goto-Kakizaki Rats, An Animal Model Of Non Obese Type 2 Diabetes, Is A Primary Event

A deficiente secreção de insulina é factor determinante da diabetes tipo 2. Para avaliar a evolução da resposta secretora, foi feito um estudo cronológico comparativo entre ratos Wistar normais (W) e ratos Goto-Kakizaki (GK), um modelo genético de diabetes tipo 2 não obesa, da dinâmica da secreção de insulina de ilhéus de Langerhans isolados em resposta à glicose e à arginina, por técnicas de isolamento e de perfusão de ilhéus e técnica de ELISA competitiva. Foi igualmente avaliada a glicémia e a insulinémia em jejum, e a tolerância à glicose. Observámos, nos ratos W, uma moderada intolerância à glicose nas duas primeiras semanas de vida. Os ratos GK foram sempre intolerantes à glicose e com hiperglicémia e hiperinsulinémia em jejum, após o primeiro mês. Os ilhéus de ratos W foram insensíveis à glicose (11mM glicose) nas duas primeiras semanas de vida mas exibiram depois uma resposta com características bifásicas bem definidas. Os ilhéus de ratos GK foram sempre irresponsivos à glicose e não adquiriram as características bifásicas da resposta normal. A arginina induziu um aumento da secreção de insulina em qualquer idade e em ambos os modelos animais; mas a resposta dos animais diabéticos foi sempre quantitativamente inferior. Em conclusão:1) nos ratos normais, a secreção bifásica, em resposta à glicose, surge somente após a segunda semana de vida, em simultâneo com a estabilização do perfil glicémico; 2) nos ratos diabéticos, a falência insular caracteriza-se pelo compromisso da primeira e da segunda fases da resposta à glicose e pela menor amplitude da resposta à arginina; acompanha o estado de intolerância marcada à glicose e precede a hiperglicémia e a hiperinsulinémia em jejum, constituindo um dos factores patogénicos primários da síndrome diabética

Endothelial dysfunction – a major mediator of diabetic vascular disease

The vascular endothelium is a multifunctional organ and is critically involved in modulating vascular tone and structure. Endothelial cells produce a wide range of factors that also regulate cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. Thus, endothelial function is important for the homeostasis of the body and its dysfunction is associated with several pathophysiological conditions, including atherosclerosis, hypertension and diabetes. Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation. Therefore, understanding and treating endothelial dysfunction is a major focus in the prevention of vascular complications associated with all forms of diabetes mellitus. The mechanisms of endothelial dysfunction in diabetes may point to new management strategies for the prevention of cardiovascular disease in diabetes. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting. Mechanisms including altered glucose metabolism, impaired insulin signaling, low-grade inflammatory state, and increased reactive oxygen species generation will be discussed. The importance of developing new pharmacological approaches that upregulate endothelium-derived nitric oxide synthesis and target key vascular ROS-producing enzymes will be highlighted and new strategies that might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated vascular complications