The molecular link between oxidative stress, insulin resistance, and type 2 diabetes: A target for new therapies against cardiovascular diseases

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAMs) means that the ROS generated in mitochondria promote ER stress. Therefore, a state of stress and mitochondrial dysfunction are consequences of this vicious cycle. The implication of mitochondria in insulin release and the exposure of pancreatic β-cells to hyperglycemia make them especially susceptible to oxidative stress and mitochondrial dysfunction. In fact, crosstalk between both mechanisms is related with alterations in glucose homeostasis and can lead to the diabetes-associated insulin-resistance status. In the present review, we discuss the current knowledge of the relationship between oxidative stress, mitochondria, ER stress, inflammation, and lipotoxicity in T2D.

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Probiotics, prebiotics, synbiotics and insulin sensitivity

Nutrition Research Reviews ◽

10.1017/s095442241700018x ◽

2017 ◽

Vol 31 (1) ◽

pp. 35-51 ◽

Cited By ~ 51

Author(s):

Y. A. Kim ◽

J. B. Keogh ◽

P. M. Clifton

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Intestinal Permeability ◽

Peptide Yy ◽

Glucagon Secretion ◽

Energy Harvest ◽

Improve Insulin Sensitivity

AbstractAnimal studies indicate that the composition of gut microbiota may be involved in the progression of insulin resistance to type 2 diabetes. Probiotics and/or prebiotics could be a promising approach to improve insulin sensitivity by favourably modifying the composition of the gut microbial community, reducing intestinal endotoxin concentrations and decreasing energy harvest. The aim of the present review was to investigate the effects of probiotics, prebiotics and synbiotics (a combination of probiotics and prebiotics) on insulin resistance in human clinical trials and to discuss the potential mechanisms whereby probiotics and prebiotics improve glucose metabolism. The anti-diabetic effects of probiotics include reducing pro-inflammatory cytokines via a NF-κB pathway, reduced intestinal permeability, and lowered oxidative stress. SCFA play a key role in glucose homeostasis through multiple potential mechanisms of action. Activation of G-protein-coupled receptors on L-cells by SCFA promotes the release of glucagon-like peptide-1 and peptide YY resulting in increased insulin and decreased glucagon secretion, and suppressed appetite. SCFA can decrease intestinal permeability and decrease circulating endotoxins, lowering inflammation and oxidative stress. SCFA may also have anti-lipolytic activities in adipocytes and improve insulin sensitivity via GLUT4 through the up-regulation of 5'-AMP-activated protein kinase signalling in muscle and liver tissues. Resistant starch and synbiotics appear to have favourable anti-diabetic effects. However, there are few human interventions. Further well-designed human clinical studies are required to develop recommendations for the prevention of type 2 diabetes with pro- and prebiotics.

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Beneficial Effects of Poplar Buds on Hyperglycemia, Dyslipidemia, Oxidative Stress, and Inflammation in Streptozotocin-Induced Type-2 Diabetes

Journal of Immunology Research ◽

10.1155/2018/7245956 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Shiqin Peng ◽

Ping Wei ◽

Qun Lu ◽

Rui Liu ◽

Yue Ding ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Blood Glucose ◽

Crude Extract ◽

Liver Homogenate ◽

Control Group ◽

Diabetic Mice ◽

Model Control

The effects of propolis on blood glucose regulation and the alleviation of various complications caused by diabetes have been widely studied. The main source of propolis in the northern temperate zone is poplar buds. However, there is limited research on the antidiabetic activity of poplar buds. In order to evaluate the effect of poplar buds on type-2 diabetes, crude extract and 50% fraction of poplar buds were used to feed streptozotocin-induced type-2 diabetic mice. The results showed that 50% fraction could increase insulin sensitivity and reduce insulin resistance, as well as decrease the levels of fasting blood glucose, glycated hemoglobin, and glycosylated serum proteins in diabetic mice. Compared with the model control group, the 50% fraction-treated group showed significant decreases of malondialdehyde (MDA) and increases of superoxide dismutase (SOD) in serum and liver homogenate. Moreover, 50% fraction could significantly decrease total cholesterol (TC), alleviate abnormal lipid metabolism, and enhance antioxidant capacity in the serum. For inflammatory factors, feeding of 50% fraction could also reduce the levels of interleukin 6 (IL-6), tumor necrosis factorα(TNF-α), monocyte chemotactic protein 1 (MCP-1), and cyclooxygenase-2 (COX-2) in liver homogenate. Taken together, our results suggest that crude extract and 50% fraction of poplar buds, particularly the latter, can decrease blood glucose levels and insulin resistance, and 50% fraction can significantly relieve dyslipidemia, oxidative stress, and inflammation caused by type-2 diabetes.

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Effects of Pterostilbene on Diabetes, Liver Steatosis and Serum Lipids

Current Medicinal Chemistry ◽

10.2174/0929867326666191029112626 ◽

2020 ◽

Vol 28 (2) ◽

pp. 238-252 ◽

Cited By ~ 6

Author(s):

Saioa Gómez-Zorita ◽

Iñaki Milton-Laskíbar ◽

Leixuri Aguirre ◽

Alfredo Fernández-Quintela ◽

Jianbo Xiao ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 1 Diabetes ◽

Animal Models ◽

Phenolic Compound ◽

Liver Steatosis ◽

Positive Effects

: Pterostilbene, a phenolic compound derived from resveratrol, possesses greater bioavailability than its parent compound due to the presence of two methoxyl groups. In this review, the beneficial effects of pterostilbene on diabetes, liver steatosis and dyslipidemia are summarized. Pterostilbene is a useful bioactive compound in preventing type 1 diabetes, insulin resistance and type 2 diabetes in animal models. Concerning type 1 diabetes, the main mechanisms described to justify the positive effects of this phenolic compound are increased liver glycogen content and hepatic glucokinase and phosphofructokinase activities, the recovery of pancreatic islet architecture, cytoprotection and a decrease in serum and pancreatic pro-inflammatory cytokines. As for type 2 diabetes, increased liver glucokinase and glucose-6-phosphatase and decreased fructose-1,6-biphosphatase activities are reported. When insulin resistance is induced by diets, a greater activation of insulin signaling cascade has been reported, increased cardiotrophin-1 levels and liver glucokinase and glucose- 6-phosphatase activities, and a decreased fructose-1,6-biphosphatase activity. Data concerning pterostilbene and liver steatosis are scarce so far, but the reduction in oxidative stress induced by pterostilbene may be involved since oxidative stress is related to the progression of steatosis to steatohepatitis. Finally, pterostilbene effectively reduces total cholesterol, LDL-cholesterol and serum triglyceride levels, while increases HDL-cholesterol in animal models of dyslipidemia.

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Abstract 18673: JNK Inhibition Restores Endothelial Function in Type 2 Diabetes Mellitus

Circulation ◽

10.1161/circ.132.suppl_3.18673 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Rosa Breton-Romero ◽

Bihua Feng ◽

Monika Holbrook ◽

Melissa G Farb ◽

Jessica L Fetterman ◽

...

Keyword(s):

Nitric Oxide ◽

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Endothelial Cells ◽

Cardiovascular Diseases ◽

Endothelial Dysfunction ◽

Diabetic Patients ◽

Jnk Activation

Introduction: Diabetes mellitus type 2 is an increasingly public health problem and it is a major cause in the development of cardiovascular diseases. Endothelial dysfunction is a key mechanism that contributes to the pathogenesis of cardiovascular diseases and is a well-known feature of clinical diabetes. Prior studies have demonstrated an impaired nitric oxide bioavailability and a reduced endothelium-dependent vasodilation under diabetic conditions and in animal models, JNK activity has been widely described to be involved in systemic insulin resistance. Hypothesis: Our study aimed to evaluate the involvement of JNK in endothelial dysfunction, studying its potential role in altered eNOS activation and NO synthesis in diabetic patients. Methods: We measured endothelial function and JNK activity in freshly isolated endothelial cells from diabetic patients (n=38) and nondiabetic controls (n=40). Results: ECs from diabetic patients displayed impaired eNOS activation and reduced NO release after insulin and A23187 stimulation, consistent with the presence of endothelial dysfunction. JNK activation was higher in diabetic (**P=0.003), and was associated with lower flow-mediated dilation (r=-0.53, *P=0.02). In endothelial cells from diabetic patients, treatment with JNK chemical inhibitor (SP600125) restored eNOS activation and insulin response (***P<0.001). Nitric oxide bioactivity after A23187 stimuli with diabetes was also recovered in endothelial cells from patients with diabetes. Conclusions: In summary, our data suggest that JNK activation contributes to vascular insulin resistance and endothelial dysfunction in patients with type 2 diabetes and may represent a target in novel therapeutic opportunities.

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