Type 2 diabetes mellitus (T2DM) is the most prevalent metabolic disorder characterized by chronic hyperglycemia and an inadequate response to circulatory insulin by peripheral tissues resulting in insulin resistance. Insulin resistance has a complex pathophysiology, and it is contributed to by multiple factors including oxidative stress. Oxidative stress refers to an imbalance between free radical production and the antioxidant system leading to a reduction of peripheral insulin sensitivity and contributing to the development of T2DM via several molecular mechanisms. In this review, we present the molecular mechanisms by which the oxidative milieu contributes to the pathophysiology of insulin resistance and diabetes mellitus.

/pdf/molecular-mechanisms-linking-oxidative-stress-and-diabetes-1qs6il75yu.pdf

Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus.

Cancer is driven by incremental changes that accumulate, eventually leading to oncogenic transformation. Although genetic alterations dominate the way cancer biologists think about oncogenesis, growing evidence suggests that systemic factors (for example, insulin, oestrogen and inflammatory cytokines) and their intracellular pathways activate oncogenic signals and contribute to targetable phenotypes. Systemic factors can have a critical role in both tumour initiation and therapeutic responses as increasingly targeted and personalized therapeutic regimens are used to treat patients with cancer. The endocrine system controls cell growth and metabolism by providing extracellular cues that integrate systemic nutrient status with cellular activities such as proliferation and survival via the production of metabolites and hormones such as insulin. When insulin binds to its receptor, it initiates a sequence of phosphorylation events that lead to activation of the catalytic activity of phosphoinositide 3-kinase (PI3K), a lipid kinase that coordinates the intake and utilization of glucose, and mTOR, a kinase downstream of PI3K that stimulates transcription and translation. When chronically activated, the PI3K pathway can drive malignant transformation. Here, we discuss the insulin-PI3K signalling cascade and emphasize its roles in normal cells (including coordinating cell metabolism and growth), highlighting the features of this network that make it ideal for co-option by cancer cells. Furthermore, we discuss how this signalling network can affect therapeutic responses and how novel metabolic-based strategies might enhance treatment efficacy for cancer.

Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer.

The prevalence of diabetes is growing worldwide with an increasing morbidity and mortality associated with the development of diabetes complications. Free radical production is a normal biological process that is strictly controlled and has been shown to be important in normal cellular homeostasis, and in the bodies response to pathogens. However, there are several mechanisms leading to excessive free radical production that overcome the normal protective quenching mechanisms. Studies have shown that many of the diabetes complications result from excessive free radical generation and oxidative stress, and it has been shown that chronic hyperglycemia is a potent inducer for free radical production, generated through several pathways and triggering multiple molecular mechanisms. An understanding of these processes may help us to improving our preventive or therapeutic strategies. In this review, the major molecular pathways involved in free radical generation induced by hyperglycemia are described.

A review of the molecular mechanisms of hyperglycemia-induced free radical generation leading to oxidative stress.

Diabetes mellitus is a metabolic disorder that majorly affects the endocrine gland, and it is symbolized by hyperglycemia and glucose intolerance owing to deficient insulin secretory responses and beta cell dysfunction. This ailment affects as many as 451 million people worldwide, and it is also one of the leading causes of death. In spite of the immense advances made in the development of orthodox antidiabetic drugs, these drugs are often considered not successful for the management and treatment of T2DM due to the myriad side effects associated with them. Thus, the exploration of medicinal herbs and natural products as therapeutic sources for the treatment of T2DM is promoted because they have little or no side effects. Bioactive molecules isolated from natural sources have been proven to lower blood glucose levels via regulating one or more of the following mechanisms: improvement of beta cell function, insulin resistance, glucose (re)absorption, and glucagon-like peptide-1 homeostasis. In recent times, the mechanisms of action of different bioactive molecules with antidiabetic properties and phytochemistry are gaining a lot of attention in the area of drug discovery. This review article presents an update of the findings from clinical research into medicinal plant therapy for T2DM.

/pdf/antioxidant-effects-and-mechanisms-of-medicinal-plants-and-a6dtnuosd3.pdf

Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review.

The aging process is known to be associated with heightened oxidative stress and related systemic inflammation. Therefore, antioxidant supplementation is regarded as a promising strategy to combat aging and associated pathological conditions. Food-grade antioxidants from plant-derived extracts are the most common ingredients of these supplements. Phyto-bioactive compounds such as curcumin, resveratrol, catechins, quercetin are among the most commonly applied natural compounds used as potential modulators of the free radical-induced cellular damages. The therapeutic potential of these compounds is, however, restricted by their low bioavailability related to poor solubility, stability, and absorbance in gastrointestinal tract. Recently, novel nanotechnology-based systems were developed for therapeutic delivery of natural antioxidants with improved bioavailability and, consequently, efficacy in clinical practice. Such systems have provided many benefits in preclinical research over the conventional preparations, including superior solubility and stability, extended half-life, improved epithelium permeability and bioavailability, enhanced tissue targeting, and minimized side effects. The present review summarizes recent developments in nanodelivery of natural antioxidants and its application to combat pathological conditions associated with oxidative stress.

/pdf/nanodelivery-of-natural-antioxidants-an-anti-aging-mna9v30zxt.pdf

Nanodelivery of Natural Antioxidants: An Anti-aging Perspective.

Most human cells utilize glucose as the primary substrate, cellular uptake requiring insulin. Insulin signaling is therefore critical for these tissues. However, decrease in insulin sensitivity due to the disruption of various molecular pathways causes insulin resistance (IR). IR underpins many metabolic disorders such as type 2 diabetes and metabolic syndrome, impairments in insulin signaling disrupting entry of glucose into the adipocytes, and skeletal muscle cells. Although the exact underlying cause of IR has not been fully elucidated, a number of major mechanisms, including oxidative stress, inflammation, insulin receptor mutations, endoplasmic reticulum stress, and mitochondrial dysfunction have been suggested. In this review, we consider the role these cellular mechanisms play in the development of IR.

Insulin resistance: Review of the underlying molecular mechanisms

It has been reported that oxidative stress has a pivotal role in many disorders such as chronic kidney diseases. Free radicals can directly attack cellular elements, trigger intracellular signaling pathways, or induce systemic responses leading to renal damages. In the current review, we evaluated the literature focusing on the main recognized effects of oxidative stress on the pathophysiology of chronic renal disorders. We searched the PubMed-Medline and Scopus databases by using the following key words: oxidative stress, kidney, chronic kidney diseases, and free radicals and found about 200 related articles. Then, we focused on the molecular mechanisms underlying chronic kidney diseases which can be induced by oxidative stress and explored how free radicals stimulate these mechanisms. By reviewing the literature, we found that there are almost nine important molecular pathways through which free radicals influence the renal function. Based on the retrieved data, oxidative stress has an important role in the pathophysiology of chronic kidney diseases. Understanding these pathophysiologic pathways may lead us to find new approaches for the management of these debilitating disorders.

Oxidative stress induces renal failure: A review of possible molecular pathways.

BACKGROUND Acute Kidney Injury (AKI) is an unsolved clinical problem in critical care patients with a high mortality rate, increasing incidence, and no definitive therapy. We studied the incidence, risk factors, and mortality associated with AKI in ICU patients. MATERIALS AND METHODS In a prospective study, patient demographics, reason for hospitalization, reason for ICU admission, Length of ICU stay, laboratory data, and Vital signs were recorded in prepared forms during the ICU stay. AKI was defined as an increase in serum creatinine (SCr) of ≥ 0.3mg/dl from the baseline. RESULTS A total of 200 patients who were enrolled in our study; 134 (67%) did not develop AKI during their ICU stay while 66 (33%) developed AKI (SCr ≥ 0.3) according to the AKIN definition. Patients with AKI had higher APACHE II scores (12.3±5.6 vs. 6.9±3.6; P< 0.001), longer ICU stays (7.6±7.6 vs. 3.7±2.8 days respectively; P< 0.001), and higher mortality (19.7% vs. 0.7%; P< 0.001). CONCLUSION The AKIN criteria are clinically valid and can be a good predictor of mortality and patient outcome in addition to APACHE II score in ICU patients.

Outcome of Acute Kidney Injury in Critical Care Unit, Based on AKI Network.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a class of newly introduced antidiabetic medications that potentially lower blood glucose by several molecular pathways. DPP-4 inhibitors are the other type of novel antidiabetic medications which act by preventing GLP-1 inactivation and thereby increasing the activity levels of GLP-1, leading to more glucose-induced insulin release from islet β-cells and suppression of glucagon release. Most patients with diabetes have concurrent hypertension and cardiovascular disorder. If antihyperglycemic agents can attenuate the risk of hypertension and cardiovascular disease, they will amplify their overall beneficial effects. There is conflicting evidence on the cardiovascular benefits of GLP-1R induction in laboratory studies and clinical trials. In this study, we have reviewed the main molecular mechanisms by which GLP-1R induction may modulate the cardiovascular function and the results of cardiovascular outcome clinical trials.

/pdf/the-effects-of-glucagon-like-peptide-1-receptor-agonists-and-13hiatd2r3.pdf

The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes.

Farin Rashid Farrokhi

Papers

Insulin resistance: Review of the underlying molecular mechanisms

Oxidative stress induces renal failure: A review of possible molecular pathways.

Outcome of Acute Kidney Injury in Critical Care Unit, Based on AKI Network.

The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes.