The incidence of global obesity and Type 2 diabetes has increased and is predicted to rise to 30% of the global population. Diet and lifestyle factors are incapable to resolve the increased incidence for obesity and diabetes in various populations of the world. Developing countries have come to the forefront because of the higher diabetic epidemic. The urbanization may possibly provide an explanation for the global diabetic epidemic. In Western countries the metabolic syndrome and non alcoholic fatty liver disease (NAFLD) have reached 30 % of the population and now at present NAFLD afflicts 20% of developing populations. Western diets and sedentary lifestyles cause metabolic disorders in developing countries which may increase neurodegenerative diseases by the disrupted metabolism of xenobiotics in urban populations. In developing countries access to high calorie diets in urban areas down regulate
liver nuclear receptors that are responsible for glucose, lipid and toxicological sensing and interrupt the metabolism of xenobiotics that become toxic to various tissues such as the pancreas, heart, kidney, brain and liver. Xenobiotics in urban areas induce epigenetic changes that involve chromatin remodelling by alterations in transcriptional regulators with modification of histones. Dysfunction of nuclear receptors such as the calorie sensitive sirtuin 1 (Sirt 1) gene involves abnormal nutrient metabolism with insulin resistance, NAFLD, energy balance and circadian rhythm disorders. In obesity and diabetes insulin resistance has been connected to poor xenobiotic metabolism
with the toxic affects of increased xenobiotic transport to the brain associated with neurodegeneration. Dietary interventions to increase xenobiotic metabolism are likely to reduce oxidative stress and neuroendocrine disease in developing countries. Prevention programs are an important goal of international health organizations and in developing countries the plans to adapt a healthy diet, active lifestyle and reduced exposure to xenobiotics are important to manage the global epidemic for obesity and diabetes.

Today obesity is known as a causal or a strong risk factor for type 2 diabetes mellitus (T2D) and many of common cancers; however, is really obesity an independent risk factor for diabetes mellitus and cancer? Studying the etiology of obesity, T2D and many types of cancers, we can see important common players.
Genetic and epigenetic similarities between the diseases, role of microbiota in their development and progression, effect of life style related factors such as physical activity, diet and etc., are some of these players. Based on these evidences and also with recent identification of metabolically healthy obese individuals, the obese individuals whose mortality and morbidity rate is the same as non-obese people, we can conclude that obesity is not an independent risk factor for diabetes or cancer per se, and it is probably results from the same risk factors as these diseases. In this review we will explain the similarities between pathophysiology of obesity, cancer and diabetes and also coexisting conditions with obesity which may relate to cancer and T2D.

Obesity is a risk factor for postmenopausal breast cancer development. We have shown that obesity increases DMBA-induced mammary tumor development in intact and ovariectomized Zucker rats. Several data suggest that DMBA requires metabolic activation to exert its carcinogenic effects. The objective of this study was to investigate the effect of obesity on hepatic expression of cytochrome P450 CYP1A1 and CYP1B1 following DMBA treatment in obese and lean ovariectomized Zucker rats. Forty day-old, ovariectomized obese (n=20) and lean (n=20) Zucker rats were placed on AIN-93 G diet and 10 days later were orally gavaged with either with sesame oil (control) or with 65 mg/kg DMBA in sesame oil. All rats were sacrificed 24 hours post-DMBA treatment. Liver microsomes were prepared, and CYP1A1 and CYP1B1 expression was measured by Western blotting using goat anti-mouse CYP1A1 and CYP1B1 antibodies. DMBA treatment significantly (p<0.001) increased expression of CYP1A1 in lean and obese ovariectomized rats compared to the control group. CYP1B1 expression was not affected by obesity or DMBA. These data suggest that DMBA can increase the expression of enzymes that are responsible for DMBA metabolism in the ovariectomized Zucker rat model.

Diabetes mellitus is one of the most common chronic diseases in the whole world. It is a complex, multi-factorial disease which affects the quality, quantity, and style of an individual’s life. The Micromelum minutum (Family Rutaceae) is a small shrub growing widely in Southeast Asia and the Pacific Islands. In the present study the evaluation of the anti-hyperglycemic, anti-hyperlipidemic and anti-apoptotic activities of Micromelum minutum seeds ethanolic extract in diabetic rats was done. After 30 days of administration the dose (100 mg/kg body weight (bwt) of ethanolic extract of the Micromelum minutum seeds and 25 mg/kg bwt Microminutinin coumarin there was a significant decrease in serum glucose levels; while following two months of administration of the same doses of the seeds extract and coumarin induced a significant decrease in the cholesterol, triglycerides and low density lipoprotein (LDL) levels and increase in the high density lipoprotein (HDL) level. The treatment with Micromelum minutum seeds extract and its coumarin ingredient to diabetic rats increased p53 expression while decreased bcl-2 expression. Histopathological investigation revealed that Micromelum minutum seeds ethanolic extract (100 mg/kg) and Microminutinin coumarin (25 mg/kg bwt) treatment also increased the number of pancreas β-cells as compared to that of diabetic animals. In conclusion, Micromelum minutum seeds ethanolic extract had anti-hyperglycemic, anti-hyperlipidemic and anti-apoptotic activities and all these activities are related to Microminutinin coumarin ingredient of the plant seeds.

Obesity, an epidemic problem in the world is associated with several health problems. An understanding of mechanisms/factors that predispose, delay or protect individuals from obesity and its associated metabolic disturbances and cognitive impairment would be invaluable. The human gut harbors a diverse population of microbial organisms which are symbiotic and important for well being. However, studies on conventional and germ-free animals have shown that alteration in normal commensal gut microbiota and an increase in pathogenic microbiome (termed “dysbiosis”) contribute to gut inflammation, generation of LPS and pro-inflammatory cytokines, gut leakage, and systemic- and neuro-inflammation. The immune mechanisms that are necessary for gut homeostasis may become dysfunctional and lead to bowel inflammation and gut-brain axis dysfunction. These factors are potentially involved in inducing obesity as well. It may be wise to consider the wider hypothesis that gut’s dysbiosis, commencing as a response to fatty food, modulates neuro-inflammation and cognitive dysfunction. This may be enhanced by concomitant noxious factors such as consumption of NSAIDS and alcohol in the elderly. The neurotoxic mechanisms when chronic may enhance vulnerability to dementia of Alzheimer’s type (AD), and perhaps contribute to other dementias as well. Therapeutic strategies for amelioration of cognitive decline and AD are desperately needed. It is pragmatic then that immunologically mediated gut dyshomeostasis is abrogated by available options including Prebiotics, Probiotics, and Synbiotics. Decreasing gut’s dysbiosis may thus attenuate neuroinflammation and provide a potential treatment for obesity-related cognitive impairment. Further, the 'gut-brain axis' or 'brain-gut axis' (depending on whether one considers bottom-up or top-down pathway) is a bi-directional communication system, comprised of neural pathways encompassing enteric nervous system and the vagus. Vagus nerve stimulation in conjunction with α7 nAChR agonists may be an important therapeutic modality in gut pathology to upregulate parasympathetic/vagal efferent function, ameliorate gut-brain axis dysfunction and neuroinflammation, and decrease vulnerability to AD.

Obesity is a known cardiovascular risk factor and it increases the risk of cardiac arrhythmias and sudden cardiac death. The most commonly reported arrhythmias are atrial fibrillation and ventricular tachycardia. The present review focuses on the mechanisms linking overweight and obesity with cardiac arrhythmias and provides a brief review of the latest studies in this area. Obesity is one of the very few identified modifiable risk factors for the occurrence and progression of atrial fibrillation, and the mechanisms linking atrial fibrillation and obesity include: structural and electrophysiological atrial remodeling, metabolic factors, sympatho-vagal imbalance, clinical links (obstructive sleep apnea, cardiovascular comorbidities) and inflammation. The main mechanisms leading to ventricular arrhythmia and sudden cardiac death in obese individuals include cardiomyopathy, metabolic factors, sympathetic hyperinnervation, obesity-induced electrophysiological remodeling, coronary heart disease as common comorbidity and radical weight reduction strategies. Electrocardiographic monitoring, including P wave and QT interval duration, are extremely important in obese patients. Weight control may be an effective strategy for reducing the burden of cardiac arrhythmias and sudden cardiac death.

Type 2 diabetes (T2DM) is characterized by insulin resistance and beta cell dysfunction. Although both factors are hallmarks of T2DM, evidence from recent studies has emerged showing that impaired beta cell function is always present in humans with T2DM, suggesting that beta cell dysfunction is a core factor in the pathogenesis of T2DM. Deficit of beta cell mass in humans with T2DM has also been reported, probably through an increase in beta cell apoptosis. Whether deficit of function or mass of beta cells is more important in beta cell dysfunction in T2DM remains unclear; however, collectively, functional beta cell mass is decreased in humans with T2DM. Beta cell dysfunction is not only present in T2DM but also progressively worsens with duration of the disease. Recent studies have also revealed that the functional beta cell mass is already impaired before the onset of T2DM, implying that beta cell dysfunction is essential in the development of T2DM. Finally, ethnic difference in beta cell function has also been proposed. Recent studies suggest that Asians have less beta cell functional capacity compared with Caucasians. Therefore, preservation or recovery of functional beta cell mass is an important therapeutic strategy to prevent, treat and even cure T2DM, and this seems to be further emphasized for Asians.

This review article evaluates the current knowledge in the prevention and treatment of diabetes and obesity. The relative abundance of food and lack of rigorous exercise common in modern life pose serious challenges in the incidence and treatment of these diseases and their complications. Although blood glucose controlling agents such as insulin and oral hypoglycemic agents are available, most currently available drugs have been shown to exhibit minimal to moderate efficacy and many of them have serious side effects. For example, rosiglitazone and pioglitazone are often prescribed to improve insulin sensitivity by increasing expression of glucose transporter-4 in muscle and fat cells; however, they can frequently induce cardiovascular complication and liver damage. Similarly, available anti-obesity drugs have not been very effective in reducing obesity and also exhibit many common side effects. We are presently testing a new drug, Cyclo (his-pro) plus zinc (Cyclo-Z), which prevents and treats diabetes without any known side effects. It is also very effective in animals and humans in the control of body weight. Our studies have shown that Cyclo-Z improves insulin sensitivity as measured by oral glucose tolerance test (OGTT), decreases fasting and postprandial blood glucose, diminishes HbA1C, and reduces body weight significantly in diabetic and obese rats and humans. Studies in Goto-Kakizaki rats, a genetic model of type 2 diabetic rats, and genetically obese diabetic ob/ob mice have confirmed the ability of Cyclo-Z to improve diabetes-related clinical abnormalities and to decrease body mass index in animals. Furthermore, we have successfully completed FDAIND approved phase 1 and phase 2a clinical trials for the treatment of diabetes alone and are currently awaiting the conclusion of another phase 2a clinical trial with obese diabetic subjects. In this paper we summarize the currently available diabetes and obesity therapies and review our studies to illustrate the effective and safe ability of Cyclo-Z to reduce and treat patients suffering from diabetes and obesity.

The vascular endothelium constitutes an important barrier for the selective passage of plasma proteins, solutes and fluid from the blood to the underlying interstitium and cells. In addition to that, the endothelium also regulates the production of various autocrine and paracrine factors in order to maintain vascular homeostasis. Hence, normal endothelial function is critical for proper vascular activity including blood vessel development and growth (angiogenesis), leukocyte trafficking, coagulation and fibrinolysis. Endothelial dysfunction results from the imbalance between vasoconstriction and vasodilation that predispose the vasculature to leukocyte adherence, endothelial proliferation as well as thrombosis. Several studies have demonstrated the implication of obesity and diabetes in the progression of endothelial dysfunction which in turn accelerates the manifestation of vascular complications. The coexistence between obesity, diabetes and endothelial dysfunction suggests the involvement of common regulators between the three entities. MicroRNAs are promising candidates of these regulators since they have the ability to control the expression of multiple genes that regulate our cellular processes. In fact, dysregulation of microRNAs is a common feature in various human diseases including obese/diabetes-associated vascular complications. This review describes the direct and indirect mechanisms of obesity and diabetes in relation to the manifestation of endothelial dysfunction. At the same time, it also summarizes the latest insights into the implications of microRNAs in the development of endothelial dysfunction and discusses their potential for the treatment of vascular pathophysiological conditions.