Pathophysiology and genetics of obesity

Obesity has become the most prevalent nutritional disorder in post-industrialised societies and it is associated with the development of severe and costly complications such as type 2 diabetes mellitus and coronary heart disease or cancer. A large proportion of the risk of obesity is determined by the genetic susceptibility of an individual, but environmental factors conducive for the disorder play an important role in its phenotypic expression. Several candidate genes emerged from studies in animal models of obesity, but human pathophysiology is likely to be more complex. Thus, most cases of human obesity probably result from subtle interactions of susceptibility genes with environmental factors favouring deposition of excess calories as fat. The recent surge of obesity may relate to past evolutionary pressure which favoured selection of mechanisms defending body-weight against caloric restriction rather than against caloric excess. Rapidly developing new techniques in quantitative genetics and growing information from functional genomics will help to understand the interaction of environmental factors with signalling networks that regulate energy metabolism. The role of previously unknown pathways in the aetiology of obesity will be uncovered. The typing of numerous genetic variants will become possible and allow individual risk assessment for obesity and/or its associated disorders. Thus, rational and individually tailored therapies may be developed to combat obesity and its associated disorders.     

Personalized nutrition and obesity

Abstract

The past few decades have witnessed a rapid rise in nutrition-related disorders such as obesity in the United States and over the world. Traditional nutrition research has associated various foods and nutrients with obesity. Recent advances in genomics have led to identification of the genetic variants determining body weight and related dietary factors such as intakes of energy and macronutrients. In addition, compelling evidence has lent support to interactions between genetic variations and dietary factors in relation to obesity and weight change. Moreover, recently emerging data from other ‘omics’ studies such as epigenomics and metabolomics suggest that more complex interplays between the global features of human body and dietary factors may exist at multiple tiers in affecting individuals’ susceptibility to obesity; and a concept of ‘personalized nutrition’ has been proposed to integrate this novel knowledge with traditional nutrition research, with the hope ultimately to endorse person-centric diet intervention to mitigate obesity and related disorders.     

Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome

Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.     

Preparing nurses to face the pandemic of diabetes mellitus: a literature review

BACKGROUND: Diabetes constitutes a global public health problem. Today about 135 million people are affected and it is estimated that the number in 2025 will be 300 million. AIMS: By reviewing existing literature the aim is to raise awareness among nurses, nurse educators and nursing students of the global epidemic of diabetes mellitus, its multiple underlying causes, especially social ones, and how to fight it. A further aim is to discuss the implications for future curriculum content in nurse education programmes. FINDINGS: The main underlying causes of the disease are genetic and environmental factors, such as urbanization and industrialization, as well as increased longevity and changes in lifestyle from a traditional healthy and active life to a modern, sedentary, stressful life and over-consumption of energy-dense foods. This process, labelled 'coca-colonization', is evident all over the world, although more so in developing countries. The prevalence of diabetes mellitus varies among populations due to differences in genetic susceptibility and social risk factors such as change in diet, obesity, physical inactivity and, possibly, factors relating to intrauterine development. Migrants are especially affected. Diabetes mellitus needs to be treated by a holistic approach through dietary adjustment, exercise, medication (if needed), education and self-care measures. Type 2 diabetes mellitus is a preventable disease. The main implication for nurses and nursing curricula is to change the focus from the individual with diabetes mellitus and management to prevent deterioration of health (secondary prevention), to population-based community-intervention programmes. These need to focus on health promoting activities to raise awareness among healthy people of the risk factors for diabetes mellitus. CONCLUSION: Nurses all over the world have an important role in fighting the diabetic pandemic by health promotion aimed to keep people healthy as long as possible.     

Obesity,Diabetes, and Gut Microbiota: The hygiene hypothesis expanded?

The connection between gut microbiota and energy homeostasis and inflammation and its role in the pathogenesis of obesity-related disorders are increasingly recognized. Animals models of obesity connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver, modulation of gut peptide YY and glucagon-like peptide (GLP)-1 secretion, activation of the lipopolysaccharide toll-like receptor-4 axis, and modulation of intestinal barrier integrity by GLP-2. Instrumental for gut microbiota manipulation is the understanding of mechanisms regulating gut microbiota composition. Several factors shape the gut microflora during infancy: mode of delivery, type of infant feeding, hospitalization, and prematurity. Furthermore, the key importance of antibiotic use and dietary nutrient composition are increasingly recognized. The role of the Western diet in promoting an obesogenic gut microbiota is being confirmation in subjects. Following encouraging results in animals, several short-term randomized controlled trials showed the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance. Future research is needed to unravel the hormonal, immunomodulatory, and metabolic mechanisms underlying microbe-microbe and microbiota-host interactions and the specific genes that determine the health benefit derived from probiotics. While awaiting further randomized trials assessing long-term safety and benefits on clinical end points, a healthy lifestyle—including breast lactation, appropriate antibiotic use, and the avoidance of excessive dietary fat intake—may ensure a friendly gut microbiota and positively affect prevention and treatment of metabolic disorders.Along with the increasing worldwide incidence of obesity-associated disorders, research has recently unraveled important pathways reciprocally connecting metabolism with the immune system. The development of obesity is a complex process involving genetic susceptibility and environmental factors, which both remain only partially understood. In such instances, gut microbiota is being increasingly recognized as an important factor connecting genes, environment, and immune system. The human gut hosts an enormous number and variety of microorganisms, including at least 10¹⁴ bacteria belonging to ∼1,000 species (1). The genome size of this microbial organ, collectively named microbiome, exceeds the size of the human nuclear genome by two orders of magnitude and provides important biological and metabolic functions that cannot be performed by researchers. Genomic and environmental factors at the basis of mutual host-microbiota interactions have been intensely investigated with metagenomic and metabolomic approaches in the last 5 years. This article will discuss recent advances in understanding the role of gut microbiota in the pathogenesis of obesity, insulin resistance (IR), and diabetes and their potential therapeutic applications.     

Genes for normal sleep and sleep disorders

Sleep and wakefulness are complex behaviors that are influenced by many genetic and environmental factors, which are beginning to be discovered. The contribution of genetic components to sleep disorders is also increasingly recognized as important. Point mutations in the prion protein, period 2, and the prepro-hypocretin/orexin gene have been found as the cause of a few sleep disorders but the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth in-depth investigations. However, single gene disorders are rare and most common disorders are complex in terms of their genetic susceptibility, environmental effects, gene-gene, and gene-environment interactions. We review here the current progress in the genetics of normal and pathological sleep.     

Genes for normal sleep and sleep disorders

Sleep and wakefulness are complex behaviors that are influenced by many genetic and environmental factors, which are beginning to be discovered. The contribution of genetic components to sleep disorders is also increasingly recognized as important. Point mutations in the prion protein, period 2, and the prepro‐hypocretin/orexin gene have been found as the cause of a few sleep disorders but the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth in‐depth investigations. However, single gene disorders are rare and most common disorders are complex in terms of their genetic susceptibility, environmental effects, gene‐gene, and gene‐environment interactions. We review here the current progress in the genetics of normal and pathological sleep.     

Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S

OBJECTIVE: Type 2 diabetes and obesity have genetic and environmental determinants. We studied the effects of different environments on these diseases in Pima Indians in Mexico and the U.S. RESEARCH DESIGN AND METHODS: Adult Pima-Indian and non-Pima populations in the Sierra Madre mountains of Mexico were examined using oral glucose tolerance tests and assessments for obesity, physical activity, and other risk factors. Results were compared with those from Pima Indians in Arizona. Both Pima populations were typed for DNA polymorphisms to establish their genetic similarity. RESULTS: The age- and sex-adjusted prevalence of type 2 diabetes in the Mexican Pima Indians (6.9%) was less than one-fifth that in the U.S. Pima Indians (38%) and similar to that of non-Pima Mexicans (2.6%). The prevalence of obesity was similar in the Mexican Pima Indians (7% in men and 20% in women) and non-Pima Mexicans (9% in men and 27% in women) but was much lower than in the U.S. Pima Indians. Levels of physical activity were much higher in both Mexican groups than in the U.S. Pima Indians. The two Pima groups share considerable genetic similarity relative to other Native Americans. CONCLUSIONS: The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. This study provides compelling evidence that changes in lifestyle associated with Westernization play a major role in the global epidemic of type 2 diabetes.     

The Gene-Diet Attica investigation on childhood obesity (GENDAI): overview of the study design.

BACKGROUND: There is limited evidence on the role of genetic and environmental factors in the etiology of childhood obesity, a major health problem worldwide. METHODS: The Gene-Diet Attica Investigation on childhood obesity (GENDAI) evaluates the contributions to and pivotal interactions of genetic, dietary and physical activity variables on children's weight. We describe the design, methodology, and present preliminary data. So far, 920 participants have been enrolled and the final projected sample is 1000 fifth- and sixth-grade students from selected elementary schools in Attica (10-14 years). In this school-based cross-sectional study, more than 400 variables describing anthropometric, dietary, clinical, genetic, sociodemographic and other lifestyle characteristics were collected from participating children and their families. RESULTS: Increased body mass index was identified in 39.3% of subjects (30.5% overweight and 8.8% obese), with males presenting a more unfavorable metabolic profile, i.e., higher blood lipids, glucose, and insulin, compared to females. Normal-weight children had a significant advantage when compared to all children of increased weight in terms of lipid profile and insulin, as well as behaviors examined. Specifically, normal-weight children exhibited less skipping of meals and less sedentary activities. CONCLUSIONS: The overall high prevalence of overweight and obesity in the current population is significant and underscores the need for environmental and genetic information that will shed light on the phenomenon of childhood obesity.     

Genetic and environmental factors of autoimmune thyroid diseases]

There is a growing consensus that autoimmune thyroid diseases, similar to other autoimmune diseases, is multifactorial: both several genetic and environmental factors interact and produce the clinical phenotype of these disorders. Twin studies and familial aggregation, including clustering within families showed that they are complex diseases with a significant genetic component. Several genetic factors associated with autoimmune thyroid diseases susceptibility have been identified, including the HLA genes, cytotoxic T lymphocyte associated-4 (CTLA-4) gene, TSH receptor and other immunoregulatory genes. Regarding environmental factors, although multiple factors including infection, stress, sex steroids, pregnancy, aging and food, are known as factors precipitating autoimmune thyroid diseases, little progress has been achieved defining them. It will be paradoxically important to identify genetic factors to investigate environmental factors.     

HLA Antigens in Insulin-Dependent Diabetes Mellitus

Diabetes mellitus is largely determined by genetic factors but environmental factors are necessary to convert genetic susceptibility into overt disease. Studies of twins show that the genetic impact in non-insulin-dependent diabetes mellitus is stronger than in insulin-dependent diabetes mellitus. The genetic factors involved in non-insulindependent diabetes mellitus are not known and the outcome of molecular genetic research has so far been disappointing. The major genetic susceptibility to insulindependent diabetes mellitus is conferred by genes in the HLA region on chromosome 6. Despite many advances in molecular genetics in insulindependent diabetes mellitus the serologically detectable HLA antigens and haplotypes are still the best available markers. This review describes the important developments in immunogenetics in insulindependent diabetes mellitus and summarises the main findings from earlier studies. Genetically the potential for primary prevention of insulin-dependent diabetes mellitus already exists and will become a reality as soon as the environmental determinants are identified. A wide application of immunogenetic methods will be needed in the prevention of insulin-dependent diabetes mellitus.     

HLA antigens in insulin-dependent diabetes mellitus.

Diabetes mellitus is largely determined by genetic factors but environmental factors are necessary to convert genetic susceptibility into overt disease. Studies of twins show that the genetic impact in non-insulin-dependent diabetes mellitus is stronger than in insulin-dependent diabetes mellitus. The genetic factors involved in non-insulin-dependent diabetes mellitus are not known and the outcome of molecular genetic research has so far been disappointing. The major genetic susceptibility to insulin-dependent diabetes mellitus is conferred by genes in the HLA region on chromosome 6. Despite many advances in molecular genetics in insulin-dependent diabetes mellitus the serologically detectable HLA antigens and haplotypes are still the best available markers. This review describes the important developments in immunogenetics in insulin-dependent diabetes mellitus and summarises the main findings from earlier studies. Genetically the potential for primary prevention of insulin-dependent diabetes mellitus already exists and will become a reality as soon as the environmental determinants are identified. A wide application of immunogenetic methods will be needed in the prevention of insulin-dependent diabetes mellitus.     

Hispanic Americans living in the United States and their risk for obesity,diabetes and kidney disease: Genetic and environmental considerations

The Hispanic American, the largest minority population in the United States, is at increased risk for obesity, diabetes and end-stage renal disease. Here we review genetic and environmental factors that might account for their increased risk for these conditions. Whereas many environmental and genetic factors have important roles in driving the increased risk for obesity and kidney disease in this population, a case is made that excessive intake of sugary beverages is a contributory cause. Studies focusing on decreasing intake of sugary beverages among the Hispanic American could potentially reduce renal and cardiovascular complications in this population.     

Racial differences in venous thromboembolism

Summary. The incidence of venous thrombosis (VTE) varies by race, with African‐Americans having over 5‐fold greater incidence than Asian‐ancestry populations, and an intermediate risk for European and Hispanic populations. Known racial differences in genetic polymorphisms associated with thrombosis do not account for this gradient of risk, nor do known racial variations in environmental risk factors. Data on the incidence of and risk factors for VTE outside of Europe and North America and in non‐European ancestry populations are sparse. Common genetic polymorphisms in European‐Ancestry populations, such as factor V Leiden and prothrombin G20210A, and environmental risk factors, such as obesity, may account for some of the increased risk in European populations, and high factor VIII, high von Willebrand factor and low protein C levels and increased prevalence of obesity may explain some of the increased risk in African‐Americans. The low rates in Asian populations may be partially explained by low clinical suspicion in a perceived low‐risk population and lack of access to healthcare in other populations. As risk factors for thrombosis, such as surgery and treatment for cancer, are applicable to more people, as obesity increases in prevalence in the developing world, and as surveillance systems for VTE improve, VTE may increase in previously low‐risk populations. While differences in VTE by race due to genetic predisposition will probably always be present, understanding the reasons for racial differences in VTE will help providers develop strategies to minimize VTE in all populations.     

Acute,Withdrawal, and Chronic Alcohol Effects in Man: Event-Related Potential and Quantitative EEG Techniques

The association of metabolic disorders with liver disease is receiving increasing attention in the gastroenterological community. Cohort studies have shown that advanced liver disease may stem from metabolic disorders, via fatty liver, non‐alcoholic steatohepatitis, cryptogenic cirrhosis, and eventually hepatocellular carcinoma. In both obesity and diabetes, deaths from cirrhosis are higher than expected, mainly in subjects with no or moderate alcohol consumption, but high rates of fatty liver disease have been associated with all features of the metabolic syndrome. Also the risk of hepatocellular carcinoma is higher than normal, being dependent on body mass index (BMI) in obesity, and independent of age, BMI, gender and race in diabetes. Finally, metabolic liver disease may interact with hepatitis C virus infection, increasing the risk of steatosis and liver disease progression, as well as reducing the chances of an effective antiviral treatment. There is evidence that treatments aimed at reducing insulin resistance are also effective in improving liver histology. Although cardiovascular disease remains the major cause of increased morbidity and excess mortality in metabolic disorders, the risk of progressive liver disease should no longer be underestimated, being a threat to millions of people at risk in the present epidemics of obesity and diabetes, and therapeutic strategies need to be tested.     

Atherosclerosis in diabetes mellitus

The clinical and epidemiological importance of cardiovascular diseases, has increased rapidly in recent years. Diabetes mellitus which serves as a basis for the development of atherosclerosis, are induced by a genetic predisposition coupled with environmental factors. Hypernutrition and insufficient exercise lead to diabetes mellitus, hyperlipidemia, hypertension, obesity, and insulin resistance in individuals genetically predisposed to these disorders, which eventually produce ischemic heart disease and cerebrovascular disease. The report of the Multiple Risk Factor Intervention Trial (MRFIT) suggested that the prevalence of atherosclerosis in patients with diabetes mellitus is two or three times that in individuals without diabetes, and a Finnish study has reported that the risk of ischemic heart disease is extremely high in patients with type 2 diabetes mellitus. In order to prevent the development of ischemic heart disease in patients with diabetes mellitus, the risks of development of hyperlipidemia, hypertension and other relevant diseases should be carefully controlled.     

Global prevalence of diabetes: estimates for the year 2000 and projections for 2030

OBJECTIVE: The goal of this study was to estimate the prevalence of diabetes and the number of people of all ages with diabetes for years 2000 and 2030. RESEARCH DESIGN AND METHODS: Data on diabetes prevalence by age and sex from a limited number of countries were extrapolated to all 191 World Health Organization member states and applied to United Nations' population estimates for 2000 and 2030. Urban and rural populations were considered separately for developing countries. RESULTS: The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men. The urban population in developing countries is projected to double between 2000 and 2030. The most important demographic change to diabetes prevalence across the world appears to be the increase in the proportion of people >65 years of age. CONCLUSIONS: These findings indicate that the "diabetes epidemic" will continue even if levels of obesity remain constant. Given the increasing prevalence of obesity, it is likely that these figures provide an underestimate of future diabetes prevalence.     

Obesity induced by abnormality in leptin receptor and melanocortin-4 receptor

Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. It increases a risk of cardiovascular and metabolic diseases such as diabetes, hypertension, and hyperlipidemia. Recent molecular genetic studies have disclosed some monogenic forms of obesity in humans. Leptin directly exerts its anorexigenic effects on hypothalamic arcuate nucleus. alpha-melanocyte stimulating hormone (alpha-MSH) derived from proopiomelanocortin (POMC) and melanocortin-4 receptor (MC4-R) have been reported to be involved in the downstream of leptin actions. In this paper, we summarize the clinical characteristics and the mechanisms of obesity caused by genetic abnormalities in leptin receptor and melanocortin-4 receptor.     

Molecular mechanism of insulin resistance in hyperlipidemia

Several types of abnormal lipoprotein particles are observed in patients with insulin resistance: elevated VLDL-triglycerides, remnant lipoprotein, small dense LDL, reduced HDL-cholesterol. These patterns are caused by environmental and genetic factors that alter the lipoprotein metabolism. These lipoprotein abnormalities cause insulin resistance through several factors which decrease LPL and PPAR gamma, on the other hand increase ACS and MTP. It is considered that increased plasma level of FFA will closely associated with these factors and their regulations. Secretion of TNF-alpha from adipocytes increases in obesity and closely relates to the pathogenesis of insulin resistance. But the genetic mechanisms are not still clear. More studies about genetic factors which affect to lipoprotein metabolism will be needed and should be considered about the role on insulin resistance.     

NIDDK International Conference Report on Diabetes and Depression: Current Understanding and Future Directions

Comorbid diabetes and depression are a major clinical challenge as the outcomes of each condition are worsened by the other. This article is based on the presentations and discussions during an international meeting on diabetes and depression convened by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in collaboration with the National Institute of Mental Health and the Dialogue on Diabetes and Depression. While the psychological burden of diabetes may contribute to depression in some cases, this explanation does not sufficiently explain the relationship between these two conditions. Shared biological and behavioral mechanisms, such as hypothalamic-pituitary-adrenal axis activation, inflammation, autonomic dysfunction, sleep disturbance, inactive lifestyle, poor dietary habits, and environmental and cultural risk factors, are important to consider in understanding the link between depression and diabetes. Both individual psychological and pharmacological depression treatments are effective in people with diabetes, but the current range of treatment options is limited and has shown mixed effects on glycemic outcomes. More research is needed to understand what factors contribute to individual differences in vulnerability, treatment response, and resilience to depression and metabolic disorders across the life course and how best to provide care for people with comorbid diabetes and depression in different health care settings. Training programs are needed to create a cross-disciplinary workforce that can work in different models of care for comorbid conditions.