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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
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PMID:Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. 1751 19

To determine whether adipocyte storage capacity influences the onset and severity of type 2 diabetes and other components of the metabolic syndrome, we made normal and db/db mice resistant to obesity by overexpressing leptin receptor-b on the aP2-Lepr-b promoter. On a 4% diet, these mice have no phenotype, but on a 60% fat diet, they resist diet-induced obesity because constitutive adipocyte-specific overexpression of Lepr-b prevents obesity via the antilipogenic autocrine/paracrine action of leptin on adipocytes. After 8 months on the same 60% fat diet, body fat of transgenic mice was 70% below WT controls. Cardiac and liver fat was elevated in the transgenics, and their hyperinsulinemia was more marked, suggesting greater insulin resistance. The aP2-Lepr-b transgene also prevented obesity in db/db mice; at 10 weeks of age their body fat was half that of the db/db mice. This lack of obesity was attributable to reduced expression of sterol regulatory element binding protein-1c and its target lipogenic enzymes in adipose tissue and a 6-fold increase in Pref-1 mRNA. Severe diabetes was present in transgenics at 4 weeks of age, 10 weeks before db/db controls. Echocardiographic evidence of cardiomyopathy appeared at 10 weeks, weeks before the db/db mice. Histologically, loss of beta cells and myocardial fibrosis was present in the transgenic group at least 6 weeks before the db/db mice. These results suggest that the expression level of genes that regulate the adipogenic response to overnutrition profoundly influences the age of onset and severity of diet-induced type 2 diabetes and co-morbidities.
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PMID:Adipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome. 1841 98

Women are doubly vulnerable to malnutrition, because of their high nutritional requirements for pregnancy and lactation and also because of gender inequalities in poverty. Undernutrition and overnutrition coexist in developing countries undergoing rapid nutrition transition, and women are susceptible to this double burden of "dysnutrition," often cumulating stunting or micronutrient malnutrition with obesity or other nutrition-related chronic diseases. The purpose of the present paper is to describe the adverse impact of income and gender inequities on women's nutritional health, and the dramatic consequences, not only for women themselves, but for children, families, and societies. Improving women's resources, including health, nutrition, education, and decisional power, is critical for equity and for the health of children and adults of future generations, since poor fetal and infancy nutrition is another risk factor for chronic diseases, in particular abdominal obesity, type 2 diabetes, hypertension, and cardiovascular disease. Addressing malnutrition and nutrition-related chronic diseases simultaneously is a challenge facing developing countries, and examples of promising initiatives are provided. Focusing on women along the lifecycle, according to the continuum of care approach, is essential to achieving the Millennium Development Goals and to breaking the intergenerational cycle of poverty, malnutrition, and ill-health.
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PMID:Poverty: the double burden of malnutrition in mothers and the intergenerational impact. 1857 81

Human overnutrition has caused a rise in the prevalence of obesity in recent years. In addition to the deleterious effects of obesity during childhood, long-term effects in adulthood have been described as well. For instance, cardiovascular diseases and type 2 diabetes are among the diseases associated with a history of obesity. Altered insulin secretion and action have been described as important links between these diseases and obesity. Insulin acts as a unique anabolic hormone providing regulation of whole-body glucose homeostasis and peripheral tissue glucose uptake in tissues such as the heart. In this study, we examined insulin signaling in the heart of obese animals using an experimental model of inducing overweight adult animals by overnutrition in early life. In these animals, overfeeding during lactation was able to induce a significant increase in body weight starting at the 10th day of life, and this increased weight persisted until adulthood. Impairment in glucose tolerance, hyperinsulinemia, and an increased insulin/glucose ratio were also observed in these animals. Moreover, an increased heart weight/tibia length ratio was also observed, indicating an enlarged heart size. The overfed animals also had decreased insulin sensitivity in the heart, as confirmed by decreased insulin receptor (IR)-beta and IR substrate-1 (Irs1) phosphorylation, increased phosphatase, non-receptor type 1 (Ptpn1)-IR-beta association, decreased -Irs1-associated activity, and reduction in anti-phospho Akt1 phosphorylation. In conclusion, our findings showed that overnutrition during early life induced obesity and insulin resistance in the adult offspring, and further increased heart size and impaired cardiac insulin signaling, putatively due to an increase in Ptpn1 activity.
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PMID:Early overnutrition impairs insulin signaling in the heart of adult Swiss mice. 1859 21

Obesity is defined as increased body weight caused by excessive accumulation of fat. Due to a very long period of undernutrition in human history, the contemporary human body regulation mechanisms seem to be biased in favor of preserving fat rather to eliminate it. At the highest risk are populations that suddenly gained wealth. The shift from undernutrition to overnutrition has occurred in a very short time, in many population groups in less than in one generation. The increase of obesity prevalence observed in the 20th century continues until present and it appears this trend will further continue in almost all countries in the world. Contemporary prevalence of adult obesity is very high in USA (33% in both gender), in oil-rich Arabian countries (30% in males, 40 % in females) and in European Union (up to 25% in both gender). The aim of contemporary research is to understand the molecular and neural systems which the body uses to regulate its storage of energy in the form of fat and how these systems can become unbalanced, leading to obesity. In spite of discovery of new hormones (e.g. leptin produced in adipose tissue) and of new mechanisms, the prevention and treatment of obesity remains an open problem. Obesity is associated with an increased risk of numerous comorbidities such as type 2 diabetes, metabolic syndrome, hypertension, cardiovascular diseases and osteoarthritis. In USA the impact of obesity on mortality may have decreased over time, perhaps because of improvements in public health and medical care. New data from USA and China suggest the lowest all-cause mortality in persons with a body mass index, BMI between 23.0 and 27.0 (Fig. 6, Tab. 1, Ref. 29). Full Text (Free, PDF) www.bmj.sk.
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PMID:Adult obesity at the beginning of the 21st century: epidemiology, pathophysiology and health risk. 1863 Aug 7

Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others are under controlled trials or their effectiveness is low. NASH is not a common indication for liver transplantation because of the older age distribution of patients and high prevalence of comorbidity, related to metabolic syndrome. Recurence of NASH in the grafted liver is also a relatively frequent complication.
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PMID:[Non-alcoholic fatty liver disease--new view]. 1870 46

Epidemiological studies have shown that infants exposed to an increased supply of nutrients before birth are at increased risk of type 2 diabetes in later life. We have investigated the hypothesis that fetal overnutrition results in reduced expression and phosphorylation of the cellular fuel sensor, AMP-activated kinase (AMPK) in liver and skeletal muscle before and after birth. From 115 days gestation, ewes were fed either at or approximately 55% above maintenance energy requirements. Postmortem was performed on lamb fetuses at 139-141 days gestation (n = 14) and lambs at 30 days of postnatal age (n = 21), and liver and quadriceps muscle were collected at each time point. The expression of AMPKalpha1 and AMPKalpha2 mRNA was determined by quantitative RT-PCR (qRT-PCR). The abundance of AMPKalpha and phospho-AMPKalpha (P-AMPKalpha) was determined by Western blot analysis, and the proportion of the total AMPKalpha pool that was phosphorylated in each sample (%P-AMPKalpha) was determined. The ratio of AMPKalpha2 to AMPKalpha1 mRNA expression was lower in fetuses compared with lambs in both liver and muscle, independent of maternal nutrition. Hepatic %P-AMPKalpha was lower in both fetuses and lambs in the Overfed group and %P-AMPKalpha in the lamb liver was inversely related to plasma glucose concentrations in the first 24 h after birth (r = 0.73, P < 0.025). There was no effect of maternal overnutrition on total AMPKalpha or P-AMPKalpha abundance in liver or skeletal muscle. We have, therefore, demonstrated that AMPKalpha responds to signals of increased nutrient availability in the fetal liver. Suppression of hepatic AMPK phosphorylation may contribute to increased glucose production, and basal hyperglycemia, present in lambs of overfed ewes in early postnatal life.
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PMID:Maternal overnutrition suppresses the phosphorylation of 5'-AMP-activated protein kinase in liver, but not skeletal muscle, in the fetal and neonatal sheep. 1878 29

Epigenetic influences on the fetus's genotype have been shown to occur during intrauterine life. Experimentally imposed extracellular dehydration in pregnant rats (a model for human hyponatremia caused by gravidic vomiting) brings about a dramatic enhancement of salt appetite not only in the dam, but also in offspring when they reach adulthood. This phenomenon has been verified in human newborn infants and adults whose mothers experienced nausea and/or vomiting during pregnancy. Alcohol consumption during pregnancy enhances its palatability for the offspring. Ingestion of olfactory test substances like anise or carrot by the mother during pregnancy gives rise to a preference for the same testants in the offspring. Under- or overnutrition in the pregnant mother appears to play a role in reprogramming the postnatal regulation of both feeding and fat reserves in offspring. Both maternal under- and overnutrition during pregnancy predispose the offspring to later development of obesity and type 2 diabetes mellitus. A careful examination of the systems concerned with the regulation of food intake, and the neurosubstances involved in such regulation, reveals some of the mechanisms by which maternal nutritional status can affect the offspring and their food-related behaviors.
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PMID:Prenatal imprinting of postnatal specific appetites and feeding behavior. 1880 61

The "metabolic syndrome" (MetS) is a clustering of components that reflect overnutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders. Because the MetS is a cluster of different conditions, and not a single disease, the development of multiple concurrent definitions has resulted. The prevalence of the MetS is increasing to epidemic proportions not only in the United States and the remainder of the urbanized world but also in developing nations. Most studies show that the MetS is associated with an approximate doubling of cardiovascular disease risk and a 5-fold increased risk for incident type 2 diabetes mellitus. Although it is unclear whether there is a unifying pathophysiological mechanism resulting in the MetS, abdominal adiposity and insulin resistance appear to be central to the MetS and its individual components. Lifestyle modification and weight loss should, therefore, be at the core of treating or preventing the MetS and its components. In addition, there is a general consensus that other cardiac risk factors should be aggressively managed in individuals with the MetS. Finally, in 2008 the MetS is an evolving concept that continues to be data driven and evidence based with revisions forthcoming.
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PMID:The metabolic syndrome. 1897 85

T2DM (Type 2 diabetes mellitus) has reached epidemic proportions worldwide, exerting major health consequences at an individual and public health level alike. Unfortunately, the molecular pathophysiology of diabetes remains incompletely understood, impairing progress towards more effective prevention and treatment strategies. Although the rapid increase in the prevalence of insulin resistance and T2DM over the past several decades highlights a major environmental contribution related to overnutrition, obesity and inactivity, susceptibility is likely to reflect individual differences in complex gene-environment interactions. In the present review, we focus on mediators of genetic and environmental risk for T2DM at a molecular level.
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PMID:Genetic determinants and molecular pathways in the pathogenesis of Type 2 diabetes. 1907 63


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