Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The levels of the liporegulatory hormone leptin are increased in obesity, which contributes to the metabolic syndrome; the latter is associated with elevated cardiovascular risk and morbidity. Leptin may play a role in the metabolic syndrome since correlations have been observed between serum leptin levels and several components of the metabolic syndrome. The association of leptinemia and hypertension or diabetes is inconsistent. Leptin levels are higher in females versus males and obese versus lean individuals. We investigated if correlations exist between leptin levels and several indices of the metabolic syndrome in obese and lean Moroccan subjects with (63 males, 129 females) and without (123 males, 234 females) diabetes and/or hypertension. Plasma glucose and insulin and systolic and diastolic blood pressures were higher in obese versus lean individuals. Obesity had no effect on lipid profile, plasma IGF-1, or C-peptide levels. Leptin levels were higher in females versus males and in obese versus lean individuals. The levels correlated significantly with body mass index. Serum leptin concentration did not correlate with either systolic or diastolic blood pressure, although there was a trend for higher blood pressure with increased leptin levels in females. There was no significant difference in leptin levels between NIDDM patients and healthy controls. However, in hypertensive patients, leptin levels were significantly higher in both lean males and females with diabetes as compared to those without diabetes. Similarly, the higher leptin levels paralleled elevated insulin levels in obese nondiabetic males and females, and in male and female diabetics with hypertension. Correlations were observed between leptin levels and C-peptide (an estimate of endogenous insulin secretion), but not with serum IGF-1. The calculated values of HOMA-IR, a marker of insulin resistance, were somewhat higher, parallel with elevated leptin levels, in obese male and female individuals compared to their lean counterparts. There was no relationship between leptin levels and serum lipids. There was a trend for increased serum uric acid levels with higher leptin concentrations. Thus, leptinemia is related to some components of metabolic syndrome, and in turn, it may contribute to the syndrome. This study is novel in that relationships were determined between leptin levels and various indices of metaboli syndrome in a large population of the same ethnic/regional background.
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PMID:Gender-specific leptinemia and its relationship with some components of the metabolic syndrome in Moroccans. 1592 Oct 74

The fat mass participates in the regulation of glucose and insulin metabolism through the release of adipocytokines in a mechanism called the adipoinsular axis. Putative adipocytokines include leptin, adiponectin and resistin. Obesity plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM). Bariatric surgery for morbidly obese patients leads to rapid and prolonged improvement in insulin resistance and T2DM in the vast majority of patients. We have previously proposed that the rapid improvement in insulin resistance observed following bariatric surgery is mediated by changes in incretin levels of the entero-insular axis and that long-term improvement is modulated by fat mass loss and changes in adipocytokine levels of the adipoinsular axis. In this review, we examine the information that supports a role of leptin, adiponectin and resistin in the development of insulin resistance and T2DM. Increasing levels of leptin and decreasing levels of adiponectin correlate with worsening insulin resistance in obese individuals. We also explore the relationship between changes in adipocytokines following bariatric surgery and long-term improvement in insulin resistance and T2DM. Leptin levels drop and adiponectin levels rise following laparoscopic adjustable gastric banding, gastric bypass and biliopancreatic diversion. These changes correlate with weight loss and improvement in insulin. Although resistin may play an important role in explaining insulin resistance, animal and human studies currently show conflicting results.
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PMID:Changes in insulin resistance following bariatric surgery and the adipoinsular axis: role of the adipocytokines, leptin, adiponectin and resistin. 1594 62

Leptin has metabolic effects on peripheral tissues including muscle, liver, and pancreas, and it has been successfully used to treat lipodystrophic diabetes, a leptin-deficient state. To study whether leptin therapy can be used for treatment of more common cases of type 2 diabetes, we used a mouse model of type 2 diabetes (MKR mice) that show normal leptin levels and are diabetic due to a primary defect in both IGF-I and insulin receptors signaling in skeletal muscle. Here we show that leptin administration to the MKR mice resulted in improvement of diabetes, an effect that was independent of the reduced food intake. The main effect of leptin therapy was enhanced hepatic insulin responsiveness possibly through decreasing gluconeogenesis. In addition, the reduction of lipid stores in liver and muscle induced by enhancing fatty acid oxidation and inhibiting lipogenesis led to an improvement of the lipotoxic condition. Our data suggest that leptin could be a potent antidiabetic drug in cases of type 2 diabetes that are not leptin resistant.
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PMID:Leptin improves insulin resistance and hyperglycemia in a mouse model of type 2 diabetes. 1594 5

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11beta-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.
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PMID:Fetal origins of insulin resistance and obesity. 1596 Aug 59

Leptin plays an important role in regulating adipose-tissue mass. Leptin controls energy balance and food intake through the leptin receptor in the hypothalamus of the brain, which suggests that some polymorphisms of the leptin receptor gene (LEPR) might contribute to obesity or obesity-related diseases. In an effort to identify genetic polymorphisms in a potential candidate gene for obesity and type 2 diabetes mellitus (T2DM) in the Korean population, we have sequenced the LEPR gene. Thirty-five sequence variants were identified (including 9 novel polymorphisms): 1 single nucleotide polymorphism (SNP) in the promoter region, 1 SNP in the 5' UTR, 8 SNPs in exons (3 non-synonymous SNPs), 23 SNPs in introns, 1 ins/del in the 3' UTR, and 1 SNP in the 3' downstream region. To investigate possible association of LEPR polymorphisms with body mass index (BMI) and the risk of T2DM, we genotyped for 11 polymorphisms in the Korean population (n = 1,463). Using statistical analyses, no significant associations between the genetic polymorphisms in the LEPR gene and the risk of T2DM were detected. However, one non-synonymous SNP in exon 3, +5193G > A (Arg109Lys), showed marginal association with BMI (P = 0.02) and gene dose-dependent genetic effects were observed. The present study provides information about additional genetic polymorphisms in LEPR and positive associations of those polymorphisms with BMI in the Korean population.
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PMID:Polymorphisms in the leptin receptor (LEPR)--putative association with obesity and T2DM. 1633 25

In addition to serving as an energy reservoir, the adipocyte has been characterized as an endocrine cell, secreting many bioactive factors which influence energy homeostasis. Being overweight, with excessive adipose tissue, is considered to be part of the pathogenesis of type 2 diabetes. Insulin resistance and beta-cell dysfunction are two major pathophysiological changes seen in type 2 diabetes. In addition to inducing insulin resistance in insulin-responsive tissues, adipocyte-derived factors play an important role in the pathogenesis of beta-cell dysfunction. Leptin, free fatty acids, adiponectin, tumor necrosis factor-alpha and interleukin-6 are all produced and secreted by adipocytes, and may directly influence aspects of beta-cell function, including insulin synthesis and secretion, insulin cell survival and apoptosis. During the progression from normal weight to obesity and on to overt diabetes, the adipocyte-derived factors contribute to the occurrence and development of beta-cell dysfunction and type 2 diabetes.
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PMID:Contribution of adipocyte-derived factors to beta-cell dysfunction in diabetes. 1637 47

Obesity is a worldwide problem which impacts the risk and prognosis of some of the more common forms of cancer, including breast cancer in post-menopausal women. As the basis for understanding the potential mechanisms of obesity and cancer relationship has advanced, a number of new hypotheses have emerged. The adipocytokines are a complex group of biologically active polypeptides. Leptin is a growth hormone, secreted by adipose tissue, whose levels are normally elevated in obese individuals and may have a promoting effect on carcinogenesis and metastasis of breast cancer, possibly in an autocrine manner. Leptin interferes with the insulin signaling pathway and in type 2 diabetes plasma leptin levels are found to be correlated with the degree of insulin resistance, a relationship independent of body mass. This relationship might provide a mechanistic explanation for promotion potential.
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PMID:Obesity, breast cancer and the role of adipocytokines. 1643 10

Leptin signaling is a critical component of normal insulin sensitivity. Overt hyperglycemia and type 2 diabetes mellitus can be manifested in states of leptin signaling deficiencies by the additional effects of other genetic factors. We have previously described the contrasting insulin sensitivities and glycemic states of two congenic diabetes (db/db) mouse strains. C57BL/6J db/db mice have mild insulin resistance and achieve euglycemia with mild hyperinsulinemia. FVB db/db mice have severe insulin resistance and are hyperglycemic despite escalating hyperinsulinemia with expanded pancreatic beta-cell mass. Analysis of obese progeny from the two reciprocal backcrosses suggests that genetic modifiers for insulin sensitivity are separable from loci that modulate beta-cell mass. A genome scan of the backcross to FVB suggests that one or more modifier genes are present on chromosome 5. This evidence is supported by the phenotypes of multiple incipient congenic strains wherein the hyperglycemia observed in obese FVB mice is reproduced. With similar degrees of hyperglycemia in obese mice of these strains, the haplotype at chromosome 5 is associated with beta-cell mass and circulating insulin concentrations. Finally, we offer arguments that production of multiple incipient congenic lines is an economical alternative to the production of speed congenic strains.
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PMID:Allelic variation on chromosome 5 controls beta-cell mass expansion during hyperglycemia in leptin receptor-deficient diabetes mice. 1648 28

It now appears that, in most obese patients, obesity is associated with a low-grade inflammation of white adipose tissue (WAT) resulting from chronic activation of the innate immune system and which can subsequently lead to insulin resistance, impaired glucose tolerance and even diabetes. WAT is the physiological site of energy storage as lipids. In addition, it has been more recently recognized as an active participant in numerous physiological and pathophysiological processes. In obesity, WAT is characterized by an increased production and secretion of a wide range of inflammatory molecules including TNF-alpha and interleukin-6 (IL-6), which may have local effects on WAT physiology but also systemic effects on other organs. Recent data indicate that obese WAT is infiltrated by macrophages, which may be a major source of locally-produced pro-inflammatory cytokines. Interestingly, weight loss is associated with a reduction in the macrophage infiltration of WAT and an improvement of the inflammatory profile of gene expression. Several factors derived not only from adipocytes but also from infiltrated macrophages probably contribute to the pathogenesis of insulin resistance. Most of them are overproduced during obesity, including leptin, TNF-alpha, IL-6 and resistin. Conversely, expression and plasma levels of adiponectin, an insulin-sensitising effector, are down-regulated during obesity. Leptin could modulate TNF-alpha production and macrophage activation. TNF-alpha is overproduced in adipose tissue of several rodent models of obesity and has an important role in the pathogenesis of insulin resistance in these species. However, its actual involvement in glucose metabolism disorders in humans remains controversial. IL-6 production by human adipose tissue increases during obesity. It may induce hepatic CRP synthesis and may promote the onset of cardiovascular complications. Both TNF-alpha and IL-6 can alter insulin sensitivity by triggering different key steps in the insulin signalling pathway. In rodents, resistin can induce insulin resistance, while its implication in the control of insulin sensitivity is still a matter of debate in humans. Adiponectin is highly expressed in WAT, and circulating adiponectin levels are decreased in subjects with obesity-related insulin resistance, type 2 diabetes and coronary heart disease. Adiponectin inhibits liver neoglucogenesis and promotes fatty acid oxidation in skeletal muscle. In addition, adiponectin counteracts the pro-inflammatory effects of TNF-alpha on the arterial wall and probably protects against the development of arteriosclerosis. In obesity, the pro-inflammatory effects of cytokines through intracellular signalling pathways involve the NF-kappaB and JNK systems. Genetic or pharmacological manipulations of these effectors of the inflammatory response have been shown to modulate insulin sensitivity in different animal models. In humans, it has been suggested that the improved glucose tolerance observed in the presence of thiazolidinediones or statins is likely related to their anti-inflammatory properties. Thus, it can be considered that obesity corresponds to a sub-clinical inflammatory condition that promotes the production of pro-inflammatory factors involved in the pathogenesis of insulin resistance.
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PMID:Recent advances in the relationship between obesity, inflammation, and insulin resistance. 1661 57

Inflammation is frequently present in the visceral fat and vasculature in certain patients with cardiovascular disease (CVD) and/or adult onset Diabetes Mellitus Type II (NIDDM). An hypothesis is presented which argues that repeated acute or chronic psychologically stressful states may cause this inflammatory process. The mediators are the major stress hormones norepinephrine (NE) and epinephrine (E) and cortisol together with components of the renin-angiotensin system (RAS), the proinflammatory cytokines (PIC), as well as free fatty acids (ffa), the latter as a result of lipolysis of neutral fat. NE/E commence this process by activation of NF(kappa)B in macrophages, visceral fat, and endothelial cells which induces the production of toll-like receptors which, when engaged, produce a cascade of inflammatory reactions comprising the acute phase response (APR) of the innate immune system (IIS). The inflammatory process is most marked in the visceral fat depot as well as the vasculature, and is involved in the metabolic events which culminate in the insulin resistance/metabolic syndromes (IRS/MS), the components of which precede and comprise the major risk factors for CVD and NIDDM. The visceral fat has both the proclivity and capacity to undergo inflammation. It contains a rich blood and nerve supply as well as proinflammatory molecules such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), leptin, and resistin, the adipocytokines, and acute phase proteins (APP) which are activated from adipocytes and/or macrophages by sympathetic signaling. The inflammation is linked to fat accumulation. Cortisol, IL-6, angiotensin II (angio II), the enzyme 11(beta) hydroxysteroid dehydrogenase-1 and positive energy balance, the latter due to increased appetite induced by the major stress hormones, are factors which promote fat accumulation and are linked to obesity. There is also the capacity of the host to limit fat expansion. Sympathetic signaling induces TNF which stimulates the production of IL-6 and leptin from adipocytes; these molecules promote lipolysis and ffa fluxes from adipocytes. Moreover, catecholamines and certain PIC inhibit lipoprotein lipase, a fat synthesizing enzyme. The brain also participates in the regulation of fat cell mass; it is informed of fat depot mass by molecules such as leptin and ffa. Leptin stimulates corticotrophin releasing hormone in the brain which stimulates the SNS and HPA axes, i.e. the stress response. Also, ffa through portal signaling from the liver evoke a similar stress response which, like the response to psychologic stress, evokes an innate immune response (IIR), tending to limit fat expansion, which culminates in inflammatory cascades, the IRS-MS, obesity and disease if prolonged. Thus, the brain also has the capacity to limit fat expansion. A competition apparently exists between fat expansion and fat loss. In "western" cultures, with excessive food ingestion, obesity frequently results. The linkage of inflammation to fat metabolism is apparent since weight loss diminishes the concentration of inflammatory mediators. The linkage of stress to inflammation is all the more apparent since the efferent pathways from the brain in response to fat signals, which results in inflammation to decrease and limit fat cell mass, is the same as the response to psychologic stress, which strengthens the hypothesis presented herein.
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PMID:The inflammatory consequences of psychologic stress: relationship to insulin resistance, obesity, atherosclerosis and diabetes mellitus, type II. 1678 Oct 84


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