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Obesity poses a serious health hazard and its treatment is often disappointing. Major advances have been made during recent years in the understanding of body weight regulation, with the discovery of leptin, a protein produced by adipocytes and acting on the central nervous system to reduce food intake, and that of beta-3 adrenergic receptors and uncoupling proteins which contribute to stimulate energy expenditure. Numerous metabolic complications are associated with abdominal obesity and most of them, such as diabetes mellitus, dyslipidaemias and arterial hypertension, appear to be linked to insulin resistance and may be part of the socalled metabolic syndrome or syndrome X. While very-low-calorie diets are usually effective in the short-term, they cannot, in the long-term and for most patients, solve the problem of severe obesity. Pharmacological antiobesity treatment may include drugs that reduce food intake, drugs that increase energy expenditure and drugs that affect nutrient partitioning or metabolism. All of these pharmacological approaches have potential efficacy, but unfortunately serious limitations. This is also the case of mechanical means, such as intragastric balloons. Consequently, bariatric surgery may be considered as a valuable alternative therapy in well-selected patients with morbid obesity refractory to classical treatments. In conclusion, obesity is a chronic disease and should be treated as such with reasonable expectations.
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PMID:Medical aspects of obesity. 1042 50

The association of several risk factors, obesity, dyslipoproteinemia, hepatic steatosis, insulin resistance and hypertension with Type 2 (non-insulin-dependent) diabetes mellitus and myocardial infarction has long been known and has been termed the "metabolic syndrome". In 1988 Reaven introduced syndrome X as the link between insulin resistance and hypertension. It has been suggested that a critical factor in the association between obesity, Type 2 diabetes and cardiovascular morbidity is the mass of intraabdominal fat. Striking similarities exist between the metabolic syndrome and untreated growth hormone (GH) deficiency in adults. The central findings in both these syndromes are abdominal/visceral obesity and insulin resistance. Other features common to both conditions are premature atherosclerosis and increased mortality from cardiovascular diseases. These similarities indicate that undetectable and low levels of GH may be of importance in the metabolic aberrations observed in both these conditions. Recent investigations have found that abdominal/visceral distribution of adipose tissue is associated with endocrine disturbances including increased activity of the hypothalamic-pituitary-adrenal axis and a blunted secretion of GH and sex steroids. Theoretically, these endocrine perturbations can be a consequence of obesity, but the endocrine aberrations may have causal effects. We studied moderately obese, middle-aged men with a preponderance of abdominal body fat. As a group, they had slight to moderate metabolic changes known to be associated with abdominal/visceral obesity. Nine months of GH treatment reduced their total body fat and resulted in a specific and a marked decrease in both abdominal subcutaneous and visceral adipose tissue. Moreover, insulin sensitivity improved and serum concentrations of total cholesterol and triglyceride decreased. Diastolic blood pressure also decreased. The finding that GH replacement in men with abdominal obesity can diminish the negative metabolic consequences of visceral obesity suggests that low levels of this hormone are of importance for the metabolic aberrations associated with visceral/abdominal obesity.
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PMID:Growth hormone and the metabolic syndrome. 1044 70

Long-term prognosis in kidney transplant recipients depends on multiple factors. The purpose of this study was to quantify the influence of hyperuricemia and hyperglycemia (elements of the so-called 'syndrome X', i.e., a combination of metabolic disorders like hyperuricemia, diabetes mellitus, hyperlipidemia, and hypertension) on organ function in 350 kidney transplant recipients who had received 375 kidney transplants up to 1990 and in whom sex, age of recipient and donor, nephrologic disease, duration of dialysis, human leukocyte antigen (HLA) classification, and duration of transplant ischemia had been well matched. We found the influence of hyperuricemia on graft survival to be statistically significant (p < or = 0.05), while a statistically significant correlation between hyperglycemia and graft survival could not be detected in the present study. The transplant survival rates 2, 4, and 5 yr post-kidney-transplantation were 96.7, 80.7, and 78.7 in normogylcemic patients vs. 96.9, 85, and 82.7% in hyperglycemic ( > 100 mg,dL) kidney transplant recipients (p > 0.05). Transplant survival in hyperuricemic patients (male, > 8 mg dL; female, > 6.2 mg/dL) 2, 4, and 5 yr post-transplantation was significantly reduced (92.2, 70.6, and 68.8% vs. 98.1, 85.6, and 83.3%), as compared to normouricemic recipients. A combined presence of both hyperuricemia and hyperglycemia probably influencing the prognosis post-kidney-transplantation failed to reach the level of statistical significance. We found a significant correlation between age of recipients and plasma glucose (p < or = 0.01) and between serum uric acid concentrations and diuretic therapy (p < or = 0.05) and gender (p < or = 0.(5). In conclusion, hyperuricemia after kidney transplantation seems to reduce graft survival, whereas an influence of the carbohydrate metabolism has to be denied.
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PMID:Influence of hyperglycemia and hyperuricemia on long-term transplant survival in kidney transplant recipients. 1051 17

Insulin resistance describes an impaired biological response to insulin, which underpins the development of type 2 (non-insulin-dependent) diabetes mellitus (T2DM). Initially, insulin resistance causes a compensatory hyperinsulinaemia, which gives way to pancreatic beta-cell failure. Insulin resistance and hyperinsulinaemia conspire together in the development of a diverse collection of risk factors for coronary heart disease, namely obesity, T2DM, dyslipidaemia, hypertension, atherosclerosis, and a pro-coagulant state. This collection of factors is commonly found in T2DM patients, and is recognised as the Insulin Resistance Syndrome or Syndrome X. By targeting insulin resistance as a treatment strategy for T2DM, it should be possible to broaden the potential benefits, so that improved glycaemic control is complemented with improvements to other components of Syndrome X. At present, metformin and thiazolidinediones are the only therapies for T2DM that directly address aspects of insulin resistance. Increasing awareness of the clinical implications of insulin resistance, and increasing knowledge of the cellular basis of insulin resistance, provide the rationale and a means for developing an anti-insulin resistance approach to the treatment of T2DM.
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PMID:Insulin resistance and antidiabetic drugs. 1053 41

It has been increasingly recognised in recent years that type 2 (non-insulin-dependent) diabetes is part of a cluster of cardiovascular risk factors known as the metabolic syndrome, but also endorsed with such names as the deadly quartet, syndrome X and the insulin resistance syndrome. Atherosclerosis is the most common complication of type 2 diabetes among Europeans, and coronary artery, cerebrovascular and peripheral vascular disease are 2 to 5 times more common in people with this condition than in those without diabetes. These observations indicate that the treatment of type 2 diabetes requires agents that do more than simply lower blood glucose levels, and a therapy with both antihyperglycaemic effects and beneficial effects on dyslipidaemia, hypertension, obesity, hyperinsulinaemia and insulin resistance is likely to be most useful. In this respect, metformin has an important and established role: this drug has been shown to lower blood glucose and triglyceride levels, and to assist with weight reduction and to reduce hyperinsulinaemia and insulin resistance. Studies in the Israeli sand rat, Psammomys obesus, have indicated hyperinsulinaemia/insulin resistance to be the initial and underlying metabolic disorder in obesity and type 2 diabetes. Thus, the well established effect of metformin in reducing insulin resistance makes this drug an excellent candidate for the prevention of progression of impaired glucose tolerance to type 2 diabetes, and for the reduction of mortality associated with cardiovascular disease.
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PMID:Clinical efficacy of metformin against insulin resistance parameters: sinking the iceberg. 1057 21

Type 2 diabetes mellitus has emerged as an important condition of older patients in which both microvascular and macrovascular complications are a common cause of morbidity and mortality. In contrast to type 1 diabetes mellitus, this endocrinopathy is clustered in minority populations and has both strong genetic and environmental factors that influence disease manifestation. A number of physiological alterations of glucose metabolism including hepatic overproduction of glucose, and reduced glucose utilization by peripheral tissues as a result of insulin resistance contribute to the development of the metabolic manifestations of this disease. Ultimately, pancreatic failure and reduced insulin secretion lead to hyperglycemia and the diabetic state. Frequently, many of these metabolic manifestations, or what has been termed Syndrome X, antecede the development of overt diabetes by many years. This syndrome is manifest clinically by such cardiovascular risk factors as hypertension, dyslipidemia, and coagulation abnormalities. This abnormal metabolic milieu contributes to the high prevalence of macrovascular complications including coronary artery disease as well as more generalized atherosclerosis. Microvascular complications have only more recently been recognized as an important and frequent complication of type 2 diabetes. Among the elderly and minority populations, this has become the single most important cause of end-stage renal failure that necessitates renal replacement therapies. The outcome for these patients on hemodialysis, the modality most frequently selected, is poor, with the majority of these patients dying of cardiovascular causes. Unfortunately, interventional strategies to reduce or prevent the microvascular and macrovascular complications have only recently received the needed attention and will require considerable effort and resources to improve the clinical outcomes and life expectancies for these patients.
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PMID:Diabetes in the elderly population. 1067 16

Insulin resistance syndrome (IRS), also termed syndrome X, is a distinctive constellation of risk factors for the development of type 2 diabetes mellitus and cardiovascular disease. The syndrome's hallmarks are glucose intolerance, hyperinsulinemia, a characteristic dyslipidemia (high triglycerides; low high-density lipoprotein cholesterol, and small, dense low-density lipoprotein cholesterol), obesity, upper-body fat distribution, hypertension, and increased prothrombotic and antifibrinolytic factors. Insulin resistance, caused by a complex of genetic and environmental influences, is now recognized not just as a mechanism contributing to hyperglycemia in type 2 diabetes, but also as an early metabolic abnormality that precedes the development of overt diabetes. The clinical definition of insulin resistance is the impaired ability of insulin (either endogenous or exogenous) to lower blood glucose. In some insulin-resistant individuals, insulin secretion will begin to deteriorate under chronic stress (glucose toxicity) and overt diabetes will result. If not, individuals will remain hyperinsulinemic, with perhaps some degree of glucose intolerance, together with other hallmarks of the IRS. The statistical correlation between hypertension and impaired glucose tolerance is clear, although the mechanism is not yet fully understood. Epidemiologic evidence of insulin resistance as an independent risk factor for atherosclerosis and coronary heart disease (CHD) completed the evolving concept of IRS as the common soil for the development of both diabetes and CHD. No single laboratory test exists for diagnosis of IRS. Rather, IRS remains a clinically evident syndrome that can be suspected on the basis of physical and laboratory findings. This identifies individual patients whom the clinician should screen for associated comorbid conditions, aggressively control cardiovascular risk factors, and tailor drug therapy for optimal benefit. This article provides practical guidelines to achieve these goals and specific strategies to ameliorate cardiovascular and metabolic risk in the IRS.
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PMID:Clinical implications of the insulin resistance syndrome. 1068 70

In 1988, Reaven used the term syndrome X to describe a relation between several disorders including hypertension, dyslipidemia, impaired glucose tolerance, obesity, and coronary heart disease. Despite a number of studies dealing with syndrome X, its genetic basis remains poorly understood. Regarding the complexity of this syndrome, it is important to use animal models developing the traits of the disease. Here we show a genetic dissection of syndrome X in the WOKW rat, an animal model of genetically determined syndrome X. We found a major quantitative trait locus (QTL) for glucose metabolism on chromosome 3 and further QTLs influencing obesity and body weight on chromosomes 1 and 5. Genetic determinants of dyslipidemia were mapped to chromosomes 4 and 17. In addition, suggestive linkage for serum insulin was found on chromosome 1 to the region previously shown to be associated with type-1 diabetes mellitus. This is the first study demonstrating independent genetic factors influencing traits of the syndrome X in the rat as well as a possible genetic relationships between syndrome X and diabetes mellitus. Moreover, regarding the close similarities between WOKW rat and human syndrome X, the study could help in a search of genetic factors involved in this complex metabolic disorder in human.
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PMID:Genetic dissection of the syndrome X in the rat. 1072 Apr 72

HIV infection induces an early decrease of cholesterol and a late increase of triglycerides (TG) with a reduction of HDL. These changes are proportional with the lowering of CD4, which reflects the infection's severity. Both the increase of TG synthesis and the decrease of TG catabolism, in relation with a reduction of lipoprotein lipase activity, are responsible of these changes. Moreover, LDL catabolism is enhanced by macrophage scavenger receptors, due to a high proportion of small, dense LDL which are more easily oxidized. Many cytokines (interferon alpha, interleukins, TNF) play probably a pathogenic role in the dyslipidemia. Some HIV patients who received antiproteases may develop lipodystrophy with central obesity, insulino-resistance, glucose intolerance and sometimes diabetes (like in syndrome X). Other patients present a cushingoid, buffalo hump. This complication may be observed also with antiretroviral treatment other than antiproteases. The physiopathology of these findings could be in relation with structural homologies between antiproteases and some important proteins, involved in lipid and adipocyte metabolism. Cardiovascular risk linked to these perturbations is evident. The treatment is not different from the treatment for seronegative, hyperlipidemic patients: struggle against risk factors, diet advices, fibrates or statins. The antiproteases bring huge contribution to the prognosis of AIDS patients but the risk of cardiovascular complications could impair this therapeutic progress. So, it is essential to understand the pathogeny of these complications in order to discover new antiproteases, without these adverse side effects.
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PMID:[Lipids and AIDS]. 1074 83

Adipose tissue only accounts for a relatively small proportion (< 10%) of the peripheral glucose utilization in response to insulin. However, the fat cells may still play an important role in insulin resistance and Syndrome X through, for instance, its endocrine functions (production of leptin, TNF alpha, PAI-1, etc.) and involvement in lipid metabolism (FFA release and hydrolysis of triglycerides). The fat cells are also highly sensitive to insulin and may thus be used to elucidate molecular mechanisms for insulin resistance in man. Examinations of the intracellular signaling mechanisms for insulin in fat cells from individuals with Type 2 diabetes revealed markedly lower insulin-stimulated PI3-kinase activity. This was due to a pronounced reduction in the cellular expression of the docking protein, IRS 1, whereas expression of IRS 2 was normal. However, IRS 2-associated PI3-kinase activity was only approximately one-third of that found to be associated with IRS 1 in normal cells. Downstream activation and serine phosphorylation of PKB/Akt by insulin were also markedly reduced in Type 2 diabetes. Furthermore, the dose-response curve for this effect of insulin was similar to that for glucose transport in both normal and Type 2 diabetic cells. Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes. We also examined whether an attenuated activation of PI3-kinase by insulin can be seen in non-diabetic insulin-resistant states. Approximately 30% of healthy subjects with at least two first-degree relatives with Type 2 diabetes exhibited perturbations in IRS-1 expression and signaling. These individuals were characterized by insulin resistance as well as other markers of Syndrome X. Thus, impaired IRS-1 expression and downstream signaling events in fat cells in response to insulin are associated with insulin resistance and Syndrome X.
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PMID:Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes. 1084 57


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