Insulin resistance and

Diabetes mellitus is defined as hyperglycaemia (fasting > 7 mM and/or 2 h postprandial >11.1 mM) due to absolute or relative lack of insulin. The most common forms are type 1 diabetes (prevalence 0.25%), with absolute lack of insulin, and type 2 diabetes (prevalence 4-6%) which is due to the combination of insulin resistance and insufficient insulin secretion. 

Thiazolidinediones (PPARy-agonists) Thiazolidine-diones ( pioglitazone, rosiglitazone) lower blood glucose levels in animal models of insulin resistance and also in insulin resistant patients. They are agonists of the peroxisome proliferator-activated receptor y (PPARy). Because they enhance the effect of insulin and reduce serum insulin levels in insulin resistant patients, thiazolidinediones are usually referred to as insulin sensitizers . 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

Disorders of lipoprotein metabolism involve perturbations which cause elevation of triglycerides and/or cholesterol, reduction of HDL-C, or alteration of properties of lipoproteins, such as their size or composition. These perturbations can be genetic (primary) or occur as a result of other diseases, conditions, or drugs (secondary). Some of the most important secondary disorders include hypothyroidism, diabetes mellitus, renal disease, and alcohol use. Hypothyroidism causes elevated LDL-C levels due primarily to downregulation of the LDL receptor. Insulin-resistance and type 2 diabetes mellitus result in impaired capacity to catabolize chylomicrons and VLDL, as well as excess hepatic triglyceride and VLDL production. Chronic kidney disease, including but not limited to end-stage... 

Clinical features NCEPATPIII criteria S3 of the criteria below WHO criteria impaired glucose regulation/insulin resistance and >2 other criteria... 

TNF is a pleiotropic cytokine exerting a wide range of cellular responses, that affect biological processes such as lipid metabolism, coagulation, and insulin resistance and the function of endothelial cells. As a major proinflammatory cytokine TNF is also involved in progression of diseases like cancer, Alzheimer, Diabetes type II, cardiovascular, pulmonary or neurological disorders, and many autoimmune diseases. Blocking the action of TNF clearly reduces its inflammatory potential on various autoimmune disorders like Crohn s disease, rheumatoid arthritis (RA), and psoriasis. 

Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Qin Invest 116 1494-1505 Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410 988-994... 

Overactivation of the sympathetic nervous system (SNS) may also play a role in the development and maintenance of primary hypertension for some individuals. Among other effects, direct activation of the SNS may lead to enhanced sodium retention, insulin resistance, and baroreceptor dysfunction.9 Regardless of which mechanism(s) underlie the role the SNS may play in the development of primary hypertension, the SNS remains a target of many antihypertensive agents. 

Type 2 DM is the most prevalent form of diabetes and accounts for approximately 90% to 95% of all diagnosed cases. Type 2 DM is usually slow and progressive in its development and often is preceded by pre-diabetes. Rising blood glucose levels result from increasing insulin resistance and impaired insulin secretion leading to a situation of relative insulin deficiency. 

Increased insulin resistance and increased prevalence of impaired glucose tolerance. 

Mutations in GK (Hx IV) causes maturity-onset diabetes of the young (MOD Y), a form of non-insulin-dependent diabetes mellitus (NIDDM) characterized by onset before 25 years of age and an autosomal dominant inheritance (PI 2). This suggests that the mutations in other forms of Hx may also contribute to the development of NIDDM. Among them, Hx II is a particularly attractive candidate, although this isozyme is not expressed in red blood cells. Hx II has been analyzed extensively in the muscle of prediabetic insulin-resistant individuals. But studies have shown that Hx II mutation alone is unlikely to have a significant role in the development of peripheral insulin resistance and NIDDM (L6). 

Aerobic exercise can improve insulin resistance and glycemic control in most patients and may reduce cardiovascular risk factors, contribute to weight loss or maintenance, and improve well-being. Exercise should be started slowly in previously sedentary patients. Older patients and those with atherosclerotic disease should have a cardiovascular evaluation prior to beginning a substantial exercise program. 

For cardiovascular risk detecting and correcting factors like hypertension, obesity, insulin resistance, and type 2 diabetes or abnormal lipid profile, according to preestablished guidelines, can dramatically diminish the number of events. 

Because of the polyfactorial nature of disease states, such as obesity, type 2 diabetes, and Metabolic Syndrome, it is expected that drugs targeting the lipid synthesis and metabolism pathways will be used in the context of combination therapy [7]. Pre-clinical and clinical results to date indicate that pronounced efficacy could be achieved toward the management of associated lipid levels and insulin resistance, and thus, investigation in these areas provides significant promise. 

The production of both anabolic sex hormones and growth hormone decreases in aging and the result is muscle loss. Also the loss of neural motor cells gives rise to atrophy of the muscles. In the aging process an increased inflammatory activity can be seen and it causes degeneration of muscle tissue through insuline resistance and activation of protein breakdown enzymes. The increased inflammatory activity is due to both normal aging as well as the presence of multiple chronic diseases (Dutta 1997. 

The following sections summarize several studies concerning the interrelationship between IMCL and insulin resistance and the regulation of IMCL, and it reviews the experiences of different working groups in the field. 

The role of IMCL in the pathogenesis of insulin resistance and type 2 diabetes... 

A brief overview about the fundamental principles of the pathogenesis of skeletal muscle insulin resistance and its contribution to the development of type 2 diabetes mellitus is given in the following. Priority is given to the role of lipid metabolism, which is the main field of the reported spectroscopic studies. Furthermore, the technique of euglycemic hyperinsulinemic glucose clamp is described allowing determination of the individual insulin sensitivity of musculature. The role of IMCL in insulin resistance of the skeletal muscle is discussed. 

To gain further insight into the mechanisms involved in defective insulin-stimulated glucose uptake in skeletal muscle of insulin-resistant subjects, the possible role of IMCL in the pathogenesis of skeletal muscle insulin resistance and type 2 diabetes mellitus was explored by comparing insulin sensitivity (GIR) and IMCL content of insulin-resistant and insulin-sensitive offsprings of patients with type 2 diabetes. Twenty-six healthy subjects were included in the first study, 13 of them classified as insulin-sensitive and further 13 as insulin-resistant. Metabolic and anthropometric data are given in Table 4. 

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