Insulin receptor defects

Non-insulin-dependent diabetes is a milder disease than the insulin-dependent form. Its onset is slow, often occurring after the age of 40. In contrast to type I patients, most individuals with type II diabetes have normal or often elevated blood levels of insulin. For a variety of reasons, type II patients are resistant to insulin. The most common cause of insulin resistance is the down-regulation of insulin receptors. (Defective insulin receptors or improper insulin receptor processing also causes type II diabetes in some patients.) Approximately 85% of type II diabetics are obese. Because obesity itself promotes tissue insensitivity to insulin, individuals who are prone to this form of diabetes are at risk for the disease when they gain weight. 

Insulin resistance is an important factor in non-insulin-dependent diabetes, and scientists are searching for the causes of insulin resistance. They have identified two possibilities. The first is that there could be a defect in the insulin receptors on cells. Like an appliance that needs to be plugged into an electrical outlet, insulin has to... 

NIDDM is strongly associated with obesity,dd and dieting and exercise often provide adequate control of blood glucose. Sulfonylurea drugs such as the following induce an increase in the number of insulin receptors formed and are also widely used in treatment of the condition.66 These drugs bind to and inhibit ATP-sensitive K+ channels in the P cell membranes. A defect in this sulfonylurea receptor has been associated with excessive insulin secretion... 

We have also come to understand that many complex diseases such as diabetes, polycystic ovary syndrome,385 Crohn s disease (inflammatory bowel disease),386 and schizophrenia are in fact multiple diseases. Diabetes is a syndrome that can arise from causes such as defective insulin receptors or defective glucose transporters or from as yet unknown metabolic problems (Chapter 17).387 Many cancers have a... 

Clinical Syndromes Associated with Cellular Defects in Insulin Receptor... 

A number of disorders are associated with the development of insulin resistance. Although some cases are due to autoimmune responses such as the development of anti-insulin or anti-insulin receptor antibodies, insulin resistance often results from defects at the cellular level in the insulin receptor or in postreceptor function. 

Kulkarni, R.N., Bruiting, J.C., Winnay, J.N., Postic, C., Magnuson, M.A., and Kahn, C.R. 1999. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96 329-339. 

Patients with Type II diabetes are often obese. Type II diabetes is frequently accompanied by target organ insulin resistance that limits responsiveness to both endogenous and exogenous insulin. In some cases, insulin resistance is due to a decreased number or mutations of insulin receptors. However, an as yet undefined defect in the events that occur after insulin binds to its receptor is believed to account for resistance in most patients. 

Whilst much is known about the physiological actions of insulin and the defects in its synthesis that occur in Type-I diabetes, it is only recently that we have begun to appreciate the nature and properties of the insulin receptor itself. 

Several studies showed that AA, EPA, and DHA are essential not only for brain growth and development but also to modulate the synthesis, release, and action of various neuropeptides. Because the brain is rich in AA, EPA, and DHA, one important function of these fatty acids in the brain could be to ensure the presence of an adequate number of insulin receptors the insulin receptor number depends on the amount of PUFAs incorporated in the cell membrane phospholipids (35-42). Thus a defect in... 

Chronic excessive nutrient intake leads to the deposition of fat, in not only its normal storage site, which is the adipose tissue, but also in liver and skeletal muscle. Nutrient excess also triggers an inflammatory response, with the release of inflammatory cytokines [tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and CRP]. These inflammatory mediators, along with the intracellular accumulation of lipid metabolites, lead to impaired insulin receptor signaling and defective metabolism in skeletal muscle and liver (37, 38). Nutrient excess also damages cells by generating reactive oxygen species, which results... 

Leprechaunism is a rare and fatal congenital syndrome of extreme insulin resistance resulting from inherited defects of the insulin receptor. Associated growth retardation and multiple somatic abnormalities may be due to coexistent resistance to other growth factors. 

The reduction in receptors may be a secondary consequence of hyper-glycaemia and hyperinsulinaemia and does not relate well to the impairment of insulin action. It therefore seems unlikely that a defect in the number or affinity of insulin receptors is a primary abnormality in NIDDM. However, it is possible that an abnormality of the portion of the insulin receptor projecting into the cell (/3-subunit) could contribute to insulin resistance. Tyrosine kinase activity of the /3-subunit appears to be intimately involved in mediating insulin action this tyrosine kinase activity is reduced in some animal models of diabetes and there is some evidence that the same is true in human NIDDM. 

The majority of Type-II diabetics are obese (II b) and suffer predominantly from an impairment of insulin action due to heterogeneous mechanisms. Decreased insulin responsiveness of peripheral tissues may be due to (1) a post-receptor defect with secondary hyperinsulinaemia, (2) down-regulation of the number of insulin receptors, or (3) the glucotoxic effect of hyper-glycaemia caused by accelerated hepatic glucose production. An additional impairment of insulin secretion is present, however, only in non-obese Type-II-a diabetics. 

In NPC mouse hepatocytes, a lipid imbalance was found, which increases lipid ordering in the plasma membrane, alters the properties of lipid rafts, and leads to defective function of the raft-associated plasma membrane insulin receptor (Vainio et al. 2005). This mechanism may participate in the pathogenesis of NPC disease and contribute to insulin resistance (Fonseca 2007) in other disorders of lipid metabolism. 

Vainio S, Bykov I, Hermansson M, et al. (2005) Defective insulin receptor activation and altered lipid rafts in Niemann-Pick type C disease hepatocytes. Biochem J 391(Pt 3) 465 72... 

S. J. Hunter and T. Garvey Insulin action and insulin resistance Diseases involving defects in insulin receptors, signal transduction, glucose transport effector system. American Journal of Medicine 105, 331 (1998). 

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