Insulin resistance, skeletal muscle

Leighton B, Cooper GJS. Pancreatic amylin and calcitonin gene related peptide causes resistance to insulin in skeletal muscle iu vitro. Nature 1988 335 632-635. 

Ann Sulin, however, has type 2 disease. In this form of the disorder, the cause of glucose intolerance is more complex, involving at least a delay in the release of relatively appropriate amounts of insulin after a meal combined with a degree of resistance to the actions of insulin in skeletal muscle and adipocytes. Excessive hepatic gluconeogen-esis occurs even though blood glucose levels are elevated. 

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... 

The exact mechanism by which PPARy ligands affect insulin resistance (improved glucose uptake by peripheral tissues, most notably skeletal muscle) remains unclear. 

Insulin is a powerful anabolic hormone but it is unlikely that insulin deficiency causes skeletal muscle atrophy by direct action on muscle fibers (as opposed to neurogenic atrophy) except in chronic untreated cases. There is however a close parallel between the catabolic states induced by glucocorticoid excess and by insulin deficiency. Moreover, impaired insulin action is implicated in other endocrine myopathies as a contributory cause of muscle wasting. Both acromegaly and thyrotoxicosis are associated with insulin resistance due to a postreceptor defect, and secondary hyperparathyroidism due to hypophosphatemia also gives rise to insulin insensitivity. 

The entry rate of glucose into red blood cells is far greater than would be calculated for simple diffusion. Rather, it is an example of facilitated diffiision (Chapter 41). The specific protein involved in this process is called the glucose transporter or glucose permease. Some of its properties are summarized in Table 52-3-The process of entry of glucose into red blood cells is of major importance because it is the major fuel supply for these cells. About seven different but related glucose transporters have been isolated from various tissues unlike the red cell transporter, some of these are insidin-dependent (eg, in muscle and adipose tissue). There is considerable interest in the latter types of transporter because defects in their recruitment from intracellular sites to the surface of skeletal muscle cells may help explain the insulin resistance displayed by patients with type 2 diabetes mellitus. 

Manco, M., Mingrone, G., Greco, A. V., Capristo, E., Gniuli, D., De Gaetano, A., Gasbarrini, G. Metabolism 49, 2000, 220-224. Insulin resistance directly correlates with increased saturated fatty acids in skeletal muscle triglycerides. 

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. 

Lipid metabolism and skeletal muscle insulin resistance... 

The prevalence of Type 2 Diabetes (T2D) is increasing world-wide and considered one of the main threats to human health in the 21st century. In 2010, 221 million patients are expected to be diabetic (compared to 151 million in the year 2000). The increase in diabetes prevalence is considered to be secondary to changes in human lifestyle accompanied by physical inactivity and unlimited food supply. Skeletal muscle insulin resistance, defined as the reduced response of skeletal muscle to a given dose of insulin, is a common finding in patients with type 2 diabetes mellitus and can be found before the onset and predict the development of the disease. Several factors determine skeletal muscle insulin sensitivity and among others alterations in fatty acid metabolism have been proposed. ... 

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. 

As a conclusion of these preliminary results of comparative studies using small cohorts of more or less matched subjects, a potential role of IMCL in the pathogenesis of skeletal muscle insulin resistance has been stated. However, it has to be taken into consideration that physical fitness as well as confounding parameters for obesity and probably genetic predispositions might also influence the individual IMCL content and insulin sensitivity. 

The increased oxidation of fatty acids decreases the rate of glucose utilisation and oxidation by muscle, via the glucose/fatty acid cycle, which accounts for some of the insulin resistance in trauma. An additional factor may be the effect of cytokines on the insulin-signalling pathway in muscle. An increased rate of fatty acid oxidation in the liver increases the rate of ketone body production the ketones will be oxidised by the heart and skeletal muscle, which will further reduce glucose utilisation. This helps to conserve glucose for the immune and other cells. 

As mentioned above, insulin secretion by p-cells of the pancreatic islets increases in response to increasing glucose concentrations. In the insulin-resistant state, despite insulin concentrations that are increased two- to three-fold, there is an excessive rate of liver-glucose production. In addition, skeletal muscle glucose disposal in response to insulin is markedly decreased. This results in increased glucose concentrations. This inability to control glucose concentrations, is referred to as impaired glucose tolerance and may ultimately lead to type-2 diabetes. 

Hamrin K, Henriksson J. Interstitial glucose concentration in insulin-resistant human skeletal muscle influence of one bout of exercise and of local perfusion with insulin or vanadate. European Journal of Applied Physiology 2008, 103, 595-603. 

Weinstein, S. P., Holand, A., O Boyle, E., and Haber, R. S. (1993). Effects of Thia-zolidinediones on Glucocorticoid-Induced Insulin Resistance and GLUT4 Glucose Transporter Expression in Rat Skeletal Muscle. Metabolism 42, 1365-1369. 

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