Insulin muscles

The increase in insulin concentrations produced by sulphonylureas lowers blood glucose concentrations through decreased hepatic glucose output and increased glucose utilisation, mostly by muscle ( insulin, insulin receptor). 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

Adiponectin Endocrine Liver skeletal muscle Insulin-sensitization... 

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. 

Specific activation or inhibition Transport of glucose can be increased or decreased by specihc compounds insulin increases the transport whereas phloridzin, a plant glycoside, inhibits glucose transport by muscle. Insulin increases glucokinase activity in liver, whereas a plant sugar, mannoheptulose, inhibits glucokinase activity. Hexokinase is inhibited by its product, glucose 6-phosphate. 

Figure 6.14 An increase in the rate of glucose transport, in response to insulin, which increases the rate of glycolysis. This is achieved by increasing the concentrations of all the intermediates in the pathway, indicated by the arrows adjacent to the intermediates. Insulin, physical activity or a decrease in the ATP/ADP concentration ratio all result in increased rates of glucose transport in skeletal muscle. Insulin increases the rate about fivefold, physical activity about 50-fold.

Figure 6.19 Regulation of the synthesis of glycogen from glucose in liver and muscle. Insulin is the major factor stimulating glycogen synthesis in muscle it increases glucose transport into the muscle and the activity of glycogen synthase, activity which is also activated by glucose 6-phosphate but inhibited by glycogen. The latter represents a feedback mechanism and the former a feedforward. The mechanism by which glycogen inhibits the activity is not known. The mechanism for the insulin effect is discussed in Chapter 12.

Malonyl-CoA inhibits fatty acid oxidation in muscle. Insulin increases the concentration of malonyl-CoA in muscle and so inhibits fatty acid oxidation. A fall in... 

The bottom line for any of the above disorders is that insulin action is lost. Insulin is the primary hormone that regulates the metabolism of glucose in its conversion to the storage of carbohydrate—glycogen stored in the liver and muscles. Insulin also... 

Cusi, K., S. Cukier, R.A. DeFronzo, M. Torres, F.M. Puchulu, and J.C.P. Redondo. 2001. Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes. J. Clin. Endo. Metabol. 86 1410-1417. 

We have observed that suppression of elevated FFA levels is a very rapid (less than 12 hour) response to treatment of insulin-resistant rats with PPARy agonists (T. Doebber, unpublished data). Since PPARy agonists are known to promote adipose tissue uptake and storage of fatty acids, it is plausible that this effect constitutes a major mechanism of insulin sensitization, whereby elevated FFAs—a known cause of hepatic and muscle insulin resistance—can be alleviated. An additional effect of in vivo PPARy activation, shown to occur in rats, was an increase in the number of small white adipocytes, along with a relative shift in the size of visceral (decreased) versus subcutaneous (increased) adipose depots (73). This has important implications because visceral adiposity and larger fat cells are both associated with insulin resistance. 

In addition, there are numerous effects of insulin, generally anabolic, not mediated through its well-known effects on glucose transport. For example, in muscle, insulin decreases glycogenolysis and proteolysis. Lipolysis is inhibited by insulin in adipocytes. The effect of insulin on hepatic tissue is to promote increased glycogen production and protein synthesis and to inhibit glycogenolysis, proteolysis, lipolysis, and gluconeogenesis (Fig. 10-1). 

Insulin is a major regulator of potassium homeostasis and has multiple effects on sodium pump activity. Within minutes of elevated insulin secretion, pumps containing alpha-1 and 2 isoforms have increased affinity for sodium and increased turnover rate. Sustained elevations in insulin cause up-regulation of alpha-2 synthesis. In skeletal muscle, insulin may also recruit pumps stored in the cytoplasm or activate latent pumps already present in the membrane. 

The quest for the molecular mechanisms of chromium in relation to diabetes continues (6,7). Chromium picolinate may aid muscle insulin sensitivity, and initial reports suggest that it is an effective therapy for type 2 diabetes (8). Chromium picolinate supplementation alone does not improve insulin sensitivity (9). 

Insulin is believed to influence protein. synthesis at the ribosomal level in various tissues. In skeletal muscles, in.sulin predominantly stimulates translation by incrcasingihc rale of initiation of protein synlhe.sis and the numbernfrilxi-sonies. In the liver, the predominant effect is on inmscri v lion. In cardiac muscles, insulin is believed to decrease the rate of protein degradation. 

Kelley DE, Williams KV, Price JC, et al. Plasmafatty acids, adiposity and variance of skeletal muscle insulin resistance in type 2 diabetes mellitus. J Clin Endocrinol Metab 2001 86 5412-5419. 

Caroni, P, Schneider, C., Kiefer, M.C. and Zapf, J. (1994) Role of muscle insulin-like growth factors in nerve sprouting suppression of terminal sprouting in paralyzed muscle by IGF binding protein 4. J. Cell. Biol. 125 893-902. 

GLUT 4 Adipose tissue Skeletal muscle Heart muscle Insulin-sensitive transporter. In the presence of insulin the number of GLUT 4 transporters increases on the cell surface. A high-affinity system... 

Muscle Insulin stimulates glycogen synthesis and protein synthesis. Glucose transport into muscle cells is facilitated by insertion of additional GLUT 4 transport molecules into cell walls. 

Ryder, J.W., Portocarrero, C.P., Song, XM., Cui, L., Yu, M., Combatsiaris, T., Galuska, D., Bauman, D ., Barbano, DM., Charron, M J., Zierath, JR., and Houseknecht, Kl. (2001) Isomer-Specific Antidiabetic Properties of Conjugated Linoleic Acid. Improved Glucose Tolerance, Skeletal Muscle Insulin Action, and UCP-2 Gene Expression, Diabetes 50,1149-1157. 

In vitro the only effect of the hormone which has been substantiated is its stimulating action on glucose uptake by muscle (insulin-like action Ottaway, 1951 Park et al., 1952). This action of the hormone may also be seen in acute experiments in vivo under suitable conditions. With more prolonged treatment in vivo the hormone may induce insensitivity to the ae-tion of insulin in normal and in hypophysectomized rats and defective... 

Bauman, D.M. Barbano, M.J. Charron, et al. Isomer-Specific Antidiabetic Properties of Conjugated Linoleic Acid. Improved Glucose Tolerance, Skeletal Muscle Insulin Action, and UCP-2 Gene Expression. Diabetes 50 1149-1157 (2001). 

Villee and his associates [116,117] also studied pyruvic acid dissimilation and usage as well as lactic acid accumulation in the presence and absence of insulin. Many of these experiments were performed in animals submitted to different hormonal treatments. Whereas in normal muscle insulin increases the amount of pyru-... 

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