Muscle insulin effect

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.

Mechanism of Action An antidiabetic that improves target-cell response to insulin without increasing pancreatic insulin secretion. Decreases hepatic glucose output and increases insulin-dependent glucose utilization in skeletal muscle. Therapeutic Effect Lowers blood glucose concentration. 

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is a very rapid (less than 12 hour) response to treatment of insulin-resistant rats with PPARy agonists (T. Doebber, unpublished data).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. 

Insulin effects on glucose transport in muscle and adipose tissue... 

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. 

Insulin action is initiated by binding of the hormone to its specific receptor at the plasma membrane. This induces a broad spectrum of distinct effects at a number of different target cells, predominantly in muscle, liver and fat. These cellular insulin effects can be divided into four categories ... 

Target tissues for the enhancement of insulin effects and/or direct effects of sulphonylureas are adipose tissue, skeletal muscle and liver. 

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... 

This insulin effect of growth hormone observed in vivo may also explain some of the discrepancies observed between in vivo and in vitro effects of growth hormones on glucose uptake by muscle. Whereas growth hormone inhibits glucose uptake in vitro, in vivo its inhibitory effect is compensated for by the insulin secreted as a result of liver gluconeogenesis. 

The administration of growth hormone to hypophysectomized animals relieves the insulin hypersensitivity and may even create some insulin resistance. In addition to its insulinic effect, growth hormone seems to have another effect on muscle that manifests itself several hours after the administration of the hormone—decreased glucose uptake and decreased insulin sensitivity. The time lapse between the injection and the manifestation suggests that the effect may result from metabolic by-products of growth hormone. 

Garlick, P.J. and Grant, I., Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Effect of branched-chain amino acids, Biochem J, 254, 579, 1988. 

Saccomani, M.P., Bonadonna, R., Bier, D.M., De Fronzo, R.A., and Cobelli, C. 1996. A model to measure insulin effects on glucose transport and phosphorylation in muscle a three-tracer study. Am. ]. Physiol. 33 E170-E185. 

P-Adrenoceptors have been subdivided into P - and P2-adrenoceptors. A third subset called nontypical P-adrenoceptors or P -adrenoceptors have been described but are stiU the subject of debate. In terms of the interactions with various subsets of P-adrenoceptors, some antagonists are nonselective in that they antagonize the effects of activation of both P - and P2-adrenoceptors, whereas others are selective for either P - or P2-adrenoceptors. P - and P2-adrenoceptors coexist in almost all organs but generally, one type predominates. The focus herein is on the clinically relevant P -adrenoceptor-mediated effects on heart and on P2-adrenoceptor-mediated effects on smooth muscles of blood vessels and bronchioles, the insulin-secreting tissue of the pancreas, and skeletal muscle glycogenolysis for side effects profile (36). 

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