Biological Actions of Insulin

The mechanism of action of insulin is complex and can be divided into three parts. The first part is the binding of insulin to its receptor on the cell membrane the second consists of postreceptor events and the third consists of biological responses. 

Model of the insulin receptor. The receptor contains two a- and two /1-subunits, held together by disulfide linkages. The a-subunits are entirely extracellular and contain the insulin binding site, The jS-subunits have transmembrane and intracellular domains. Both autophosphorylation and tyrosine kinase activity reside in the -subunit and are markedly enhanced upon insulin binding. 

The importance of the biological actions of insulin on target cells is underscored by defects in any of the five steps involved in receptor function. These steps are analogous to the scheme described for LDL receptor gene defects (Chapter 20). Mutations can lead to  

Examples of disorders caused by mutations in the insulin receptor gene are leprechaunism and type A insulin resistance. A severe form of leprechaunism is due to mutations in both alleles of the insulin receptor gene. These patients exhibit insulin resistance, intrauterine growth retardation, and many other metabolic abnormalities. Patients with type A insulin resistance exhibit insulin 

Paracrine regulation of islet cell hormonal secretion. , Stimulation  

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Phosphorylated IRS promotes activation of other protein kinases and phosphatases, reading to biologic actions of insulin. 

Vanadate (VOj or H2VO4 ) was first recognized in 1979 as having insulin mimetic properties [258]. Since then, vanadate and vanadyl (V ) have been shown to mimic most but not all biological actions of insulin in vitro and to lower blood glucose in streptozotocin-treated rats [259, 260]. Vanadate is a potent inhibitor of phosphotyrosine phosphatases, an interesting activity since the insulin receptor is a tyrosine kinase, and some of the actions of insulin have been proposed to take place via autophosphorylation of the insulin receptor and phosphorylation of cellular substrates on tyrosine residues [261]. Some recent developments on the mechanism and the in vivo activity of vanadate and its derivatives are presented here. 

The insulin receptor in rat liver membranes has been found to interact with another membrane glycoprotein that may represent either a non-recognition portion of the receptor oligomer, or an effector molecule related to the biological action of insulin. ... 

Antidiabetic Drugs other than Insulin. Table 2 Tissue expression, ligands, genes activated, and biological actions of the peroxisome proliterator-activated receptor-y (PPARy)... 

Chromium also slimulales fatty acid and cholesterol synthesis from acetate in liver. Thai chromium is an essential cofaclor for the action of insulin on the rat lens was shown by Parkas in 1964. In the absence of the element, no significant insulin effect on glucose utilization of lens can be demonstrated. Chromium supplementation to the donor animals resulls in a significant response of lens tissue to the hormone. Numerous other findings indicate that chromium may play several vital roles in biological systems. 

There is now much interest in the biology of chromium,1086"1088 which has been suggested to be involved not only in the action of insulin, but also in the activation of certain enzymes, and, possibly, the stabilization of nucleic acids. Chromium is also known to be carcinogenic and mutagenic at high concentrations, particularly as chromate. Chromate is reduced in rat liver microsomes to Crm and Crv. Crv is labile and may well be the carcinogenic form.1089... 

In humans and animals, chromium(ni) is an essential nutrient that plays a role in glucose, fat, and protein metabolism by potentiating the action of insulin (Anderson 1981). The biologically active form of chromium, called glucose tolerance factor (GTF), is a complex of chromium, nicotinic acid, and possibly amino acids (glycine, cysteine, and glutamic acid). Both humans and animals are capable of converting... 

Polyclonal antibodies have been prepared against partially purified rabbit mammary gland receptors [42-44], and have been used to demonstrate that the receptors really are involved in mediating the biological actions of prolactin. Anti-receptor antibodies that blocked binding of labelled prolactin were able to inhibit prolactin-stimulated casein synthesis and amino acid transport in rabbit mammary gland explants in vitro [43,45] (Fig. 4). They had no effect on the actions of insulin... 

The 1950s also saw the first evidence that chromium might be a dietary essential. Chromium is believed to promote the action of insulin and thus influences the metabolism of carbohydrates, fats, and proteins. Reports of severe human deficiency of chromium are rare and have been found primarily in people receiving only intravenous feedings for several months or years. Only a few laboratories in the world can accurately measure the amount of chromium in foods and body tissues because chromium is present in stainless steel, which is ubiquitous in analytical laboratories and easily contaminates biological samples. 

At the cellular and molecular level, the binding of insulin to a specific membrane spanning receptor initiates a signal transduction cascade which ultimately produces the biological actions of the hormone. The insulin receptor is a tetrameric protein comprised of two a subunits that bind to insulin and two j3 subunits that are linked by disulfide bonds (55,56), and belongs to a subfamily of receptor typrosine kinases which also includes the insulin-like growth factor I (IGF-I) receptor. The a subunits are extracellularly located, while (S subunits span the membrane and have... 

Mechanism of actions of vanadium in mediating the biological effects of insulin (1998),describing the mechanisms by which vanadate enables its insulin-like effect at the molecular level. 

See also Action of Insulin, Action of Glucagon, Hormonal Regulation of Fuel Metabolism, Neurotransmitters and Biological Regulators... 

The question whether Cr(III) might be toxic is complicated by the fact that it is considered an essential metal. Biologically active Cr(III) facilitates the action of insulin. Chromium deficiency results in impaired glucose tolerance, which can be corrected by the administration of chromium (Anderson et al. 1983 Anderson 1986). Hypoglycemia and its associated symptoms can also be corrected by administration of chromium (Anderson et al. 1987). These effects of chromium supplementation are often associated with improvements in lipid levels, with a net decrease in total lipids and cholesterol and an increase in the ratio of HDL cholesterol to LDL cholesterol (Riales and Albrink 1981 Mossop 1983 Evans 1989 Wang et al. 1989). 

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