Insulin actions/effects

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

Table 11.2 Selected genes whose rate of transcription is altered by binding of insulin to its receptor. In virtually all instances, the ultimate effect is to promote anabolic events characteristic of insulin action. Two-dimensional gel electrophoresis has also pinpointed dozens of proteins of unknown function whose cellular level is altered by insulin...

In summary, results from several studies in to the effects of impaired insulin action can now be linked to CVD. Because of the numbers of people exhibiting sings of insulin resistance, there has been a lot of research effort has gone in to finding suitable therapeutic interventions. One group of drugs in particular, the thiazolidinediones (also known as glitazones) has attracted attention because they both increase insulin sensitivity and help to normalize plasma lipid concentrations. 

Vanadium(III) (118) and vanadium(V) (430) complexes, like vana-dium(IV), enhance insulin action. The vanadium(III) complexes are more resistant to aerial oxidation than expected, so need not be ruled out on that count. However the vanadium(III) and vanadium(V) complexes tested so far have not proved as effective as BMOV (431). 

A paper published six decades ago was the first to draw attention to the possibility that a change in the rate of transport of a molecule across the plasma membrane conld play a role in regulation of both intra- and extracellnlar metabolism that is, the regulation of the blood glncose level and the intracellular metabolism of glucose. The paper was entitlied A hypothesis of insulin action is proposed which attributes to insulin the role of facilitating the rate of transport of some hexoses into the cell as opposed to a direct effect on intracellular metabolism (Levine et al. 1950). 

Diabetes mellitus is characterized by hypergly-caemia and disturbances of carbohydrate, fat and protein metabolism that are associated with absolute or relative deticiencies in insulin action and/or insulin secretion. Although diabetes is an endocrine deficiency or resistance state its major manifestations are those of metabolic disease with wide ranging tissue effects. Insulin resistance does exist in type 2 diabetes, however it is also exists in many individuals without diabetes. It is difficult to accept insulin resistance is the sole determining pathogenic factor in type 2 diabetes. Therefore, it is more appropriate to describe type 2 diabetes as a condition of /3-cell dysfunction in an insulin resistance background. 

II.f.2.2. Sulphonylureas. These drugs stimulate pancreatic /3-cell insulin secretion, reduce serum glucagon levels, potentiate insulin action on target tissues, and improve /3-cell function. The sulphonylureas differ in their potency, extent of hepatic metabolism, hypoglycaemic activity of their metabolites, renal excretion, peak and duration of action, side effects and costs. 

Shechter, Y., G. Eldberg, A. Shisheva, D. Gefel, N. Sekar, S. Qian, R. Bruck, E. Gershonov, D.C. Crans, Y. Goldwasser and others. 1998. Insulin-like effects of vanadium reviewing in vivo and in vitro studies and mechanisms of action. ACS Symposium Series 711 308-315. 

Potential Direct Effects on Insulin Signaling and Insulin Action in Cells... 

GH administered to hypophysectomized rats in vivo causes a drop in the level of plasma non-esterified fatty acids (NEFA), followed by a prolonged increase in this level [89]. This appears to be due to increased utilization of lipids - increased uptake of NEFA by muscle preceding increased output by adipose tissue. As a consequence GH diverts the energy metabolism of the organism from carbohydrate utilization to lipid utilization, and acts to oppose the effects of insulin. Actions of GH on lipid metabolism are particularly marked in man, where GH levels become elevated on fasting and presumably serve to help stimulate the increased lipid utilization seen in this condition. In contrast, in the rat, GH levels fall on fasting. 

Vestri, H., Maianu, L., Moellering, D., Garvey, W. (2007). Atypical antipsychotic drugs directly impair insulin action in adipocytes Effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology, 32, 765-772. 

Stevenson et al. (1991) studied the effects of engli-tazone in nondiabetic rats and found no overt hypogly-caemia but an enhancement of insulin action. 

Lee MK, Olefsky JM (1995) Acute effects of troglitazone on in vivo insulin action in normal rats. Metabolism 44 1166-1169... 

Sharma, P.M., Egawa, K., Huang, Y., Martin, J.L., Huvar, I., Boss, G.R., and Olefsky, J.M., 1998, Inhibition of phosphatidylinositol 3-kinase activity by adenovirus-mediated gene transfer and its effect on insulin action. J. Biol. Chem. 273 18528-18537. 

Sulfonylurea derivatives such as tolbutamide (Figure 5.14) bind to the sulfonylurea receptor and thereby promote the closing of the Kj, channel. This amplifies the secretion of insulin - a desirable effect in type II diabetics, who suffer not from an absolute lack of insulin (as type I diabetics do) but from an inadequate response to it. Sulfonylurea drugs can be used orally, which is more convenient than insulin therapy. It is also less prone to result in excessive insulin action (hypoglycemia), since the physiological signal is amplified but not substituted. However, commonly the (3-cells wear out eventually, and insulin therapy has to be instituted anyway. 

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