Insulin actions

This is a crystalline product of insulin and an alkaline protein where the protein/insulin ratio is called the isophane ratio. This product gives a delayed and uniform insulin action with a reduction in the number of insulin doses necessary per day. Such a preparation may be made as follows 1.6 g of zinc-insulin crystals containing 0.4% of zinc are dissolved in 400 ml of water, with the aid of 25 ml of 0.1 N hydrochloric acid. To this are added aqueous solutions of 3 ml of tricresol, 7.6 g of sodium chloride, and sufficient sodium phosphate buffer that the final concentration is As molar and the pH is 6.9. 

Type 2 diabetes is a heterogeneous and progressive endocrine disorder associated with insulin resistance (impaired insulin action) and defective function of the insulin-secreting (3-cells in the pancreatic islets of Langerhans. These endocrine disorders give rise to widespread metabolic disturbances epitomised by hyperglycaemia. The present classes of antidiabetic agents other than insulin act to either increase insulin secretion, improve insulin action, slow the rate of intestinal... 

Biguanide Metformin Improve insulin action Oral... 

Thiazolidinediones Pioglitazone, rosiglitazone Improve insulin action (PPARy agonists) Oral... 

Metformin restrains hepatic glucose production principally by suppression of gluconeogenesis. The mechanisms involve potentiation of insulin action and decreased hepatic extraction of certain gluconeogenic substrates such as lactate. In addition, metformin reduces the rate of hepatic glycogenolysis and decreases the activity of hepatic glucose-6-phosphatase. Insulin-stimulated glucose uptake and glycogenesis by skeletal muscle is increased by metformin mainly by increased... 

The insulin-binding domain of the INSR is located within a cystein-rich region of the a-subunits. Alternative splicing of exon 11 generates two isoforms of the a-subunit which differ in their C-terminus and in their tissue distribution (type A leukocytes type B liver type A and B skeletal muscle and fat). The isoforms differ in their affinity to insulin (A > B), but then-relevance for normal and impaired insulin action is not entirely clear [1,2]. 

Taken together, these data emphasize the importance of insulin action in the liver for glucose homeostasis, in the regulation of insulin secretion from (3-cells and indicate that the INSR plays an important role in the central regulation of body weight and reproduction [4, 5]. 

Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways insights into insulin action. Nat Rev Mol Cell Biol 7 85-96... 

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. 

Under normal feeding patterns the rate of tissue protein catabolism is more or less constant throughout the day it is only in cachexia that there is an increased rate of protein catabolism. There is net protein catabolism in the postabsorptive phase of the feeding cycle and net protein synthesis in the absorptive phase, when the rate of synthesis increases by about 20-25%. The increased rate of protein synthesis is, again, a response to insulin action. Protein synthesis is an energy-expensive process, accounting for up to almost 20% of energy expenditure in the fed state, when there is an ample supply of amino acids from the diet, but under 9% in the starved state. 

Nicotinic acid Increase Impairs insulin action, increases insulin resistance... 

Impairs post-receptor insulin action. Hyperglycemia... 

Hyperosmolar hyperglycemic state A potentially fatal short-term complication most commonly seen in older patients with type 2 diabetes caused by an insufficiency of insulin action that leads to alterations of osmolality and hyperglycemia, but without the ketosis and acidosis seen in diabetic ketoacidosis. 

Osborne TF. Sterol regulatory element binding protein (SREBPs) Key regulators of nutritional homeostasis and insulin action. J Biol Chem 2000 275 32379-32382. 

At present, antioxidants are extensively studied as supplements for the treatment diabetic patients. Several clinical trials have been carried out with vitamin E. In 1991, Ceriello et al. [136] showed that supplementation of vitamin E to insulin-requiring diabetic patients reduced protein glycosylation without changing plasma glucose, probably due to the inhibition of the Maillard reaction. Then, Paolisso et al. [137] found that vitamin E decreased glucose level and improved insulin action in noninsulin-dependent diabetic patients. Recently, Jain et al. [138] showed that vitamin E supplementation increased glutathione level and diminished lipid peroxidation and HbAi level in erythrocytes of type 1 diabetic children. Similarly, Skyrme-Jones et al. [139] demonstrated that vitamin E supplementation improved endothelial vasodilator function in type 1 diabetic children supposedly due to the suppression of LDL oxidation. Devaraj et al. [140] used the urinary F2-isoprostane test for the estimate of LDL oxidation in type 2 diabetics. They also found that LDL oxidation decreased after vitamin E supplementation to patients. 

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 order to prolong the duration of insulin action, soluble insulin may be formulated to generate insulin suspensions. This is generally achieved in one of two ways ... 

Rhodes, C. and White, M. 2002. Molecular insights into insulin action and secretion. European Journal of Clinical Investigation 32, 3-13. 

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). 

I have already mentioned leptin. There are several others, notably including adiponectin, a protein present in high concentrations in blood. Adiponectin is an antihyperglycemic agent, acting to increase insulin sensitivity. There is a close relationship between obesity, insulin action, and development of type 2 diabetes. Withont listing additional peptides secreted by adipose tissue, it is important to understand that fat is an important player in human physiology. 

Wfe are proposing that the transfer of glucose into the cell is similarly not a free and unlimited process but rather an important limiting factor upon which insulin acts to promote entry. The subsequent fate of the glucose will depend on the presence and state of activity of the enzyme apparatus.. . A hypothesis of insulin action is proposed which attributes to insulin the role of facilitating the rate of transfer of some hexoses into the cell. 

Koch L, Wunderlich FT, Seibler J et al (2008) Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest 118 2132-2147... 

Schalkwijk, C. G., Brouwers, O., and Stehouer, C. D. (2008). Modulation of insulin action by adavanced glycation endproducts A new player in the field. Horm. Metab. Res. 40, 614-619. 

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