Insulin susceptibility factors

Lew, A., Rutter, W. J., Kennedy, G. C. (2000). Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-l/MAZ. Proc Natl Acad Sci U SA 91, 12508-12512. 

Susceptibility factors Age Older adults who are on insulin or other oral hypoglycaemic agents, are about fom- to seven times more likely than yoxmger persons to experience adverse drug events (ADEs). The most frequent ADE that causes hospitalisation (>90%) is hypoglycaemia. Insulin causes hypoglycaemia that requires hospitalisation more... 

Apart from PKA, some other protein-kinases were found to be controlled by forskolin, such as cytosolic sphingosine kinase in rat periosteal cells [186] and protein kinase B (PKB) [187]. The latter was found to be stimulated by the activation of PKA through a PI3 (phosphatidylinositol 3)-kinase-independent pathway. Furthermore, a distinct activation mechanism was suspected, other than that normally observed by growth factors such as insulin, since substitution of the serine at the S473 position of PKB with alanine could not prevent activation by forskolin. The JAK family of protein kinases in T lymphocytes can also be regulated by forskolin through the activation of PKA [188]. Thus it seems obvious that many other enzymes could be susceptible to control by forskolin. 

Control of physiological responses often involves several hormones. In some systems, two or more hormones act in opposition to each other (e.g., insulin and glucagon in the regulation of blood glucose). In other control systems, several hormones act in information hierarchies. Section 16.4 begins with a description of the best-researched example of such a hierarchy, referred to as a hormone cascade mechanism. This is followed by a discussion of growth factors, specialized proteins that stimulate cell division in susceptible cells. 

D) antibodies attack the acetylcholine receptors in postS5maptic membranes. In Graves disease aberrant antibodies are directed against receptors for thyrotropin. They have a stimulatory rather than an inhibitory effect and cause hyperthyroidism. Childhood onset (lype I) diabetes results from destruction of insulin-secreting cells by an autoimmune reaction triggered by environmental factors in genetically susceptible persons (Box The... 

Furthermore, adipose tissues were found to have some possible links between obesity and insulin resistance [89]. Obesity often causes insulin resistance, a decline in the ability of insulin to stimulate glucose uptake in the body leads to compensatory oversecretion of this hormone by the pancreatic cells and eventually, to cell exhaustion and development of type-2 diabetes mellitus [11,75]. Likewise in type-1 diabetes mellitus, the role of genetic factors has been studied to highlight the relation between inflammation, oxidant stress, and insulin insensitivity. Nuclear factor kappa B (NFkB) is a crucial transcription factor for response to oxidative stress and inflammation. Investigations about NFkB gene have shown its possible role in the susceptibility to type-1 diabetes by means of allelic differentiations, individuals with the AlO allele may be more likely to develop diabetes compared with those with the A14 allele [90]. 

On the basis of theoretical considerations, it had been su ested that the beta cell may have a low GSH content (44). The synthesis of insulin by the beta cell appears to be dependent upon a continuous supply of sulfur-amino acids, for when rabbits are placed on a cystine-methionine-deficient diet the insulin content of the pancreas is decreased (32). Insulin, in contrast to most other proteins, contains 12 % cystine (45). Since cysteine or its oxidized derivative, cystine, is a constituent of both GSH and of insulin, there may well be competition for this amino acid within the beta cell. Thus the GSH concentration within the beta cell may be low as a consequence of insulin synthesis (44). Furthermore, the oxidation-reduction potential in the beta cell may favor the oxidation of GSH to its oxidized form (GSSG) (44). Both of these factors would increase the susceptibility of the beta cells to alloxan, for it is the reduced form of GSH which reacts with alloxan (26). 

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