Diabetogenes

Human growth hormone is a very complex molecule biologically. Several diverse biological activities such as anaboHc, insulin-like, diabetogenic, and lactogenic activities have been ascribed to hGH, which also appears to promote water and salt retention. An in-depth discussion of these activities may be found in several excellent reviews available in the Hterature (34—36). 

Alloxan (1003) has been observed in the mucus associated with dysentery and it was the very first pyrimidine made synthetically when Brugnatelli oxidized uric acid in 1818. Alloxan has an interesting diabetogenic action which appears to be associated with removal of essential zinc from insulin by chelation. Such permanent diabetes may be induced in fish, dogs, cats, sheep, some birds, monkeys and other creatures, but not in man, owls or guinea-pigs certain pyrimidines related to alloxan show some such activity. 

Diabetogenic actions of alloxan ARDS (some forms) ... 

Klinkhammer, C., Popowa, P. and Gleichmann, H. (1988). Specific immunity to the diabetogen streptozotocin cellular requirements for induction of lymphoproliferation. Diabetes 37 74— 80. 

Theoretically, diabetes could be as readily caused by overproduction of the pituitary hormone as by the underproduction of insulin. Actually both activities probably vary greatly, and the diabetes results from an imbalance. Even when diabetes has its origin in an overactivity of the pituitary in producing the diabetogenic hormone, insulin may still be an effective remedy. Actually, of course, diabetes is sometimes insulin-resistant, which fact reveals that the disease does not always have the same origin. 

Since the major part of this section was written, evidence has been published [326a] demonstrating that the above diuretics are possibly even more diabetogenic than the thiazides (judged by inhibition of C-labelled glucose utilization in adipose tissue), with a mechanism of action probably similar to that of the earlier drugs. This work seems more enlightening on this controversial point than any hitherto presented. 

Thiazides should be used cautiously in the presence of severe renal and hepatic disease, since azotemia and coma may result. The most important toxic effect associated with this class of diuretics is hypokalemia, which may result in muscular and central nervous system symptoms, as well as cardiac sensitization (see Hypokalemia). Periodic examination of serum electrolytes for possible imbalances is strongly recommended. Appropriate dietary and therapeutic measures for controlling hypokalemia are described later in this chapter. The thiazides also possess some diabetogenic potential, and although pancreatitis during thiazide therapy has been reported in a few cases, the major mechanism contributing to the potential for glucose intolerance is not known. 

Furosemide, torsemide, and bumetanide are sulfonamide derivatives, hence chemically related to the thiazides. They share the thiazides adverse effects of serum uric acid elevation and diabetogenic potential. Ethacrynic acid (Edecrin) is chemically unrelated to other diuretics and does not appear to have diabetogenic potential. 

Diabetogenic effect. Chromatographic fraction of the fresh stem, administered intragastrically to rats at a dose of 1 g/kg, was active. The fraction inhibited the elevation of semm TG, lipid peroxides, and insulin of rats fed on a high-sugar diet for 61 days . 

Reported rate constants for the reaction of 02 with GSH have varied from 102 to > 105 M 1 s. A re-examination of this reaction by spin trapping with DMPO established that earlier studies had been confounded by the direct reduction of the DMPO/ OOH adduct to DMPO/ OH by GSH. Taking account of this reaction, the revised rate constant was reported to be 200 M-1 g-i.25i.2S2 other workers have examined, for example, the effects of GSH and N-acetyl-L-cysteine on lipid peroxidation 253 and the role of GS in the toxicity of the diabetogenic agent alloxan.254 Direct EPR has been used to detect binuclear Cu(II) complexes of homocysteine. The interactions of such complexes with blood-vessel linings may account for the link between elevated homocysteine and atherosclerosis.255... 

Ahren B, Adner N, Svartberg J, Petrella E, Holst JJ, Gutniak MK. Anti-diabetogenic effect of the human amylin analogue, pramlintide, in Type 1 diabetes is not mediated by GLP-1. Diabet Med 2002 19(9) 790-2. 

Prolonged administration of nicotinic acid can have a diabetogenic effect and decompensation of previously stable diabetes can occur. Severe hyperglycemia has been precipitated by nicotinic acid treatment of hyperlipidemia (24). 

Dehydroascorbic acid appears to have a diabetogenic effect and ascorbic acid causes increased excretion of glucose. High ascorbic acid concentrations can delay the insulin response to a glucose challenge and prolong postprandial hyperglycemia (170). 

Jindal RM, Popescu I, Schwartz ME, Emre S, Boccagni P, Miller CM. Diabetogenicity of FK506 versus cyclosporine in liver transplant recipients. Transplantation 1994 58(3) 370-2. 

Panz VR, Bonegio R, Raal FJ, Maher H, Hsu HC, Joffe BI. Diabetogenic effect of tacrolimus in South African patients undergoing kidney transplantation. Transplantation 2002 73(4) 587-90. 

Junod A, Lambert AE, Stauffac W, Renold AE. Diabetogenic action of streptozotocin relationship of dose to metabolic response. Journal of Clinical Investigation 1969, 48, 2129-2139. 

Human HLA-A2.1 Class I Molecules Transgenically Expressed in NOD Mice Mediate Diabetogenic CD8 T-cell Responses... 

Use of N0D.fi2mnull.HHD Mice for Identifying Means to Block HLA-A2.1 -Restricted Diabetogenic T-Cell Responses... 

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