July 13, 2007

Treating Type2 DM

So far, we have discussed about insulin, its actions, type 1 diabetes mellitus and its treatment. In contrast to type 1 DM, type 2 DM is characterized by end organ (tissue level) insensitivity to insulin. Thus insulin is present in normal or more than normal quantity, but somehow it can not deliver its message across the cell. Obviously such a state cannot be addressed by giving more insulin, but in making the cell more responsive to its effects. This is done by administering oral hypoglycemic drugs (OHD). (Although, in complicated type2DM or when there is an added stress like a fracture, emotional trauma, surgery; insulin has to be administered, in addition).

Sulfonylurea group of drugs act by closing the SUR (Sulfonylurea) channel, which is in fact, a part of the ATP sensitive potassium channel. Closing this channel would mean build up of potassium inside the cell, thus neutralizing the electro negativity inside, making the cell depolarized. This in turn will lead to influx of calcium ions from outside, which in turn will lead to release of stored insulin. Thus these groups of drugs are also referred to as insulin releasers. Of these, short acting sulfonylureas like glimiperide or glyclazide are preferred over their long acting cousins like chlorpropamide. This is due to the adverse effect of hypo glycemia, which, naturally tend to be long and more profound with long acting sulfonylureas.

Biguanides like metformin are very helpful, specially in obese diabetics. It acts in various ways, though its exact mechanism of action hasn't yet been worked out. It is also effective in the treatment of PCOD (poly cystic ovarian syndrome). Phenformin, a biguanide, which caused fatal lactic acidosis, was withdrawn from the market.

Meglitinides are a group of drugs which act by releasing insulin, in much the same manner as the sulfonylurea drugs. Repaglinide and nateglinide are examples of this group.

Thiazolidinediones, which include pioglitazone and rosiglitazone, are novel drugs which target PPAR-gamma (peroxisome proliferator-activator receptor-gamma), an intracellular receptor.
The Tzds as they are better known, combine with the intra nuclear receptor, thereby modifying gene activation and thus bring about their actions. PPAR-gamma are located in muscle cells, fat cells, liver and other organs. Their effects take time, since they act through genetic transcription, translation etc. In addition to sensitizing the tissues to insulin, they also lower LDL, increase HDL in those taking it. Thus, they also correct, to some extent, the metabolic disorders which usually accompany diabetes.

Then there are also alpha glucosidase inhibitors, like acarbose and miglitol, which prevent the breakdown of polysaccharides in the intestine, to smaller molecules like glucose or fructose. As the intestine cannot absorb carbohydrate molecules other than simple sugars, blocking polysaccharide breakdown in the gut will thus reduce the sugar load into the blood stream.

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