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Theories of Pathophysiology of diabetic complication

  1. First Theory
    1. Intracellular glucose can be converted to so-called Amadori products, and these in turn can form advanced glycosylation end products (AGEs), which cross-link matrix proteins.
    2. This damages blood vessels.
    3. The AGEs also interfere with the leukocyte responses to infection.
  2. Second Theory-
    1. Hyperglycemia increases the formation of diacylglycerol leading to activation of protein kinase C (PKC). PKC alters the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells and neurons.
  3. Third theory –
    1. Hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and proteoglycan production.
    2. Hexosamine pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor ß (TGF-ß) or plasminogen activator inhibitor-1 (PAI-1).
  4. Fourth theory
    1. In diabetes glucose is converted into sorbitol which is a tissue toxin. Q
    2. Enzyme required in this step is aldose reductase. Q
    3. Recently a new drug Epalrestat (PNQ) Q has been launched which is a aldose reductase inhibitor. (PNQ) Which is supposed to reduce the complication of diabetes.
Recent Advances:

Epalrestat is a aldose reductase inhibitor (PNQ) Epalrestat is a recently launched drug in Indian Market. Its name is not there in Harrison 18th Edition also!!!.


Important Points (Ref. Hari.18th ed. , Pg- 2981)

International research studies which prove that intensive diabetes control Significantly reduced microvascular end points.

  1. Kumamoto Study
  2. The United Kingdom Prospective Diabetes Study (UKPDS)
  3. The seno-2 study
  4. DCCT (Diabetes Control and Complication Trial)
Extra Edge:
  1. The DCCT demonstrated that improvement of glycemic control reduced nonproliferative and proliferative retinopathy (47% reduction), microalbuminuria (39% reduction), clinical nephropathy (54% reduction), and neuropathy (60% reduction). Improved glycemic control also slowed the progression of early diabetic complications. There was a nonsignificant trend in reduction of macrovascular events during the trial
  2. The UKPDS demonstrated that each percentage point reduction in A1C was associated with a 35% reduction in microvascular complications.
  3. One of the major findings of the UKPDS was that strict blood pressure control significantly reduced both macro- and microvascular complications. In fact, the beneficial effects of blood pressure control were greater than the beneficial effects of glycemic control. Lowering blood pressure to moderate goals (144/82 mmHg) reduced the risk of DM-related death, stroke, microvascular end- points, retinopathy, and heart failure (risk reductions between 32 and 56%).
  4. The findings of the DCCT, UKPDS, and Kumamoto study strongly support the idea that chronic hyperglycemia plays a causative role in the pathogenesis of diabetic microvascular complications.

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