Diabetes and Inflammation

Drugs that lower blood sugar in diabetics may reduce some inflammation, but enhance other inflammatory cellular markers that are risk factors for cardiovascular disease.

A recent research article show that two popular drugs for lowering diabetic blood sugar, metformin and rosiglitazone, are effective in reducing hyperglycemia, but differ in their impact on oxidative stress. High blood sugar can lead to accumulation of advanced glycation endproducts (AGE), that result from spontaneous chemical reactions between high concentrations of blood glucose and the amino groups of proteins. AGE are inflammatory and some of the symptoms of diabetes are associated with the hyperglycemia. What the recent research shows, is that metformin can effectively lower blood sugar, some forms of inflammation resulting from residual oxidative stress persist. Rosiglitazone lowers glucose, as well as lowering oxidative stress and thereby reduces chronic inflammation more effectively.

Metformin is an interesting diguanide that mimics the overall properties of many plant alkaloids and is transported into cells using the same organic cation transporters (OCTs). My students and I have studied how alkaloids, sugars and metformin interact with protein enzymes and transporters. Amazingly all of these small molecules, ligands, bind with differing affinities to similar structures in the proteins -- a flat platform of aromatic amino acids exposed to surface water. We have even observed that a common enzyme, beta-galactosidase, that hydrolyzes the terminal galactose sugar from lactose, milk sugar, binds all of these molecules. Thus, the enzyme is inhibited by metformin binding in the active site in place of lactose. This underscores the broad generalization that all of these molecules, carbohydrates, alkaloids and many drugs have a mixture of both hydrophilic and hydrophobic properties, i.e. they act like detergents. It should not be surprising that the molecule that dominates the extracellular signaling environment, heparin sulfate, has detergent-like properties and binds to basic amino acids that have similar detergent-like properties with opposite charges, i.e. cationic and anionic detergents.