20. Molecular events associated with diabetes

I recommend you to read topic 21 before you read this.

Advanced glycation end-products

Advanced glycation end-products (AGEs), are normal molecules which have reacted non-enzymatically with glucose to form dysfunctional molecules. This reaction is called a Maillard reaction. Any biological molecule can become an AGE, including proteins and lipids. Especially proteins, when reacting with glucose, lose their normal function which can cause a variety of adverse effects.

The formation of AGEs is one of the major mechanisms by which diabetes damages all kinds of organs in the body.

AGEs can also bind to a type of receptor in the body called “receptor for AGEs”, often called RAGEs. When AGEs bind to RAGEs, bad things happen.

(Some) medications which can be used to treat type 2 diabetes

Thiazolidinediones (glitazones)

The PPARs have already been introduced in biochemistry 1, and were mostly talked about here.

PPARγ increase the expression many enzymes and proteins involved in fatty acid metabolism. One of them is lipoprotein lipase, which releases free fatty acids from lipoproteins. It also increases expression of fatty acid transporters. Lastly, it increases transcription of PEPCK in the adipocyte. The combination of these three mechanisms increase the flow of FFAs into adipocytes.

A type of drug called thiazolidinediones, which are PPARγ agonists, are used as antidiabetic medication. However, they have been associated with many adverse effects, like stroke, and are therefore rarely used today.

DPP-4 inhibitors (gliptins)

Incretins are hormones that decrease blood glucose levels by increasing the secretion of insulin and decreasing the secretion of glucagon. Intestinal cells produce incretins after a meal. Incretins stimulate β-cells to produce insulin. The two important incretins are GLP-1 and GIP.

An enzyme called dipeptidyl peptidase 4 or DPP-4 breaks down GLP-1 and GIP so that they no longer have effects. By inhibiting DPP-4, we can increase the lifetime of GLP-1 and GIP, which is good.

Many DPP-4 inhibitors exist and are used as antidiabetic medication. These drugs increase the effect of the incretins and therefore lower blood glucose levels.

SGLT2 inhibitors (gliflozins)

SGLT2 is a transport protein which reabsorbs glucose from filtrate in the kidneys. SGLT2 inhibitors exist, which reduces the amount of glucose which is reabsorbed. This is an effective way of letting the body get rid of excess glucose in diabetes.

However, an interesting side effect of these drugs is the increased incidence of urinary tract infections. This is because, as the urine contains more glucose, bacteria have an easier time colonizing the urinary tract.

These drugs were recently discovered to treat heart failure as well.