PEPCK and type II diabetes (non–insulin-dependent diabetes mellitus)

Type 2 diabetes is a growing epidemic in the United States and the world.  In light of this, there is intense research in both the basic science of diabetes as well as clinical treatments.  One of the hallmarks in the progression of Type-2 diabetes is that diabetic patients no longer respond to insulin as well as non-diabetics.   Increasing the transport of glucose in to cells in response to increased in blood glucose levels is the primary function of insulin.  The loss of the acidly to stimulate glucose transport is one of the main reasons for persistent high blood glucose levels seen with the disease.

Insulin itself has many more functions besides regulating glucose transport.  It is a hormone that causes widespread changes in gene expression and protein production.  In the case of PEPCK, insulin decrease the amount of the enzyme expressed, and inhibits its up regulation by other hormones (see PEPCK transcription). Given PEPCK’s role in gluconeogenesis, this reciprocal action of insulin and PEPCK makes sense.  When blood glucose levels are elevated, we do not want to keep producing glucose via gluconeogenesis.   However this is precisely what happens in diabetic individuals.  The ability of insulin to regulate PEPCK expression is lost and glucose output from the liver is greater than non-diabetics.  This increased glucose output contributes to the elevated blood glucose levels in diabetics under fasting and non-fasting conditions.

A second aspect of diabetes is discussed in the glyceroneogensis section.  Insulin resistance has been shown to be correlated with free fatty acid (FFA) levels in the blood.  PEPCK activity in adipose tissue (fat) can directly regulate the concentration of FFA’s in the blood by converting FFA’s to triglycerides.   The new class of insulin sensitizing agents call Thiazolidinediones targets the expression of PEPCK in adipose tissue. These compounds decrease fasting blood glucose levels as well as gluconeogenesis in diabetics. Other pharmacological interventions of PEPCK are also under development.

Copyright 2011 Steve Kriegler