News & Research

    Medical College of Wisconsin, Milwaukee, Wisconsin

Mechanisms of ENaC regulation by insulin and PPARgamma

General Research Subject: Type 2 Diabetes

Focus: Insulin Action\Insulin Resistance, Islet Biology\Channels, Single Cell Studies, and Calcium Signaling, Signal Transduction (Non-Insulin Action)\Hormones

Type of Grant: Basic Science

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Diabetes Type: Type 2 diabetes

Research Description

Non-insulin dependent diabetes (NIDDM) is marked by the inability to properly use insulin to control blood glucose.  One strategy for treating NIDDM is to administer drugs called thiazolidinediones (TZDs) that increase insulin sensitivity.  TZDs are synthetic peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists.  Synthetic insulin and TZDs are often given together.  Insulin promotes inappropriate sodium retention at the kidney leading to expansion of blood volume, which has the potential to increase blood pressure.  This, in part, explains why NIDDM is often associated with hypertension.  The epithelial Na+ channel (ENaC) controls plasma sodium and volume levels in the aldosterone-sensitive distal nephron and thus, sets blood pressure. This proposal tests whether ENaC is regulated by PPARgamma agonists and antagonists and whether TZDs enhances insulin action on this target protein.  The results from this comprehensive study will provide rich information about the molecular mechanisms of regulation of this important ion channel and thus it will be possible to determine if insulin and TZDs directly or through signaling cascade regulate sodium reabsorption and ENaC activity. The rationale for this important line of questioning is that both TZDs and synthetic insulin are needed to counter improper glucose usage in NIDDM, but these drugs have dangerous side-effects that limit their effectiveness.  If this hypothesis is correct, there is a relatively easy means to counter these side effects using existing medicines, such as inhibitors of ENaC, that themselves have little side effects.

Research Profile

What area of diabetes research does your project cover?  What role will this particular project play in preventing, treating and/or curing diabetes?

Non-insulin dependent diabetes (NIDDM) is marked by the inability to properly use insulin to control blood glucose.  One strategy for treating NIDDM is to administer drugs called thiazolidinediones (TZDs) that increase insulin sensitivity.  TZDs are synthetic peroxisome proliferator-activated receptor-? (PPAR?) agonists.  Synthetic insulin and TZDs are often given together.  Insulin promotes inappropriate sodium retention at the kidney leading to expansion of blood volume, which has the potential to increase blood pressure.  Insulin increases Na+ reabsorption in the distal renal nephron likely by targeting the epithelial Na+ channel (ENaC) localized to the luminal membrane of principal cells.  Thus, it is important to understand the relationship between insulin, PPAR? activation and increased Na+ reabsorption by the kidney.  This, in part, might explain why NIDDM is often associated with hypertension.  This proposal tests whether ENaC is regulated by PPAR? agonists and antagonists and whether TZDs enhances insulin action on this target protein.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

This research proposal focuses on testing the central hypothesis that Na+ transport mediated by active epithelial Na+ channels plays a fundamental role in the non-insulin-dependent diabetes mellitus (NIDDM).  The results from this study will provide rich information about the molecular mechanisms of regulation of the epithelial Na+ channel (ENaC) and thus it will be possible to determine if insulin and PPAR? agonsits/antagonists directly or through signaling cascade regulate sodium reabsorption and ENaC activity. The rationale for this important line of questioning is that both PPAR? agonists (thiazolidinediones) and synthetic insulin are needed to counter improper glucose usage in NIDDM, but these drugs have significant side-effects that limit their effectiveness.  If this hypothesis is correct, there is a relatively easy means to counter these side effects using existing medicines, such as inhibitors of ENaC, that have little side effects.

Why is it important for you, personally, to become involved in diabetes research?  What role will this award play in your research efforts?

I have been personally profoundly affected by type 2 diabetes. My close friends are suffering from this severe disease which emerged as the looming threat for the US health system. Especially it is severe when children diagnosed with diabetes at earlier age. Furthermore diabetes is more complicated due to various side effects. I believe that I am uniquely positioned to study novel mechanisms of the progression of diabetes which involved physiology and pathophysiology of epithelial ion channels. Thus this award will now enable me to focus research of my laboratory to the understanding of the mechanisms of the progression of diabetes and eventually provide basis for the development of novel therapeutic strategies.

In what direction do you see the future of diabetes research going?

One of the major goals of diabetes management is to keep blood glucose levels as close to normal as safely possible.  However, the management of type 2 diabetes mellitus is complicated by the presence of risk factors such as overweight and obesity.  We need to find treatment for the diabetes. However the future of diabetes research is not only preventing consequences but also about studies of causes of diabetes. Studying of the cellular mechanisms of diabetes using molecular and genetic tools will be helpful to identify the causes of this disease and provide the means for prevention of diabetes.