News & Research

Research Description

Patients with type 2 diabetes mellitus (T2DM), obesity, and related syndromes are said to have 'insulin resistance'.  The usual way to overcome insulin resistance is to give more insulin.  The problem in these conditions is that insulin fails to properly regulate blood sugar, but insulin still robustly stimulates the liver to make fat.  The imbalance in insulin effects -- some don't work but others still do -- causes fatty liver and poor glucose control, which together elevate blood lipids and glucose, leading to large- and small-vessel complications, disability, and death. 

Our recent work identified a molecule, NOX4, as a master regulator of insulin action.  In the livers of obese, T2DM animals, NOX4 does not work correctly.  Thus, liver cells become insulin resistant for controlling sugar, but insulin still drives fat synthesis and fatty liver.  It's a new insight into harmful imbalances in insulin's effects.

This research proposal will answer two new questions: what goes wrong with NOX4 and how can insulin still stimulate fat synthesis in 'insulin-resistant' livers?  Importantly, each of these questions comes with a new therapeutic possibility.  If we learn what's wrong with NOX4, we could design new strategies to fix it, to restore normal balance among insulin's actions.  If we learn how insulin still causes hepatic fat synthesis, we could stop it, to block fatty liver and its complications. 

Overall, the proposed research will identify, then improve, our hypothesized causes for both fatty liver and poor glucose handling in T2DM -- and hence their deadly consequences.

Research Profile

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

Patients with type 2 diabetes mellitus (T2DM), obesity, and related syndromes are said to have 'insulin resistance'.  The usual way to overcome insulin resistance is to give more insulin.  The problem in these conditions is that insulin fails to properly regulate blood sugar, but insulin still robustly stimulates the liver to make fat.  The imbalance in insulin effects -- some don't work but others still do -- causes fatty liver and poor glucose control, which together elevate blood lipids and glucose, leading to large- and small-vessel complications, disability, and death. 

Our recent work identified a molecule, NOX4, as a master regulator of insulin action.  In the livers of obese, T2DM animals, NOX4 does not work correctly.  Thus, liver cells become insulin resistant for controlling sugar, but insulin still drives fat synthesis and fatty liver.  It's a new insight into harmful imbalances in insulin's effects.

This research grant will answer two new questions: what goes wrong with NOX4 (Aim 1) and how can insulin still stimulate fat synthesis in 'insulin-resistant' livers (Aim 2)?  Importantly, each of these questions comes with a new therapeutic possibility.  If we learn what's wrong with NOX4, we could design new strategies to fix it, to restore normal balance among insulin's actions.  If we learn how insulin still causes hepatic fat synthesis, we could stop it, to block fatty liver and its complications. 

Overall, the proposed research will identify, then improve, our hypothesized causes for both fatty liver and poor glucose handling in T2DM -- and hence their deadly consequences.

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

Since the work of Sir Harold Himsworth in the 1930s, we've known that insulin does not work properly to lower blood sugar concentrations in type 2 diabetes mellitus (T2DM).  Why insulin loses this specific function has remained unknown. 

The situation seemed to become more complicated when it was realized in the late 1990s that some actions of insulin paradoxically remain fully responsive in T2DM.  The actions that remain responsive are clinically undesirable, such as insulin-stimulated fat production in the liver, which elevates blood lipid levels and contributes to vascular complications. 

Our research has identified a new master regulator of insulin action.  We have found that this master regulator, which is called NOX4, controls the balance amongst different downstream actions of insulin.  In T2DM, obesity, and related syndromes, NOX4 does not work correctly.  The result is fatty liver and poor glucose control. 

If we learn what's wrong with NOX4, we could design new strategies to fix it, to restore normal balance among insulin's actions.  If we learn how insulin still causes hepatic fat synthesis, we could stop it, to block fatty liver and its complications.

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

Diabetes remains a significant, and growing, health problem in the U.S. and worldwide.  We have remarkable medications in clinical practice, yet patients with diabetes continue to suffer from high rates of complications, particularly vascular disease.  Our goal is to improve diabetic therapies, to prevent these disabling and deadly consequences. 

This award comes at a crucial time in our research.  Having identified NOX4 as a master regulator of the balance amongst different actions of insulin, we now need to take full advantage of this new insight.  This award provides key resources to understand why insulin does not work properly in T2DM - and to see how we can fix this problem.

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

In type 2 diabetes mellitus, we need to understand why insulin works in an imbalanced fashion, so that we can fix the problem. 

Though not a part of our current research, we also need to find effective ways to help populations in industrialized and developing regions of the world to eat less and move more.