Perreault, Leigh , MD
Exploring defects in glucose production and sensing in people with impaired fasting glucose
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action\Glucose Transport, Integrated Physiology\Liver
Type of Grant: Career Development
Project Start Date: July 1, 2009
Project End Date: June 30, 2014
Type 2 diabetes is considered one of the greatest public health issues of our time. Despite the notion that obesity is the #1 risk factor for diabetes, only 2-13% of people with obesity will ever acquire diabetes. In contrast, up to 70% of those with pre-diabetes will develop the disease. Pre-diabetes is not a singular entity, however, but a heterogenous group of metabolic defects that precede type 2 diabetes. Surprisingly little is known about the differences between the types of pre-diabetes. Our group and others have shown that people with impaired fasting glucose (one type of pre-diabetes) have the distinguishing feature of too much glucose coming out of the liver.
Why this is the case is not known. We propose that the liver makes too much glucose because it has lost the ability to sense glucose (and therefore down-regulate its production) in people with IFG. We also propose that liver glucose sensing (and glucose production) can be normalized by activation of the glucose sensor (glucokinase). An elegant series of experiments are described to systematically assess these hypotheses. The glucose sensor (glucokinase) holds considerable promise as a target for drug therapy in the prevention of type 2 diabetes.
What area of diabetes research does your project cover?
Area of diabetes research covered: Pre-diabetes
What role will this particular project play in preventing, treating and/or curing diabetes?
Obesity is considered the #1 risk factor for type 2 diabetes. Although two-thirds of people with type 2 diabetes are obese, only 2-13% of those who are simply obese will develop diabetes. In contrast, people with pre-diabetes carry up to a 70% lifetime risk of acquiring the disease. Therefore, exploiting the differences between simple obesity and pre-diabetes has significant public health implications.
Pre-diabetes is not a singular entity, however, but a heterogeneous mix of metabolic derangements that precede diabetes. Impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and IFG/IGT are equally represented in the mix. Our lab, and others, have found that people with IFG have inappropriate endogenous glucose production (EGP) and defective 1st phase insulin secretion as defining features. This project aims to explore defects in glucose production and sensing in the liver of people with IFG. Our collective hypotheses contend that people with IFG cannot sense (and therefore normally regulate EGP) in response to mild hyperglycemia. We believe this failure to sense hyperglycemia is due to a defect in glucokinase. Our study design will recapitulate the abnormality in EGP and show that by enhancing glucokinase activity the abnormality can be reversed.
As glucokinase activators are an intense are of therapeutic development, results from this study have enormous potential to treat IFG and prevent diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
It is unlikely that this project will directly benefit people with existing diabetes. The major benefit of this project will be in diabetes prevention for the estimated 20 million Americans with impaired fasting glucose (IFG). Specifically, the following benefits are expected:
1. Delineation of pre-diabetes from simple obesity as a far greater risk factor for diabetes, therefore deserving of greater and earlier intervention.2. Challenging the prevailing paradigm that all pre-diabetes is the same, and instead demanding treatment and prevention strategies targeted for the different types.3. Rigorous exploration into glucokinase as a therapeutic target for people with IFG.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
At the beginning of my scientific adventure, I found the pathophysiology and natural history of diabetes simply fascinating. It motivated me to write my recently completed NIH K23 in the area of pre-diabetes. Working closely with the research volunteers then watching many of them progress to type 2 diabetes was devastating. Thus, my passion for diabetes prevention became focused.
This award is vital in increasing our current understanding of possible treatment targets for people with impaired fasting glucose. It is my great hope that we may eventually slow the massive growth in the prevalence of type 2 diabetes through such research.
In what direction do you see the future of diabetes research going?
Impaired glucose tolerance (IGT) with or without impaired fasting glucose (IFG/IGT) are also discreet forms of pre-diabetes that deserve further exploration. Unveiling of therapeutic targets in IGT and/or IFG/IGT could also prevent diabetes, as it would instituting therapies in people with IFG.
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