News & Research

    Yale University School of Medicine, New Haven, Connecticut

Mechanism of insulin resistance in aging

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Integrated Physiology\Insulin Resistance, Insulin Action\Insulin Resistance, Integrated Physiology\Muscle

Type of Grant: Distinguished Clinical Scientist

Project Start Date: July 1, 2009

Project End Date: June 30, 2013

Research Description

Type 2 diabetes is one of the most common chronic diseases in the elderly affecting approximately 23% of Americans over the age of 60 years. Insulin resistance plays a major role in the development of Type 2 diabetes in the elderly but the mechanisms remain poorly understood. Recent studies using magnetic resonance spectroscopy (MRS) have shown that lean, healthy older people have reduced muscle mitochondrial function or reduced energy expenditure in the muscles. The elderly also have increased lipid content in the liver and muscle cells and muscle insulin resistance. These studies will examine whether the higher lipid content in muscle and liver of the elderly may be due to the reduced muscle energy expenditure, and that the lipid in muscle and liver blocks insulin signaling and cause insulin resistance. Body fat distribution and muscle mass may also change with aging and these changes in body composition with aging may affect metabolism.

The studies in this proposal will explore: 1) The potential role of muscle insulin resistance in increasing the risks for increased blood lipid and cholesterol levels, cardiovascular disease, fatty liver and the metabolic syndrome. 2) To use MRS to directly measure rates of muscle specific glucose and lipid oxidation in healthy normal weight, older subjects (65-80 years) as compared to young (18-30 years) gender-body weight-BMI and activity matched control subjects, 3) Directly measure body composition, muscle mass and fat distribution in young and older people.

Reseacher Profile

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

Type 2 diabetes is reaching epidemic proportions in the United States. While the precipitating factors causing this disease are unknown it is clear that insulin resistance has a major role in its development. The primary objective of my studies is to examine the molecular mechanism(s) responsible for insulin resistance, in healthy subjects at high risk such as older people (over the age of 65 years) and young, insulin resistant offspring of parents with type 2 diabetes, in the hope that this will enable the rational development of new therapeutic agents to reverse this pathologic condition. Since liver and muscle are the two key insulin responsive organs, which account for most of the glucose metabolized in humans, we are currently focusing our attention on the liver and muscle using magnetic resonance spectroscopy (MRS) in combination with stable isotopes to assess alterations in carbohydrate and fat metabolism that cause insulin resistance.

This approach has major advantages over existing techniques used for clinical investigation in that it is noninvasive, it involves no ionizing radiation and repeated measurements of biochemical metabolites in liver, muscle and brain can be performed which then yield localized rates of glucose and fat metabolism. The goal of this ADA Distinguished Clinical Scientist Award is to provide the support necessary to develop novel MRS techniques in order to elucidate the molecular mechanisms responsible for insulin resistance and the metabolic syndrome while simultaneously training the next generation of patient-oriented clinical investigators in the use of these state-of-the art techniques.

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

Insulin resistance occurs years before the development of type 2 diabetes, virtually all people with type 2 diabetes are insulin resistant and it is the best predictor for a high risk for type 2 diabetes. Insulin resistance is a state where the muscle and liver do not respond so well to the signals from insulin to take up glucose from the blood stream. The body has to make more insulin in order to get the muscles and liver to respond. This increased demand for insulin may over time cause the insulin producing cells to tire out and when they can no longer keep up with the increased demands for insulin blood glucose levels rise and type 2 diabetes happens. Our studies are focused on understanding why insulin resistance in muscle and liver occurs in healthy people such as healthy older and young offspring of parents with type 2 diabetes. If we can understand this we may be able to reverse insulin resistance, lower the demand for insulin production, and in this way lower the risk for the development of type 2 diabetes. Our studies have shown that insulin resistance in muscle and in liver occurs when fat builds up inside these tissues. Fat seems to block insulin action by blocking some of the enzymes, which should normally be activated by insulin.

In support of this hypothesis we found that a small weight loss (approximately 18 lbs) in obese patients with type 2 diabetes was enough to normalize their fasting blood glucose levels and normalize the production of glucose in the liver. The reason for these dramatic effects of such a small weight loss was that the weight loss melted away the fat in the liver and in this way normalized insulin sensitivity in the liver.

Our studies are also focusing on the metabolic syndrome, which is a cluster of abnormalities such as fatty liver, high cholesterol, low HDL, and high blood pressure. The underlying cause of the metabolic syndrome is currently unknown. We are examining whether muscle insulin resistance and the elevated blood insulin levels in insulin resistant individuals, such as healthy, lean older people, may lead to the early features of the metabolic syndrome. We are studying how the insulin resistance in muscle and the accompanying high blood insulin levels after a meal may cause the liver to produce lipids, which will increase lipids in the bloods as cholesterol and cause fatty liver. Together muscle insulin resistance and increased lipid production in the liver may be earliest features of the metabolic syndrome.

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

In my career as a scientist I have been part of a group pioneering new methods using stable isotopes and MRS to directly study glucose and fat metabolism in the liver, muscle and brain.  We have for the first time been able to identify some of the mechanisms of how insulin resistance likely occurs in obese people, insulin resistant offspring of parents with type 2 diabetes, and in healthy young people when we raise plasma fatty acid levels. In addition, my studies have focused on insulin resistance in patients with type 2 diabetes and studying how some of the new medications (metformin and thiazolidinediones) as well as simple weight loss work to improve insulin sensitivity and lower blood glucose in diabetes. As a physician and clinical investigator I feel it is a privilege and an important challenge for me to further this work and move forward in our understanding of this devastating disease.

This ADA Distinguished Clinical Scientist Award application will play a very important role in my patient-oriented research on the cellular mechanisms of insulin resistance. It will allow me to expand this research into examining the mechanisms of in healthy aging, and begin a new focus on assessment of potential changes in body composition, visceral fat volume and whole body muscle mass and its impact on muscle insulin sensitivity in the elderly.  It will also provide me with protected time for mentoring medical trainees and junior faculty, who will be the next generation to carry forward diabetes research. 

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

Our hypothesis is that muscle insulin resistance is the first step in the development of insulin resistance, the metabolic syndrome, NAFLD and type 2 diabetes. Muscle insulin resistance may be the primary drive for changing the pattern of how energy from food is distributed and stored in the body. In muscle insulin resistance glucose uptake in muscle is impaired and the combination of high insulin levels and high blood glucose up-regulates lipid production in the liver resulting in high blood lipids (triglycerides and cholesterol) and fatty liver. Fatty liver is becoming the most common liver disorder and it is strongly associated with obesity and the metabolic syndrome. Therefore, I anticipate future diabetes research to turn towards examining lipid metabolism, blood lipid regulation, fatty liver, and the metabolic syndrome. However, since the underlying pathologic feature of these abnormalities is likely muscle insulin resistance this remains to be the key issue to be understood and resolved.