Kitt Falk Petersen, MD
Kitt Falk Petersen, MD
Associate Professor, Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine
|ADA Research Funding|
Distinguished Clinical Scientist Award
Insulin resistance is a surprisingly common condition that occurs when your body produces insulin but your cells don’t respond properly. Insulin resistance may not automatically lead to type 2 diabetes, but it is one of the most significant risk factors.
Here’s why: Insulin is a hormone that sends a signal to the cells in your muscles and liver that they should absorb glucose, or sugar, a fuel source that circulates in the bloodstream. When that signal is ignored, the body’s insulin producers—beta cells—have to work harder and harder, overproducing insulin to get the job done.
That kind of overproduction is good enough, for a while. “As long as you can push out enough insulin to get the muscle and liver to respond, your blood sugar will be fine, but the high insulin levels will cause the liver to produce fat, which can lead to high plasma triglycerides and fatty liver,” says Kitt Falk Petersen, MD, a researcher at Yale University’s School of Medicine. “And you stress the beta cells, which wear out over time.” By the time most people are diagnosed with type 2 diabetes, they have already lost some of their ability to make insulin.
Petersen’s research, supported in part by the American Diabetes Association, focuses on the causes of insulin resistance. She’s particularly interested in something no one can control: aging. There is a statistical spike in type 2 diabetes cases that takes place after the age of 65.
It turns out that aging and insulin resistance are closely connected, just as insulin resistance is tied to type 2. “After the age of about 65, diabetes takes off in a rampant way,” the Yale researcher says. “Forty percent of us have diabetes or impaired glucose tolerance by the age of 65.”
Because many people gain weight and become more sedentary when they get older, Petersen needed a way to make sure age was the only variable in her experiments. She selected a group of young and older people who were of normal body weight and matched in terms of weight, exercise levels, and diet. The only difference between them was age: One group was made up of participants in their 20s and 30s, the other of people over 65. She found that even these normal-weight older people had insulin resistance, which suggests that getting older in itself increases the risk for getting type 2 diabetes.
The two biggest differences between the two groups were the extent of muscle insulin resistance and fat in their muscle cells. On both counts, the older participants scored much higher. “There’s a strong correlation between muscle and liver insulin resistance and fat in the muscle and the liver,” Petersen says. “We found that even these normal-weight, healthy older people all had muscle insulin resistance.”
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To understand what’s behind the rise in insulin resistance later in life, Petersen delves deep within the body’s cells, where structures called mitochondria produce the energy we need to live. Her hypothesis is that as we age our mitochondria slow down and cannot convert sugar and fat into energy as efficiently as when we are young. As we get older, fat builds up inside the muscle and liver cells and ultimately makes them less sensitive to insulin.
The chain of events that links aging and insulin resistance may be breakable. The key is making the fat in muscle and liver cells disappear. “The obvious thing to do would be to not get old,” the Danish-born researcher says with a laugh. “But barring that, eating less as we get older would prevent fat from building up inside the muscle and liver cells. We’d also like to find out whether we can avoid mitochondrial dysfunction in aging through exercise.”
By clearing out some of the fat stored in cells, Petersen suggests, the cell may respond better to insulin. “If you can speed up mitochondria function and burn off more fat and glucose, you would slow down insulin resistance,” Petersen says. “If we could melt that fat away, would that normalize everything?”
To find the answer to that question, Petersen put a different group of people—this time, all with type 2 diabetes—on a restricted diet. The participants ate only 1,300 calories per day for 13 weeks. On average, they lost 16 pounds, or about 8 percent of their body weight, over the course of the experiment. The weight loss came with promising results, such as blood glucose levels close to normal and a dramatic decrease in the amount of fat in participants’ livers.
In parallel studies, Petersen is also looking at the liver’s role in turning excess glucose into fat and the remarkable role of exercise in encouraging muscle cells to take up sugar before the liver turns it into fats, which leads to fatty liver and high blood triglycerides. She’s even using specially bred mice to demonstrate the links between inefficient mitochondria and diabetes risk.
Put together, the results could mean a simple fix for age-related insulin resistance. “It’s possible we could get rid of the whole thing if we had older folks lose a little weight,” Petersen says. “After all, we were probably all meant to be a little thinner than we are.”