A Missing Link Between Insulin Resistance and Obesity?
Hideo Makimura, MD, PhD
Endocrinologist, Massachusetts General Hospital
ADA Research Funding
Obesity and insulin resistance are two top metabolic indicators of prediabetes, elevated blood glucose levels that aren’t quite high enough to diagnose as type 2 diabetes but may worsen over time. The two metabolic disorders are related, somehow: Obesity increases the likelihood the body will have trouble responding to insulin. And the more trouble the body has responding to insulin, the more the pancreas has to produce—until it gets worn out. That, in turn, is when type 2 diabetes sets in.
But how, exactly, obesity and insulin resistance are connected is unclear. To understand what’s going on, Harvard Medical School endocrinologist Hideo Makimura, MD, PhD, is starting with fatty acids, a group of molecules that includes omega-3s. “You can think of it as fat in the blood,” Makimura says.
Some fatty acids are good, some are bad, but on the whole, you don’t want too many of them floating around your body. Added weight, unfortunately, puts you at a disadvantage: Obesity is associated with increased amounts of fat in the blood. Studies have shown there’s a direct relationship between that fat and the body’s response to insulin. “If you reduce fatty acids, you can make people more insulin sensitive,” says Makimura.
So what’s the missing link? Makimura points to mitochondria, structures inside the body’s cells that are sometimes called “the body’s engines.” Like the motor in your car turning gas into go, “mitochondria break down sugar and fat to produce energy,” Makimura says.
Fatty acids might be to blame for underperforming mitochondria. “If you raise the levels of fatty acids in healthy men, you can reduce mitochondrial efficiency or activity,” Makimura says. And some scientists suspect that malfunctioning or underperforming mitochondria may be partly responsible for insulin resistance.
To sum up: Obesity is associated with higher levels of fat in the blood. More fat in the blood means less-efficient mitochondria. Mitochondrial dysfunction leads to insulin resistance. And insulin resistance leads to type 2 diabetes.
That’s the theory, at least. (Keep in mind, the links haven’t been proven.) Many of the studies looking at insulin resistance and mitochondria have been done in mice, and Makimura wants to see what’s going on in people. “We’re trying to understand human physiology,” he says. “To understand what’s going on with diabetes, mouse models are great, but ultimately we need to study humans.”
To investigate, Makimura is using a drug called acipimox to target one link in the chain: fat in the blood. “We’re hoping to reduce fatty acids and improve mitochondrial function and reduce insulin resistance,” Makimura says.
The Boston-based researcher has recruited almost 40 people with prediabetes for his study. Half of them are given acipimox; half receive a placebo. It’s what’s called a double-blind trial, which means neither the patients nor the researchers know who’s getting what until the end of the experiment.
At the beginning, Makimura puts study participants in a cutting-edge variation of an MRI machine to see what the cell’s engines, the mitochondria, are doing in real time. While in the scanner, participants exercise on a specially designed leg press, pushing their cell’s engines, the mitochondria, into action. Makimura, meanwhile, can monitor chemicals the mitochondria produce to see how well they’re performing.
There are also biopsies and other tests designed to give a complete picture of a person’s sensitivity to insulin and other indicators. Collecting the basic data requires a 12- to 14-hour commitment, with participants undergoing everything from a muscle biopsy to an MRI. “We’re really grateful to our patients,” Makimura says. “It’s a very involved study.”
The same tests are all repeated at the end of the six-month study. The hypothesis: Patients whose fatty acid levels were reduced using acipimox over the course of the study will also have more efficient mitochondria in the end—and, most important, be more sensitive to insulin.
If Makimura’s theory is correct, then there’s a chance the links between fatty acids, malfunctioning mitochondria, insulin resistance, and diabetes can be broken. If he can establish the way one influences or causes the next, he thinks it may be possible to come up with treatments to break the chain of events. “We want to find new ways to improve insulin sensitivity, to reduce the risk for diabetes,” he says.
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