Finding the Key To Prevent And Cure Type 2 Diabetes

Type 2 diabetes is the most common form

Type 2 diabetes, the most common form of the disease, is a chronic condition that reduces the body’s ability to process glucose (blood sugar). It commonly occurs in people who are obese. While Type 1 diabetes (the kind believed to be linked to genetics) is relatively rare, Type 2 diabetes affects almost 10 percent of the U.S. population (29.1 million people). Another 40 percent (86 million adults) have prediabetes, or higher than normal blood sugar levels, according to the U.S. Centers for Disease Control and Prevention.

Researchers in UCLA’s Metabolic Research Theme are working to find ways that metabolism can unlock the key to preventing or curing Type 2 diabetes. Two avenues of exploration hint that changing the way the pancreas secretes insulin might keep people healthy.

Taking a new look: What causes insulin resistance?

Researchers have long thought Type 2 diabetes occurs because tissues resist the effects of insulin or because the pancreas doesn’t make enough insulin to sufficiently regulate blood sugar. Either way, the result is too much insulin secreted into the blood, leading to insulin resistance.

Normally, the hormone insulin, produced by beta cells in the pancreas, regulates the movement of blood sugar into cells. The cells burn or store the sugar. In Type 2 diabetes, this process doesn’t function as it should.

Too much blood sugar is indeed linked to obesity, which is a strong risk factor for Type 2 diabetes. But Orian Shirihai, MD, PhD, director of the Metabolic Theme, believes the disease actually stems from poor quality control in mitochondria within pancreatic beta cells. Read more about mitochondrial quality control.

More About Mitochondrial Quality Control

Dr. Shirihai and his team argue that:

  • Evidence exists that insulin resistance occurs because some people secrete a high level of insulin continuously, not because there is too much sugar in the blood.
  • This occurs because the mitochondria in the beta cells cannot remove, repair and restore themselves. Read more about how mitochondria work in metabolism, obesity and Type 2 diabetes.
  • The way to treat diabetes is to make the beta cells in the pancreas secrete less insulin.

Diabetes usually starts when too much insulin is secreted into the blood, leading to insulin resistance. We argue that the way to treat diabetes is to make the beta cell secrete less insulin.

Dr. Orian Shirihai

Learning from obese people without type 2 diabetes

Many obese people develop Type 2 diabetes, requiring long-term treatment with insulin or other medications. Marc Liesa-Roig, PhD, an assistant professor in the department of medicine, aims to better understand the metabolism of people with obesity who don’t develop Type 2 diabetes.

The ability to avoid Type 2 diabetes may come down to hemes (iron-containing molecules). Heme is an essential component of mitochondrial function, because it helps with the electron transport chain that produces usable energy in the form of ATP (adenosine triphosphate). The best-known heme is hemoglobin, which transports oxygen in the blood.

Liesa-Roig is working to understand the paradox of heme, obesity and Type 2 diabetes:  

Dr. Marc Liesa - researching type 2 diabetes
  • Heme production: Without heme, the mitochondria do not work, but at the same time, people need mitochondria to synthesize heme.
  • Reactive oxygen species (ROS) byproducts: Heme increases ROS byproduct production. The mitochondria in pancreatic beta cells need some ROS because, at low levels, they act as signaling molecules that promote insulin release. But during times of stress, ROS byproducts can damage cells.
  • The pancreas and insulin: The hormone insulin tells the body to take sugar from the blood after food is eaten and consume it to produce energy or heat in tissues or to store it in fat. When tissue no longer pays attention to insulin, people have both sugar and insulin in their blood. Pancreatic beta cells try to compensate by secreting more insulin via the ROS signal.
  • Type 2 diabetes: In obese people who end up developing Type 2 diabetes, the body may limit insulin secretion by removing ROS. Those people then need to use supplemental insulin.
  • Balancing blood sugar and insulin: Some metabolically healthy obese people can balance excess blood sugar with insulin secretion.

Our goal is to discover how to alter ROS signaling so that pancreatic beta cell mitochondria can adapt to obesity and secrete as much insulin as needed, eliminating need for therapy.

Dr. Marc Liesa