Resisting Insulin

The hormone insulin, a key part of diabetes, may be the real culprit in everything from cancer to Alzheimer's disease.

by Monika Guttman

Richard Bergman, Ph.D., is receiving some surprising invitations these days. He is known worldwide as an expert on diabetes and the metabolism of diabetes, so he has given more lectures than he can count on the subject.

But recently, Bergman is being asked to speak at events for cancer research. “I tell them I only know two things about cancer—how to spell it, and that I don’t want it,” he jokes.

Bergman is in high demand because he knows a lot about an incredibly hot topic in cancer research these days: insulin, the hormone produced in the tiny beta cells of the pancreas that allows food energy (glucose) to enter the cells. Insulin, according to a slew of new studies, may play a role in everything from cancer to hypertension to cardiovascular disease.

For example, last winter a startling study from the National Cancer Institute suggested that high levels of insulin might be linked to the development of pancreatic cancer. The study, which appeared in the Journal of the American Medical Association, looked at research data of male smokers in Finland and focused on 169 men who developed pancreatic cancer. By examining blood samples given by the men at least five years before any of them were diagnosed with the cancer, the researchers found that those men with higher levels of insulin (and higher levels of blood glucose) were more likely to develop pancreatic cancer.

The study received a lot of media coverage, and not just because pancreatic cancer is the fourth leading cause of U.S. cancer deaths. What received the most notice was the author’s proposal that avoiding high levels of insulin “could possibly impact pancreatic cancer development, as well as other cancers and chronic diseases.”

Another study suggested endometrial cancer is linked to high levels of insulin as reflected in reduced adiponectin—a protein secreted by fat cells when there is reduced insulin resistance. Insulin resistance is a state in which the cells have been bombarded by so much insulin—thanks in part to overeating, which constantly stimulates release of insulin from the pancreas—that they no longer accept insulin as readily as before, often leaving higher levels of insulin and glucose circulating in the body. Although endometrial cancer has long been associated with obesity, the researchers were looking deeper to see what, precisely, might be the trigger. They came up with hyperinsulemia—high levels of insulin from insulin resistance—as the possible culprit.

recent study from Brown University surprised everyone by showing that insulin may be expressed in the brain as well as in the pancreas. The same group of researchers had already looked at insulin levels early in the course of the disease. In a study in the Journal of Alzheimer’s Disease, the authors found brain insulin disappears early and dramatically in Alzheimer’s disease. And many of the unexplained features of Alzheimer’s, such as cell death and tangles in the brain, appear to be linked to abnormalities in insulin signaling in the brain.

“Historically, we all thought insulin resistance was a risk factor or cause of diabetes alone,” explains Bergman, the W.M. Keck Chair in Medicine, chair of the Department of Physiology and Biophysics and director of the Metabolic Research Laboratory at the Keck School. “Over the years, it has become clear that insulin resistance is only one cause of that disease. There are also altered functions of the beta cells involved, there are genetic factors involved, and all of this has to be balanced with how much insulin is released by the pancreas itself. It’s not a simple cause/effect equation.” But over the past decade, “research has shown insulin resistance is also a risk factor for other diseases, including hypertension and cardiovascular disease and now cancer,” he says. “If insulin resistance is associated with other diseases, then the question becomes why is that? And that’s why researchers started to focus on insulin itself, which is usually elevated in states of insulin resistance.”

Insulin is a relative newcomer to the medical world. For thousands of years, diabetes was known as the sugar disease, the wasting disease, and was a death sentence. Although by the mid-1800s physicians knew the disease had to do with a malfunction of the individual cells in the pancreas, they did not know what, exactly, was going wrong.

Then in the early 1920s at the University of Toronto, Canada, Frederick Banting, M.D., and Charles Best, a medical student assigned as Banting’s research assistant, made an extract from partially atrophied dog pancreases. The crude formula was then given to diabetic dogs, with various, but encouraging results. Spurred by these results, Banting’s supervisor J. J. R. Macleod, M.D., and biochemist James B. Collip, Ph.D., helped Banting and Best purify what became known as insulin. Within months, insulin was put into mass production and used to save millions of lives, while the medical world turned its attention to the mechanics and promise of this fascinating new hormone.

Insulin research proved pivotal to diabetes. The association is most obvious in Type 1 diabetes, when the beta cells that produce insulin are destroyed by the body’s immune system gone awry, and thus the body produces no insulin at all. These diabetics stay alive only by injecting insulin. In Type 2 diabetes, insulin is often still produced. But the pancreatic cells lose their efficiency at producing or distributing it, and usually other cells in the body have a difficult time responding to it because they have become “insulin resistant”.

Insulin also is important for a host of other functions in the body. In recent years researchers have studied links between insulin and aging and insulin and muscle mass; the body needs insulin to help turn proteins from food into proteins in muscle, a process called protein anabolism. Insulin also is necessary for normal bone formation, and insulin deficiency is suspected to lead to osteoporosis, while high levels of insulin may play a role in osteoarthritis.

Insulin affects fat metabolism in that it can change the liver’s ability to release fat stores. Insulin helps the liver store glucose in a form called glycogen and helps fat cells convert glucose to triglycerides. A low level of insulin causes the liver to release glycogen and can inhibit the body from absorbing potassium or cause the muscles of artery walls to contract. High levels of insulin, on the other hand, may be linked to higher levels of other hormones in the blood, such as estrogen or progesterone and may lead to inflammatory conditions.

Perhaps most significantly, insulin stimulates the production of insulin-like growth factor (IGF-1) in the liver, a separate hormone that greatly resembles insulin and is intimately involved in cell growth and death. According to Leslie Bernstein, Ph.D., Keck School professor of preventive medicine, Rudolf Kaaks, Ph.D., at the International Agency for Research on Cancer in France, suggested that insulin and IGF-1 can promote tumor development by inhibiting apoptosis (cell death), and by stimulating cell proliferation, thus playing a role in cancers of the colon, pancreas, endometrium, breast and prostate. “One of the pathways to breast and endometrial cancer was thought to be the pathway of diabetes, but perhaps that is really just insulin levels,” she speculates. “Obesity affects insulin sensitivity and works through the steroid hormone pathways. There’s a sort of a cascade between obesity, inflammation, insulin levels and disease.”

Studies by Bernstein, who is the AFLAC Chair in Cancer Research, show that exercise activity can lower levels of female hormones circulating in the blood, particularly estrogen and progesterone. Exercise also increases insulin sensitivity and lowers the concentration of insulin in the blood. Lack of exercise would contribute to a higher concentration of insulin in the blood, which may result in higher levels of female hormones, she says, “which would help explain a connection.”

Linking insulin itself to disease is not new, notes Thomas Buchanan, M.D., professor of medicine and obstetrics/gynecology and associate dean for clinical research at the Keck School. “Insulin became measurable in the blood in the 1950s,” he says. “Some researchers at the time proposed that insulin was associated with many diseases, but that research sort of fell out of favor for a while.”

Then in the 1980s, when diabetes rates started to soar, studies began to measure the levels of insulin in the blood and noted that higher levels were associated with cardiovascular disease and other conditions like hypertension. “That’s when it was first proposed that something more than just diabetes was at work in these diseases. And epidemiologic studies found that if you measure high insulin levels you find all sorts of other risk factors clustered together: obesity, inflammation, insulin resistance,” Buchanan says. The first name given to this condition was Syndrome X. Today it is known as Metabolic Syndrome or prediabetes, and is characterized by a conglomeration of factors that include obesity, high levels of insulin, inflammation, hypertension and high triglycerides.

What makes it difficult to separate out insulin as a disease trigger is that getting a model for testing “is almost impossible,” Bergman says. “There is no one without insulin. Type 1 diabetics have to inject it. And those who have high insulin levels usually have high glucose levels as well, so it’s difficult to distinguish between the two. There may also be genes for hyperinsulemia as well. So it’s difficult to know if it’s the insulin itself, or something else. The question is not settled.”

Bergman notes that some researchers are looking at whether reducing the amount of insulin in the blood lowers risk for disease. “There are ways to lower insulin with drugs, and the question will be asked whether that reduces risks,” he says. For example, one of the medications given to those with Type 2 diabetes and insulin resistance is metformin, which reduces the amount of glucose produced by the liver. “As the glucose goes down, the insulin goes down,” Bergman explains. “This is not something I’m endorsing, but it will be studied.”

Bergman believes the real understanding of insulin and its role in disease will come from in vitro models as opposed to human models. “From in vitro studies of insulin, we know it’s a growth factor and we know it may have something to do with the laying down of atherosclerosis,” he says. “But we’re a long way from knowing everything about it.”

The rush is on to discover how, when and where insulin is secreted. In the laboratory of Robert Chow, M.D., Ph.D., associate professor of physiology and biophysics, Chow and postdoctoral fellow Darren Michael are trying to monitor insulin secretion from the 10,000 tiny vesicles in each beta cell of the pancreas. “The mystery is how their secretion is regulated,” Chow says. Using electrophysiology or microscope imaging, the researchers have found only a small pool of about 100 vesicles actually send out the insulin. Michael says that figuring out how to get insulin crystals out of the other 9,900 vesicles could be key to helping provide more insulin needed in Type 2 diabetes.

Some researchers like Howard Hodis, M.D., the Harry Bauer & Dorothy Bauer Rawlins Professor in Cardiology and director of the Atherosclerosis Research Unit at USC, remain skeptical of any solo role for insulin in triggering disease. “When you take the totality of the data, when you look at it from 10,000 feet, it’s going to be the interrelation of a number of factors—not just insulin, but obesity and insulin and glucose and genetic factors and environmental factors,” Hodis says. “There’s no doubt that insulin resistance plays an important role in atherosclerosis in humans. And rarely is high insulin shown to be protective. But blaming it all on a single molecule? Biology is just not that simple.”

It may not even be important to distinguish whether it is the insulin or the obesity or the inflammation that causes these diseases, adds Bernstein. “For example, we don’t know why smoking affects lung cancer. Does it cause inflammation? Is it an irritant? But we don’t have to know why if we can make a change that will lower our risk. Not smoking reduces lung cancer risk. Exercise and losing weight lowers risk of the diseases linked to insulin levels or obesity or metabolic syndrome. That may be enough.”

Indeed, says Buchanan, there is no one-size-fits-all relationship between obesity, high insulin levels and disease. “One person may develop hypertension and cardiovascular disease, another may have a fatty liver and another may have polycystic ovarian syndrome. To the extent that treating the obesity reduces the downstream morbidity and mortality, that may be all the clinician needs to know. As disease progresses, we then have to treat the conditions separately, as there’s no uniform treatment that will treat, say, both high triglycerides and hypertension. It may be the insulin. It may be the inflammation. It may just be the obesity. For now, it’s hard to say.”

Bergman says he expects research in the next five years to help answer these questions, and he personally believes hyperinsulemia will be found to play a significant role in disease. “That’s just my own opinion, because it makes a lot of sense based on what we know about insulin, about what it does. But right now it’s just a bias.” And what Bergman knows will keep the invitations coming from the cancer community and the research moving forward in the medical community.