Diabetes and metabolism - The how of clinical studies
The body's metabolism directly impacts how well a person can regulate insulin and, in turn, control type 2 diabetes. Mayo Clinic's long-standing expertise in diabetes is due, in part, to clinical research by leaders such as K. Sreekumaran Nair, M.D., Ph.D. His work, along with many others', is setting the stage for a major initiative against the disease.
Mark Amols, M.D.
K. Sreekumaran Nair, M.D., Ph.D.
An electron microscope image of skeletal muscle (25,000x) showing mitochondria (the organelle in a cell responsible for energy metabolism) within the myofibrillar area (responsible for muscle contractile function).
Mark Amols, M.D., is gazing at the result of two days of painstaking work: A beige dot, about the size of a pinhead, nestled in the bottom of a test tube. Although it may not look like much, that dot — actually a clump of human mitochondria, the parts of cells that convert food energy into energy the body can use — holds important clues to metabolic disorders.
Less than an hour earlier, the mitochondria were functioning invisibly within the muscle cells of a Mayo Clinic study participant who is insulin-resistant. To protect her privacy, we'll call her Marie. After numbing Marie's leg, Dr. Amols, a specialist in reproductive endocrinology at Mayo Clinic, used a needle to extract a sample of muscle tissue. The tissue, which had to be processed quickly to prevent degradation, was carried to a research lab right down the hall. Three technicians immediately began processing the sample, placing some of it in what looks like a drill press but is actually an instrument that can finely grind tissue without damaging the cells. After a couple of spins in the centrifuge, the mitochondria were isolated. Other pieces of the tissue were processed differently, for tests involving oxygenated molecules and protein.
This clinical study of insulin resistance and mitochondrial function may eventually provide pieces to solve the complicated puzzle of type 2 diabetes. "The goal is to find the cause of diabetes," says Dr. Nair, the Mayo Clinic endocrinologist leading the study. "If you know the cause, you can target it and thereby figure out how to prevent diabetes or at least delay the onset."
Once known as adult-onset or noninsulin-dependent diabetes, type 2 diabetes is a chronic condition that affects the way the body utilizes sugar (glucose). People with type 2 diabetes don't produce enough insulin — a hormone that regulates the absorption of sugar into cells — and their cells resist the effects of insulin (insulin-resistant). Type 2 diabetes costs the United States $170 billion annually and is the leading cause of cardiovascular deaths, kidney failure, blindness, sexual dysfunction and many other chronic complications.
In partnership with the University of Minnesota, Mayo has launched the Decade of Discovery, a 10-year research effort to end diabetes. "Type 2 diabetes is an ancient disease, but is on the ascent," Dr. Nair says. "It is becoming a global epidemic and will be the major health problem of the 21st century."
For three decades, Dr. Nair's research lab has studied the importance of mitochondrial function and altered protein turnover in diabetes. Protein turnover is the balance in cells between the creation of new protein and the removal of older protein. It varies among individuals in ways that researchers don't yet fully understand. One research path involves exploring whether altered protein turnover causes damaged protein to accumulate in cells, factors that may contribute to insulin resistance.
In the current clinical study, insulin-resistant women are being compared with a control group with normal insulin sensitivity. "Our hypothesis is that women who have insulin resistance are going to have lower protein turnover and accumulate a lot of that older protein," Dr. Amols says. "Women who are less insulin-resistant will have more protein turnover. The new proteins will be made, and the old ones will be removed, with fewer modifications."
The study includes only women because the high level of insulin resistance required for participation is associated with polycystic ovary syndrome (PCOS), a hormonal disorder in women that causes infertility. In addition to protein turnover, the researchers are collecting data on mitochondrial function and the effects of oxygen-containing molecules on cell metabolism.
In a later study phase, the insulin-resistant women will be divided into two groups, with one completing an exercise program. Afterwards, insulin sensitivity and protein turnover will be measured again. "We expect that the women who exercise will have increased protein turnover," Dr. Amols says.
One of the challenges of diabetes is that people respond differently to various strategies for controlling insulin resistance. Dr. Amols notes that while exercise might work for people with a lower body mass index, others might need to limit calories aggressively. Still others might benefit from medications that reduce insulin resistance. Mayo researchers hope to pinpoint the diabetes-prevention measures that work for various groups of people.
"It's so engrained that certain things are good for you or not good for you." Dr. Amols says. "But that's not research-based."
Mayo's commitment to precise research and evidence-based patient care is epitomized by its Clinical Research Unit (CRU), the site of the Nair team's study. Located inside Saint Marys Hospital, the 21-bed CRU offers Mayo investigators the support they need for research designed to improve patient care as quickly as possible. CRU nurses, dietitians and support staff undergo specialized training and work only in the CRU. Participants can spend part of a day or stay overnight if necessary. "These are all highly specialized people," Dr. Nair says. "Their only focus is to make sure everything is done precisely." Another CRU at Mayo is located in the Charlton Building of Rochester Methodist Hospital; an extended CRU serves research participants who may be on the hospitals' other floors; and there is yet another — a mobile CRU housed in a customized motor home — that facilitates research off campus.
Dr. Nair was instrumental in creating Mayo's CRU, one of the few such facilities in the U.S. The unit at Methodist Hospital has nine beds for outpatients as well as a kitchen where patients' meals are monitored so closely that extra crumbs are wiped from plates with spatulas to ensure precise nutritional measurement. "Research is about controlling the control variables," Dr. Amols says. "The more you control, the more you can uncover causation. The CRU allows you to have the ideal research environment."
On a recent morning, the environment inside Marie's CRU room is relaxed yet focused. On this first day of tests, her insulin resistance is measured. Having stayed overnight at the CRU for monitoring, Marie laughs about how well she slept: "It's so quiet here — no snoring, no cats." Glucose and insulin are injected intravenously. Like a well-choreographed ballet that starts and stops, conversation ceases every 10 minutes while the nurses draw blood samples that are analyzed in the room with results given to Dr. Amols.
The glucose contains a heavy-water isotope tracer, which allows the lab team to differentiate between the infused glucose and glucose from the participant's liver. Before the muscle biopsy the following day, the study participant will receive another, unique chemical tracer that highlights newly synthesized protein in her muscle cells. When the protein is later examined in the lab, "Only the new protein will have the tracer in it," Dr. Amols explains. This new methodology allows researchers to differentiate between old and new protein, and thus determine protein turnover.
Nestled within Mayo's campus, the CRU might seem a remote outpost in the war on diabetes. But Mayo's research efforts have a global reach. Along with the University of Minnesota, Mayo recently signed a research agreement with the Karolinska Institute of Stockholm, one of Europe's top-rated medical research universities. Under the agreement, called Frontiers in Biomedical Research, the three institutions will share ideas, scientists and research projects in several areas, including metabolic studies. The goal is to rapidly translate biomedical discoveries into improved patient care across the globe. Dr. Nair, who initiated a research relationship with Karolinska nearly two decades ago, received an honorary doctorate from the institute in 2008.
For Dr. Nair, scientific discovery has no borders. "To be creative, you need to exchange ideas," he says. "That's the best thing about scientific culture — you share with others so ultimately patients will benefit."