New Weapons to Combat an Ancient Disease: Treating Diabetes

The Pima Indians of Arizona are known in history for the fierce battles they fought against neighboring Apache Indians. Now, however, remnants of the two tribes live in harmony amid the urban sprawl of Tucson. But today, many of these Pima Indians must fight a different yet deadly foe-type 2 diabetes-that hampers the body's ability to use the sugars in food for energy. The end result is telltale high levels of sugar in the blood and urine. Diabetes causes numerous complications and could be fatal if left untreated. It strikes about half of all adult Pima Indians in this country, making them susceptible to premature death from heart disease and stroke and prone to blindness, kidney failure, nerve damage and limb amputations. But the Pima Indians aren't the only ones plagued with type 2 diabetes and its complications. This disease, which is common in virtually all ethnic groups, is rapidly reaching epidemic proportions in the United States. According to the Centers for Disease Control and Prevention, the incidence of diagnosed diabetes among adults increased 49 percent from 1990 to 2000; 17 million people have diabetes in this country; and more than 200, 000 people die each year from related complications. The costs of treating diabetes and its complications exceed 100 billion each year in the United States, and those costs are likely to soar in the near future. Some experts predict that 25 years from now as many as one in four people may develop diabetes; that is, unless we effectively battle the disease in its early stages, before it has a chance to wreak havoc in the body and cause irreversible damage. Fortunately, we have some weapons. Over the last century, dozens of researchers have whittled away at the mystery of what causes diabetes, and we have gained an extraordinary amount of knowledge about the disease. That insight has blossomed into an armory of drugs that not only effectively treat type 2 diabetes, but also are also likely to prevent or forestall its development. Curious scientists exploring such basic questions as “What does the pancreas do? ” and “What causes fat cells to mature? ” have fine-tuned our understanding of what goes wrong in diabetes and how to right those wrongs. Diabetes is an ancient disease. Its symptoms, which include excessive drinking of water and frequent urination (to wash away the excess sugar in the blood), were noted on a scrap of Egyptian papyrus more than 3, 500 years ago. The ancient Roman doctor Aretaeus of Cappadocia also gave a vivid description of diabetes, describing it as “a melting down of the flesh and limbs into urine. ” Since then, many physicians have remarked on the sweet taste of diabetics' urine. Indeed, the technical term for this disease, diabetes mellitus, means “sweet flow” or “syphon. ” Because of this hallmark of diabetes, the disease was thought to be a disorder of the kidneys and bladder for more than two thousand years. Canadian orthopedist Frederick Banting, medical student Charles Best, and an experimental diabetic dog. When Banting and Best showed, in 1921, that they could keep this dog alive with their insulincontaining pancreatic extracts, they opened the door to the exciting possibility of treating diabetic patients with insulin. Image courtesy of the National Library of Medicine. What caused sugar to show up in the urine of diabetics remained a mystery until 1889, when two European physicians conducted an experiment to settle a debate. Joseph von Mering wanted to know what role the comma-shaped organ nestled in between the stomach and small intestine played in digestion. One way to figure that out would be to remove the organ, called the pan-creas, in experimental animals and see how such removal affected their functioning. But von Mering didn't think such a procedure was possible. His colleague, Oskar Minkowski, disagreed. To prove his point he took out the pancreas of a healthy dog. A few days later, Minkowski noticed that the dog kept urinating on the laboratory floor, even though he was housebroken and taken out regularly. Recognizing that frequent urination is one of the symptoms of diabetes, Minkowski tested the dog's urine and found it was high in sugar. At this point, von Mering and Minkowski rightly suspected they had created diabetes by removing the dog's pancreas. Further study led them to conclude that the pancreas secretes a substance that affects the body's use (metabolism) of sugar. That conclusion triggered a flurry of research aimed at isolating this substance, which was later given the name insulin. But such isolation proved difficult because insulin-containing pancreas extracts often also contained enzymes that ate up insulin or sparked severe reactions when tested in animals. Fortunately, a 30-year old Canadian orthopedist with a slow practice and lots of time on his hands was intrigued by the quest to isolate insulin. This doctor, Frederick Banting, had never treated any diabetic patients and had little research expertise. But one night, when he was having trouble falling asleep, he got an idea of how to avoid the enzymatic digestion of insulin. Banting rightly suspected that when researchers made extracts of the entire pancreas, the digestive enzymes secreted by cells called acini destroyed the insulin made by other pancreas cells (beta cells). Other researchers had shown that when they blocked the pancreatic duct, which is an outlet for the digestive enzymes made by the pancreas, just the acini cells die. Banting reasoned that if he tied off the pancreatic duct of dogs and waited several weeks until their acini cells died, he could prevent their destructive enzymes from contaminating the insulin-containing extracts he would later make from remaining pancreas beta cells. He convinced University of Toronto physiologist J. J. R. Macleod to let him try this game plan in Macleod's lab, along with a medical student, Charles Best. During the summer of 1921, while Macleod was vacationing in Scotland, Banting and Best isolated a pancreatic extract that instantly brought the blood sugar levels of severely diabetic dogs back to normal, relieved many of their symptoms, and kept them alive. The biochemist James Collip was then brought on board to help purify their extracts using methods developed to study enzymes. The efforts of these Canadians opened the door to the exciting possibility of treating diabetic patients with insulin. The photo on the left shows the gaunt condition of a diabetic child before beginning insulin therapy. This therapy dramatically improved the child's condition, as can be seen in the photo on the right. Courtesy of Eli Lilly and Company Archives. At the time, there was no effective treatment for diabetes, which causes the body to gradually break down protein and fat stores to supply its desperate need for energy. Children with diabetes wasted away, usually dying within a few years of being diagnosed with the disorder. So it was nothing short of miraculous, consequently, when a skeletal 14year-old diabetic boy on the verge of death was restored to good health within a few months of being given regular injections of Banting and Best's insulin preparation in 1922. With the introduction of insulin treatment, a diagnosis of diabetes was no longer a death knell. But insulin merely sustained life; it didn't cure diabetes. As diabetic patients lived longer, it became apparent that even with insulin therapy, the disease wreaked havoc on many of their organs and tissues. The complications of diabetes typically shorten the lifespan by about 15 years and increase the likelihood of a person becoming disabled. To better prevent or treat diabetes and its complications, researchers needed to better understand what caused it. But progress on that front couldn't be made until scientists discovered that diabetes was not one disease, but at least two. The remarkable success at using insulin to treat diabetes led to the notion that the disease was caused by a lack of insulin. But a series of observations in the 1930s by the British clinician Harry Himsworth led to a startling new view of diabetes. Curious about how diet affects sensitivity to insulin, Himsworth conducted a series of experiments in both animals and people that led him to the discovery that the body's use of sugar depends not only on how much insulin is present, but on how sensitive the body is to the effects of insulin. So, he reasoned, diabetes could be caused not only by a lack of insulin but also by a lack of sensitivity to insulin. To test out this theory, Himsworth gave diabetic patients sugar and insulin simultaneously and then checked to see how well the insulin fostered their use of the sugar. If they were relatively insensitive to the effects of insulin, their blood sugar levels shot up. These experiments showed that there were two types of diabetes: type 1 and type 2. People with type 1 diabetes were sensitive to insulin and had a history of suddenly developing the disease at a young age; those with type 2 diabetes were relatively insensitive to insulin and tended to gradually develop a milder form of the disease at middle age or older. Over several years, other researchers confirmed Himsworth's findings with more sophisticated techniques and revealed that most of those with diabetes (about nine out of ten) have type 2. Then in the 1950s, research by a nuclear physicist and an internal medicine doctor led to a surprise finding that changed the course of diabetes research and treatment and earned the scientists the Nobel Prize. Nobel-prize-winning nuclear physicist Rosalyn Yalow. She used radioactive insulin and antibodies to show that type 2 diabetics often produce more than normal amounts of insulin. This was a major breakthrough in diabetes research that changed knowledge and treatment. Photo courtesy of the National Library of Medicine. In the 1950s, Himsworth's notion that type 2 diabetes involved reduced sensitivity to insulin was not yet well accepted by the biomedical community. Another researcher, Arthur Mirsky, gave a different explanation for adult-onset diabetes– that it was due to rapid enzymatic digestion of insulin. Rosalyn Yalow and Solomon Berson, researchers at New York's Veterans Administration Hospital, set out to test this hypothesis. They gave radioactively labeled insulin to people with and without diabetes. According to Mirsky's theory, the insulin given to those with diabetes should have disappeared more quickly than that given to normal individuals. But Yalow and Berson found it disappeared more slowly! Puzzled, the researchers conducted additional tests that led them to conclude that the slower rate of disappearance was due to an immune response to the insulin used in the experiments. This response, which involved the production of antibodies, fouled up Yalow and Berson's attempts to test Mirsky's theory, but it led the researchers to discover something far more useful –a tool to measure circulating levels of insulin and other biologic compounds present in the blood at nearly invisible levels. The researchers combined the knack of antibodies to selectively seek out and latch on to highly specific substances with the ability of radioisotopes to be easily detected at miniscule levels. The end result was the radioimmunoassay-a technique that enabled researchers to measure exquisitely minute quantities of hormones (one thousand-billionth of a gram per milliliter of blood) and other compounds coursing through the bloodstream. This method is still in wide use today. In 1960, Yalow and Berson used their new technique to measure and compare the insulin response to sugar in those with type 2 diabetes to those without the disease. They discovered that instead of producing less insulin after being given sugar, people with type 2 diabetes often generated more insulin than did those without diabetes. This perplexing finding was totally unexpected and jolted the diabetes research community. Other researchers then discovered that although people in the early stages of type 2 diabetes produce more than the normal amounts of insulin, over time their insulin levels fall until eventually they dip below that seen in normal individuals and their diabetes becomes severe. The net result of all these findings was the hypothesis that to compensate for their lack of sensitivity to insulin (insulin resistance), people with type 2 diabetes initially produce excess insulin. That excess allows them to sufficiently convert the sugar in their diet to energy their tissues can use. But eventually the insulin-producing cells in the pancreas deteriorate and can't keep up with the need for insulin. At this point, these people's diabetes becomes severe, requiring insulin treatment. If this is an apt scenario, then people should produce higher than normal amounts of insulin before they become diabetic. Research by many investigators in the 1980s and 1990s showed that this was indeed the case. This led to the notion that type 2 diabetes is a slowly progressing disease that starts many years before people develop any obvious signs of the disease. And it begged the obvious question, “What can be done to stop this debilitating progression? ” Before that question could be addressed, researchers had to answer another question: “How can you detect diabetes-bound patients? ” Detecting high insulin production or insulin resistance was not practical or reliable enough in a clinical setting. More evidence was needed to pin down the suspect pre-diabetic patient. Fortunately, researchers had several tantalizing clues to go by, including an observation by Himsworth in the 1930s that many people with type 2 diabetes tended to be obese and have high blood pressure and atherosclerosis. These traits could be attributed to the older age at diagnosis of type 2 diabetes, rather than to the diabetes itself. But later research revealed that Himsworth was on to something, because type 2 diabetes is a multi-faceted metabolic disorder in which far more is disrupted than just blood sugar levels. This research uncovered that people with insulin resistance and/or those that produce excessive amounts of insulin often have a cluster of abnormalities known as the “metabolic syndrome. ” These abnormalities not only can serve as a clinical red flag for preventive measures, they can also help explain the mystery of why people with diabetes frequently succumb to cardiovascular and kidney disease. Telltale signs of the metabolic syndrome include high blood levels of triglycerides combined with low blood levels of high-density lipoprotein (HDL) cholesterol-traits that dramatically increase the risk of developing heart disease. Based on studies on animals and on liver cells grown in the laboratory, we now know that signs of the metabolic syndrome develop when people first start producing too much insulin and stem from insulin's effect on the liver. People with the metabolic syndrome also tend to have high blood pressure, which heightens their risk of stroke and heart and kidney disease. Obesity, especially excess abdominal fat, is another facet of the metabolic syndrome. Genetic research with mice led to the discovery of hormones released by fat cells that seem to foster or worsen insulin resistance. The most reliable marker of impending diabetes is an elevated blood sugar level following a meal (impaired glucose tolerance) that isn't quite high enough to suffice for a diabetes diagnosis. This marker tends to occur several years after the body has been exposed to high amounts of insulin and shortly before diabetes is diagnosed. A recent study found that up to one in four adult Americans has the metabolic syndrome. That's a disturbing finding considering that between 5 and 10 percent of patients with metabolic syndrome develop diabetes every year. Fortunately, there are more than a dozen drugs on the market now that are likely to help prevent or delay people from progressing from pre-diabetes to diabetes or can treat the disorder once it ensues. 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