By Wayne Clark | February 11, 2010 5:57 pm
Diabetes was described as early as 1552 BC, but it wasn’t until the late 1800’s that it was linked to the pancreas, and not until 1936 that it was classified into two different types. Today, the cause of Type 2 diabetes, the most common form, is still an open question. Still, scientists are closing in on a more thorough understanding of what Dr. J. Denis McGarry, former Professor of Internal Medicine and Biochemistry at the University of Texas, Southwestern Medical Center, once described as “the enormous complexity of a disease process in which almost every aspect of the body’s metabolism goes awry.”
What causes Type 2 diabetes is an important question, not least because people with diabetes want to know why they have it. The questions only go on from there: Could it have been prevented? Can it be reversed? Are my children at risk? Does obesity cause diabetes, or does diabetes cause obesity? Does insulin resistance (the reduced ability of muscle, fat, and other cells to respond to insulin) harm the insulin-producing beta cells of the pancreas, or is insulin resistance the result of damaged beta cells?
These “chicken and egg” questions are at the heart of current investigations into the cause of Type 2 diabetes. What is immediately apparent is that diabetes is more than a disease; it is a disease process. It begins long before it becomes evident, as much as 15 years before the appearance of any signs or symptoms. More and more, in fact, it is obvious that it begins at conception.
“It’s widely felt that genetics plays a role in why some people can be subjected to the obesifying environment in which we live and not develop diabetes, and others can become equally obese and develop it,” says David E. Cummings, MD, Associate Professor of Medicine at Seattle VA Puget Sound Health Care System. “It largely has to do with the health of their beta cells.”
There is an undeniable association between obesity and diabetes. In one study, 30% of people newly diagnosed with diabetes had a body-mass index (BMI) of 25—30 kg/m2, and 60% had a BMI greater than 30 kg/m2. A BMI of 25—30 is considered overweight, and a BMI above 30 is considered obese.
Genetic mapping has found a number of genes that are associated with diabetes, and others associated with obesity. Recently, a gene locus was identified that influences the risk of diabetes primarily by increasing fat mass. A study of the Pima Indians of Arizona found an exact match between the locations of an obesity susceptibility gene and a diabetes susceptibility gene. These are the first, but likely not the last, indications that diabetes and obesity may be “co-inherited.”
Generally, obesity is believed to be a genetic predisposition, though one that can be compensated for by behavior. As evidence, Dr. Cummings points to studies of identical twins in which both will become obese even if raised in different environments, and studies of fraternal twins (who are not genetically identical) in which one will become obese and one not, even though raised in the same environment. These studies and others demonstrate, he says, that 70% to 80% of obesity has a genetic basis.
“The fallacy of the ‘willpower’ argument,” Dr. Cummings says, “is the genetic basis of obesity. It is possible to modify lifestyle and achieve a 5% to 10% reduction in weight, and this should be encouraged, but the biological set-points are difficult to change.”
Obesity is a problem because it increases insulin resistance, limiting the body’s ability to use insulin. Insulin resistance is believed to be the first sign of what can become diabetes. As it turns out, fat is not just an inactive tissue that sits there in the body. It produces, especially when inflamed, cytokines (a type of protein) that affect the liver, which in turn produces substances that interfere with insulin usage.
Another potentially negative impact of excess fat is that people who are obese have high levels of free fatty acids (FFAs) in their blood. Various tissues take up the FFAs and use them instead of glucose as fuel. The result is insulin resistance and increased blood glucose levels.
Obesity is not a guarantee of diabetes, however. In fact, only 20% to 25% of people at risk for diabetes (whether obese or not) will develop abnormal beta-cell function and ultimately diabetes. The reason goes back to Dr. Cumming’s reference to the “health” of the individual’s beta cells, and is thought to be tied to the cells’ genetic programming.
An increase in insulin resistance causes the beta cells to compensate by increasing secretion of insulin. In fact, people who are obese and have insulin resistance actually increase the number of beta cells and their output of insulin. This compensation keeps blood glucose levels normal. The compensation can go on for many years, or for a lifetime. People can be obese and even insulin resistant their entire lives and never develop diabetes. In diabetes, however, the compensation either fails to occur at all, or cannot keep up with the insulin resistance. Essentially, the beta cells are either genetically programmed to compensate, or they aren’t.
Taken as a whole, the most common contemporary view is that a genetic predisposition to diabetes is necessary – but not sufficient – to develop the disease. The trigger is environmental: obesity (which itself has a genetic basis), aging, and/or lifestyle. Once the process starts, a cascade of dysfunctions occurs: The beta cells begin to fail, there is an increase in glucose secretion by the liver, and insulin resistance increases. The beta cells cannot compensate, and they continue to deteriorate, raising blood glucose levels – a vicious cycle.
There is another view, however. Dr. Daniel Porte, Jr., Professor of Medicine at the University of California, San Diego, School of Medicine, and his collaborators have suggested that a “primary defect” in the beta cell reduces insulin secretion. This affects the complex central nervous system regulatory mechanism that controls energy homeostasis, or a state of equilibrium in the body. Specifically, in this theory, reduced insulin availability to the brain causes signals to increase food intake, leading to obesity and subsequent obesity-induced insulin resistance. Ultimately, the same vicious cycle is created. The difference is that the “neurocentric” model places the beginning of the process in the beta cells rather than in excess body fat.
The neurocentric model would place more emphasis on environmental factors such as abundant, high-calorie foods and lack of physical activity. Both of these factors enhance the response to the brain’s hunger signals.
Another interesting hypothesis that may ultimately support either of the others is the “fetal origins” hypothesis. It has long been observed that there is a relationship between birth weight and the risk of developing diabetes later in life. Some researchers have described the relationship as “linearly inverse”–that is, low birth weight is a predictor of diabetes–while others have described it as “u-shaped,” meaning that there are consequences to both low and high birth weight. Various causal factors that have been suggested include either maternal undernutrition or overnutrition.
Notably, a relationship has been observed between the risk of diabetes associated with low birth weight and the risk of later development of diabetes in the father. This could indicate a genetic link in support of the fetal origins hypothesis.
Given the genetic link, prevention of diabetes even in the presence of the predisposition is a major research goal. Clinical trials have demonstrated that the number of people who develop diabetes can be reduced by 25% to 62% over a period of three to six years. The concept is to reduce body fat or to counter the effect that excess fat has on insulin resistance.
The Finnish Diabetes Study in Finland and the Diabetes Prevention Program in the United States showed that reducing caloric intake and increasing physical activity can reduce the risk that people with impaired glucose tolerance (sometimes called prediabetes) will go on to develop diabetes. The “Xenical in the Prevention of Diabetes in Obese Subjects” study combined this kind of intensive lifestyle modification with the weight-loss drug orlistat and produced a 37% relative risk reduction for diabetes compared with lifestyle intervention alone. Several studies using the diabetes drugs known as glitazones (Actos and Avandia), metformin, and acarbose (brand name Precose) have also resulted in significant risk reductions.
There is another way to reduce body fat, and to reduce it dramatically: bariatric surgery. A trial in Australia randomly assigned study participants with recently diagnosed Type 2 diabetes to either lifestyle modification or laparoscopic adjustable gastric banding (commonly referred to as the Lap-Band procedure). After two years, 73% of the people who had had the Lap-Band surgery were diabetes- free, compared with just 13% of those in the lifestyle group.
An even more dramatic result has been reported in studies of the impact of the Roux-en-Y gastric bypass procedure on diabetes and obesity. Some 84% of people who have the surgery have complete remission of diabetes following the procedure. What’s more, a third of those people go into remission before they even leave the hospital, and most of the rest are diabetes-free within a month.
“It’s true that gastric bypass surgery causes diabetes to remit long before it would be expected to do so as a result of the weight loss,” Dr. Cummings says. “Also, people who lose weight due to bypass surgery have better glucose tolerance later on than do those who have lost equivalent weight due to diet or banding.”
Scientists speculate that the bypass surgery brings other factors into play beyond the loss of weight. One theory is that after bypass, food is brought to the far end of the small intestine more quickly, where it stimulates production of the hormone glucagon-like peptide 1 (GLP-1). GLP-1 stimulates the secretion of insulin and may also send signals of satiety (fullness) to the brain. This “antidiabetic” effect could account for the rapid resolution of diabetes. Another possibility is that the procedure impairs the production of the hormone ghrelin in the stomach. Ghrelin is a hunger hormone and has the opposite effect of GLP-1.
This is a treatment, or arguably a cure, for existing Type 2 diabetes. The exciting possibility, however, is the potential for using the procedure to prevent diabetes from developing in obese people who have insulin resistance. Dr. Cummings explains that early in the development of diabetes, the beta cells are overwhelmed and eventually lose the ability to secrete the insulin they’re still producing. However, the cells are not destroyed, and significant weight loss can bring them back to normal functioning.
“You might say we should do bypass surgery earlier, because if you wait too long, the cells are gone and you can’t rescue them,” he says. “There is controversy about this approach, but perhaps it would be best to reduce the weight earlier, and skip the 20 years of toxicity from high blood sugar levels and the development of complications.
“The difference between the 84% of people whose diabetes disappeared after bypass surgery and the 16% who remained diabetic,” he points out, “was the length of time they had the disease.”
The Swedish Obese Subjects Study compared surgical versus nonsurgical interventions in 4,000 obese people and found that people in the surgical group not only had improved remission of diabetes, but also improved prevention of new diabetes. There is even evidence that bariatric surgery lowers long-term mortality.
The final answer, or answers, will take some time. As recently as 2008, researchers at Joslin Diabetes Center published work demonstrating that insulin resistance in the liver alone could, in mice, cause the development of metabolic syndrome. The metabolic syndrome is a collection of conditions – high blood pressure, high cholesterol, glucose intolerance, and obesity – that is generally viewed as a precursor to diabetes.
The Joslin researchers tested their hypothesis by genetically engineering mice with no insulin receptors in their livers, mimicking insulin resistance in the organ. The mice developed many of the conditions of metabolic syndrome and, when fed a high-fat diet, they all developed coronary artery disease. The control animals with normal livers did not display these results, leading to the conclusion that if insulin uptake in the liver is compromised, the metabolic syndrome and, potentially, diabetes will result. The study did not address the possible cause of insulin resistance in the liver in humans, so it opens yet another line of investigation into the cause or causes of Type 2 diabetes.
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