Why is it important to fight diabetes?

Diabetes affects 17 million Americans, 6.2% of the population. In some ethnic groups, the prevalence of diabetes exceeds 15%. Every year, 1 million people aged 20 years or older are diagnosed with diabetes. Direct medical and indirect expenditures attributable to diabetes in 2002 were estimated at $132 billion. Of the 17 million diabetic patients in the United States, about 10% have type 1 diabetes, and the remaining 90% suffer from type 2 diabetes.

The situation regarding type 2 diabetes is particularly concerning, because its prevalence is reaching epidemic proportions. In the United States, the number of affected adults has increased by almost 50% between 1991 and 2000. Even more concerning is the fact that type 2 diabetes, which used to be only seen in middle-aged individuals, is more and more frequently diagnosed in children, in association with the increasing prevalence of obesity. The appearance of diabetes among children will undoubtedly have devastating consequences, because these patients will have much more time to develop the long-term complications of diabetes, such as kidney failure, blindness, nerve damage, heart attack, and strokes.

What do we know today about diabetes?

Basically, diabetes is defined by abnormally elevated levels of glucose in the blood. Because insulin is the only hormone that can lower blood glucose, diabetes is due to an absolute or relative insulin deficiency. Absolute means that there is no insulin production by the pancreas whatsoever, which is what happens in type 1 diabetes. Relative insulin deficiency means that there is some insulin but it is not effective in lowering blood glucose levels. Its secretion is quantitatively or qualitatively insufficient to maintain normal levels of glucose in the circulation. This is what happens in type 2 diabetes.

It has long been thought that type 2 diabetes was strictly due to insulin resistance, which is the inability of the tissues such as the fat and the muscles to respond to the action of insulin. In the last 20 years, however, it has become more and more obvious that the secretion of insulin by the pancreas is abnormal in type 2 diabetic patients. In non-diabetic individuals the secretion of insulin is a highly regulated process. What that means is that insulin is not just continuously released by the pancreas at a constant level throughout the day, but is constantly regulated, in real time, as a function of variations in blood glucose levels that normally occur during the day. In type 2 diabetes, this fine-tuning is lost, leading to inadequate insulin secretion. Therefore, the concept is now generally accepted that both insulin resistance and defective insulin secretion are necessary, and must be present simultaneously for type 2 diabetes to occur.

Over the past 6 years or so, the work of my laboratory has focused on the effects of fat on the secretion of insulin. We know that obesity is a risk factor for developing type 2 diabetes, we know that one of the reasons for that is that obesity creates insulin resistance, and we believe that an additional reason is that obesity and high levels of fat impair insulin secretion.

Our current working hypothesis can be summarized as follows: Initially, type 2 diabetes develops as a result of both insulin resistance and defective insulin secretion. The nature of the initial defect that causes abnormal insulin secretion is unknown. However, once diabetes is established, it is well known that the function of the pancreatic beta-cell inexorably deteriorates. No matter how intensive the treatment is, in diabetic individuals the secretion of insulin always declines over the years. We believe that there are 2 major reasons for this. One is the elevated levels of glucose themselves, which are known to further contribute to the deterioration of insulin secretion, a phenomenon called glucose toxicity. The second phenomenon is the harmful effects of fatty acids, the fatty molecules that circulate in the blood, a phenomenon referred to as lipotoxicity. Indeed, what we have shown in our laboratory is that elevated levels of fatty acids impair the ability of the pancreatic beta-cell to secrete insulin when glucose levels are also elevated. In other words, if one has normal glucose levels, high levels of fatty acids in the blood do not harm the beta cell. In contrast, if one has type 2 diabetes and their blood glucose levels are elevated, the same high levels of fatty acids become toxic to the beta-cell and impair insulin secretion.

Besides the effects of fat on insulin secretion which have been the focus of our work, considerable progress has been made in several important areas of research. For instance, we now know a lot more about the set of genes that determine a stem cell to become a beta-cell. This, ultimately, should allow us to force differentiation of multipotent cells into pancreatic beta-cells in the laboratory, thereby providing a virtually unlimited supply of beta-cells available for transplantation. Much progress has been made, also, in understanding the mechanisms that regulate the production and secretion of insulin. Identifying these mechanisms is critical, because they are dysfunctional in type 2 diabetes. If we can better understand how the beta-cell normally works, then we can start to pinpoint what precisely, at the cellular and molecular level, is abnormal in type 2 diabetes, and begin to devise specific targets for therapeutic interventions.

In this context, what is the role of the American Diabetes Association?

Unfortunately, in times of economic uncertainty, it is more important than ever that private organizations such as the ADA support diabetes research. Such organizations do much more than substituting for federal funding: they support young investigators.

I arrived at Pacific Northwest Research Institute in Seattle 5 years ago. I was starting a laboratory and a new project, and despite a generous start-up package from my institution the agreement was, as it always is, that I had to fairly rapidly obtain my own independent funding. The first grant that I obtained was a research award from the ADA, which allowed me to generate preliminary data to then write a proposal to the NIH and obtain federal funding. Later, I obtained a Career Development Award from the ADA to allow me to strengthen and expand my research group, and to establish myself as an independent investigator. Needless to say if it weren't for the ADA, I would probably not be doing research in this country.

Indeed, the competition for funding by the NIH is such that young investigators are in a catch 22 situation: you need money to generate sufficient preliminary data for an NIH grant, and you need preliminary data to obtain a grant. So, organizations such as the ADA have a very specific role to play in ensuring the critical transition from junior faculty to independent investigator. Young investigators are the future of diabetes research. In this context, the ADA has a very special role, because it is the only private organization that supports research on all aspects of diabetes in this country. For these reasons, I urge you to support, or to continue to support, the American Diabetes Association, so that, together, we can continue the relentless fight against diabetes.