Typically, we think of diabetes as falling under two main classifications: type 1 diabetes (T1D) and T2D. I often hear the argument: T2D is caused by poor diet and lifestyle choices; what's so complex about it? People just need to eat less and exercise more. The fact of the matter is that many people do, in fact, eat a healthy diet, exercise regularly and make good lifestyle choices, yet still have pre-diabetes or develop diabetes. So, why is it that some people are predisposed to develop diabetes? Why are some people more apt to gain weight—a known risk factor for T2D—and others have difficulty losing weight and maintaining weight loss? What we are learning is that T2D diabetes patients actually can be classified into many further subpopulations. Hopefully, in the future, knowledge about these subpopulations will help inform a patient's susceptibility to develop the disease and certain related risk factors, and also predict response to specific treatments.

 

To date, there are already 25 disorders that have been identified in which the alteration of a single gene results in abnormal glucose levels with clinical features that overlap with typical T2D. Most of these metabolic disorders are rare, accounting for no more than 5 percent of all diabetes cases. However, when you consider that hundreds of millions of people have this disease globally, 5 percent is a significant number. Like other rare diseases, these disorders often go undiagnosed or misdiagnosed due to a lack of appropriate diagnostic guidelines and tools—and a general lack of awareness about the existence of these disorders. In other words, many patients are being treated (unsuccessfully) for T2D when in fact they actually have a different disease.  

 

Beyond these examples, what about the millions of people with diabetes whose disease is, in fact, caused by excess weight, poor diet and lack of physical activity? Where does "personalized medicine" come into play here? While we need to stress prevention and healthy lifestyle at every turn, we can't ignore the fact that hundreds of millions of people around the world are very sick today as a result of this disease. We also need to consider the fact that emerging research shows that many patients are resistant to the beneficial effects of exercise. In addition, weight loss from dieting is more difficult for patients with diabetes. We don't fully understand why these variances occur, but they point to the diabetes' heterogeneous nature. A therapeutic approach focused merely on reduction in plasma glucose concentration ignores the varied pathophysiological disturbances at play from individual to individual.

 

 

By shedding light on the complex pathophysiology of diabetes, we can move beyond the current standard of treatment and arrive at more personalized—and more effective—therapies and treatment approaches, and hopefully, someday, cures for certain patients. What's more, by better understanding the molecular pathways at play in T2D, we may be able to identify and detect subpopulations who are at higher risk for developing complications and co-morbidities that often accompany the disease, such as hypertension, hypertriglyceridemia, hypercholesterolemia and inflammation (what we've previously referred to as metabolic syndrome). Ultimately, the goal would be to develop therapies that address the underlying cause that leads to both T2D and associated co-morbidities, or to preempt the onset of co-morbidities through early intervention.   

 

To move us in this direction, we need to embrace—and act on—a more modern, more logical view that there is a broad list of tissues known to play an important role in T2D pathophysiology, including adipocytes (fat cells), the GI tract and enteroendocrine cells in the gut, pancreatic alpha-cells, the kidneys and the brain. The relative impact of each of these organs on the underlying disease process in an individual is unknown.  

 

For instance, exciting new data suggests that bariatric surgery is highly effective in controlling—and in some patients, completing eliminating—T2D symptoms. Why is this? We now know that bariatric surgery triggers massive changes in metabolism, specifically related to the gut and hormones, which leads to a decrease in appetite and improved diabetes. Preclinical and some early clinical efforts to replicate these hormonal changes without surgery are quite promising. While surgery is certainly an important option right now for overweight patients with diabetes, our long-term focus should be on accelerating research efforts in this area. If we can produce the same hormonal changes without surgery and elicit the same improvement in diabetes, imagine the far-reaching impact that would have on treating this disease.  

 

From concept to reality: What will it take?

 

As our understanding of the complex genetic and molecular causes of diabetes matures, so will our need for companion diagnostics. The only diagnostic criterion clinicians utilize today for diabetes is measuring blood glucose levels, and glucose is the target of the clinical management of diabetes. As our knowledge base of diabetes expands, we will have to expand, in parallel, the methods and algorithms with which we diagnose the subtypes of diabetes to help identify patients who are most likely to respond to a treatment and/or patients' risk levels for diabetes complications.  

 

From a more universal standpoint, advancing the concept of personalized medicine in diabetes will require a general acceptance and a greater understanding of the heterogeneity of T2D. It will also require focused resources and commitment at both the government and industry levels to help drive progress forward. We have a great deal of work ahead of us. But, given the broad and significant ramifications of diabetes from a medical, economic and societal standpoint, this is a wise investment in our future—one we can't afford to overlook.  

 

Dr. Steven R. Smith is the scientific director of the Translational Research Institute for Metabolism and Diabetes (TRI), an innovative partnership between Florida Hospital and Sanford-Burnham Medical Research Institute. The TRI is focused on the advancement of a new paradigm of personalized approaches to researching and treating diabetes and obesity.