Paradigm shift: Rethinking type 2 diabetes as a heterogeneous disease

The only way we will see true, long-term success in treating diabetes is by fundamentally rethinking this disease and shifting our focus to pursue a targeted, personalized approach to prevention, diagnosis and treatment.

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By now, you're probably familiar with the alarmingstatistics about diabetes. Twenty-six million people in the United States havediabetes today, with type 2 diabetes (T2D) accounting for 95 percent of alldiabetes cases. Seventy-nine million people in this country have pre-diabetes,and an estimated one in three people will have diabetes by 2050. Despite theintense focus on diabetes, and the availability of myriad therapies and othertools for diabetes management, we largely aren't effective in treating thisdisease. In fact, an estimated 60 percent of T2D patients don't achieveadequate glycemic control —resulting in poor patient outcomes and skyrocketinghealthcare costs. Where are we falling short?
I believe the primary reason we aren't effectively treatingdiabetes today is because our current understanding of this disease is quiterudimentary. Our lack of awareness and appreciation about the inherentcomplexity and heterogeneity of diabetes has confined us to a one-size-fits-allparadigm for managing this disease. For millions of patients, this approach issimply not working.
Our current methodology of trial-and-error drug developmentand prescribing is neither prudent nor sustainable—and its days are numbered.The whole model of medicine is shifting to one that is centered on patientsubpopulations—defining, identifying and grouping patients by diseasesubclassifications, and then prescribing treatment regimens tailored to thosesubclassifications. Thanks to the increasing sophistication and use ofinnovative technology platforms such as genetics and epigenetics, genomics,proteomics and metabolomics, personalized medicine has been gainingmomentum—with the most notable early success being in the oncology field.
With the influx of and access to massive amounts ofinformation at the genetic and molecular levels, we are faced with the arduoustask of sifting through and understanding the data, determining what isrelevant and potentially clinically applicable and then figuring out how toultimately translate all of this information to real-world patient care. It'snot an easy task, and we'll have many trials and errors along the way. But thekey is that we are most definitely "along the way." Consider that 30 percent ofall treatments in late-stage clinical development and 60 percent of alltreatments in preclinical development today rely on biomarker data.
We are at the point where we should be applying these sametools and technologies to revolutionize and deepen our understanding ofdiabetes. I believe the only way we will see true, long-term success intreating diabetes is by fundamentally rethinking this disease and shifting ourfocus to pursue a targeted, personalized approach to prevention, diagnosis andtreatment.
What's so complexabout T2D?
Typically, we think of diabetes as falling under two mainclassifications: type 1 diabetes (T1D) and T2D. I often hear the argument: T2Dis caused by poor diet and lifestyle choices; what's so complex about it? Peoplejust need to eat less and exercise more. The fact of the matter is that manypeople do, in fact, eat a healthy diet, exercise regularly and make goodlifestyle choices, yet still have pre-diabetes or develop diabetes. So, why isit that some people are predisposed to develop diabetes? Why are some peoplemore apt to gain weight—a known risk factor for T2D—and others have difficultylosing weight and maintaining weight loss? What we are learning is that T2Ddiabetes patients actually can be classified into many further subpopulations.Hopefully, in the future, knowledge about these subpopulations will help informa patient's susceptibility to develop the disease and certain related riskfactors, and also predict response to specific treatments.
To date, there are already 25 disorders that have beenidentified in which the alteration of a single gene results in abnormal glucoselevels with clinical features that overlap with typical T2D. Most of thesemetabolic disorders are rare, accounting for no more than 5 percent of alldiabetes cases. However, when you consider that hundreds of millions of peoplehave this disease globally, 5 percent is a significant number. Like other rarediseases, these disorders often go undiagnosed or misdiagnosed due to a lack ofappropriate diagnostic guidelines and tools—and a general lack of awarenessabout the existence of these disorders. In other words, many patients are beingtreated (unsuccessfully) for T2D when in fact they actually have a different disease.
Beyond these examples, what about the millions of peoplewith diabetes whose disease is, in fact, caused by excess weight, poor diet andlack of physical activity? Where does "personalized medicine" come into playhere? 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 worldare very sick today as a result of this disease. We also need to consider thefact that emerging research shows that many patients are resistant to the beneficialeffects of exercise. In addition, weight loss from dieting is more difficultfor patients with diabetes. We don't fully understand why these variancesoccur, but they point to the diabetes' heterogeneous nature. A therapeuticapproach focused merely on reduction in plasma glucose concentration ignoresthe varied pathophysiological disturbances at play from individual toindividual. 
By shedding light on the complex pathophysiology ofdiabetes, we can move beyond the current standard of treatment and arrive atmore personalized—and more effective—therapies and treatment approaches, andhopefully, someday, cures for certain patients. What's more, by betterunderstanding the molecular pathways at play in T2D, we may be able to identifyand detect subpopulations who are at higher risk for developing complicationsand co-morbidities that often accompany the disease, such as hypertension,hypertriglyceridemia, hypercholesterolemia and inflammation (what we'vepreviously referred to as metabolic syndrome). Ultimately, the goal would be todevelop therapies that address the underlying cause that leads to both T2D andassociated co-morbidities, or to preempt the onset of co-morbidities throughearly intervention. 
To move us in this direction, we need to embrace—and acton—a more modern, more logical view that there is a broad list of tissues knownto play an important role in T2D pathophysiology, including adipocytes (fatcells), the GI tract and enteroendocrine cells in the gut, pancreaticalpha-cells, the kidneys and the brain. The relative impact of each of theseorgans on the underlying disease process in an individual is unknown.
For instance, exciting new data suggests that bariatricsurgery is highly effective in controlling—and in some patients, completingeliminating—T2D symptoms. Why is this? We now know that bariatric surgery triggersmassive changes in metabolism, specifically related to the gut and hormones,which leads to a decrease in appetite and improved diabetes. Preclinical andsome early clinical efforts to replicate these hormonal changes without surgeryare quite promising. While surgery is certainly an important option right nowfor overweight patients with diabetes, our long-term focus should be onaccelerating research efforts in this area. If we can produce the same hormonalchanges without surgery and elicit the same improvement in diabetes, imaginethe far-reaching impact that would have on treating this disease.
From concept toreality: What will it take?
As our understanding of the complex genetic and molecularcauses of diabetes matures, so will our need for companion diagnostics. Theonly diagnostic criterion clinicians utilize today for diabetes is measuringblood glucose levels, and glucose is the target of the clinical management ofdiabetes. As our knowledge base of diabetes expands, we will have to expand, inparallel, the methods and algorithms with which we diagnose the subtypes ofdiabetes to help identify patients who are most likely to respond to atreatment and/or patients' risk levels for diabetes complications.
From a more universal standpoint, advancing the concept ofpersonalized medicine in diabetes will require a general acceptance and agreater understanding of the heterogeneity of T2D. It will also require focusedresources and commitment at both the government and industry levels to helpdrive progress forward. We have a great deal of work ahead of us. But, giventhe broad and significant ramifications of diabetes from a medical, economicand societal standpoint, this is a wise investment in our future—one we can'tafford to overlook.
Dr. Steven R. Smith is the scientific director of theTranslational Research Institute for Metabolism and Diabetes (TRI), aninnovative partnership between Florida Hospital and Sanford-Burnham MedicalResearch Institute. The TRI is focused on the advancement of a new paradigm ofpersonalized approaches to researching and treating diabetes and obesity.

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