Medical experts from around the world gathered recently for the 47^th European Association for the Study of Diabetes (EASD) annual meeting in Lisbon, Portugal to review the latest research findings and trends in diabetes and metabolic disease. This year’s Scientific Program included a symposium sponsored by EASD, The Endocrine Society and the American Diabetes Association (ADA) entitled, “Obesity and Type 2 Diabetes: What’s Similar and What’s Different?” The symposium was largely based on a recent consensus report in Diabetes Care and the Journal of Clinical Endocrinology and Metabolism [^1] representing the views of an international working group of 32 experts in obesity and/or type 2 diabetes that had convened  to discuss the links and differences between diabetes and obesity.

I, along with three of the report’s co-authors—Ele Ferrannini, MD; Steven Kahn, MB, CHB; and David Nathan, MD—participated in the EASD symposium. Below I highlight some key points  we covered there.

Traditionally, the widely held link between diabetes and obesity is that weight gain leads to insulin resistance, which causes beta cells (β-cells) in the pancreas to produce more insulin to compensate in order to keep blood sugar within a normal range. Eventually, β-cells cannot produce enough insulin to satisfy the body’s demand, and blood sugar levels become unchecked, leading to type 2 diabetes. Yet, while excess weight is an established risk factor for type 2 diabetes, not all people who are obese develop type 2 diabetes. This raises a question as to what predisposes some people with obesity to develop type 2 diabetes and not others. In addition, there is a growing school of thought that β-cell dysfunction occurs ahead of insulin resistance. These are just some of the many unanswered questions we have about obesity and type 2 diabetes. Improving our understanding of how these diseases are similar—and how they are different—will help us identify and develop more effective – even “personalized” – approaches to treatment.

The influence of obesity on type 2 diabetes risk is determined not only by how overweight a person is but also by where fat accumulates in the body. Increased upper body fat, including excess fat in the abdominal region, is associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease,[^2] although the underlying mechanisms remain unclear. In addition, emerging evidence suggests that different fat cell types and subtypes have distinct functions and discrete impacts on metabolic processes.

While the precise mechanisms for progressive β-cell dysfunction in some people with obesity remain unknown, there may be certain predisposing factors–including genetic mutations or environmental influences that unfavorably modify β-cell function. A growing understanding of genetics and functions of the β-cell will allow us to identify potential mediators that predispose certain obese individuals to type 2 diabetes. This, in turn, may help provide insights into the development of new therapies that can target specific patient subpopulations.

Thus far, there about 40 genes [^3,4] associated with type 2 diabetes and a similar number of largely different genes associated with obesity. Yet, these genes are estimated to predict only 15% of type 2 diabetes risk and 5% of obesity risk.[^5] This low predictive value suggests that other factors play a key role in the development of these diseases, such as environmental factors and gene-gene interactions.

Research is also underway to understand whether a shared disease process underlies both obesity and type 2 diabetes. One link could be sustained cell exposure to nutrient concentrations exceeding energy requirements, which, in turn, could lead to a cascade of cell damage. Another link could be the impairment of brain neurocircuits that regulate both energy balance and insulin action.

Interventions for obesity fall into three main categories: lifestyle programs, medications, and bariatric surgery. Some patients experience success with lifestyle interventions; however, after 6-12 months, too many people experience weight regain. Historically, obesity-related medications that have successfully made it to market have been plagued with safety issues that often have outweighed intended benefits. Health benefits of bariatric surgery, determined largely from nonrandomized studies, are being increasingly recognized. Indeed, for extreme obesity, surgery is now the preferred, and currently the only effective, treatment option available. While acute morbidity and mortality of surgical approaches have been dramatically reduced, the risk/benefit ratio still must be carefully considered. Moreover, how the duration of diabetes and/or the extent of β-cell dysfuntion influence the long term outcome remains uncertain.

A vast array of barriers–from deficits in basic research to socioeconomic and individual psychological factors–undermines current efforts to manage obesity, particularly in individuals with type 2 diabetes. As we continue to learn more about the many factors that lead to obesity, we hope to better understand how to implement optimal lifestyle interventions and develop safe and effective drugs and/or minimally invasive devices.

To advance the development of effective interventions, we must further expand our understanding of the basic disease process linking obesity and type 2 diabetes. Other key areas of focus should include expanding research on how obesity is different from type 2 diabetes; developing innovative approaches to pharmacological and surgical management; and emphasizing primary prevention of obesity and type 2 diabetes.

In addition, we need to explore a disease management approach for obesity and diabetes care, including basing interventional approaches on the severity and duration of the disease as well as the individual’s risk/benefit profile. It’s imperative that we overcome the common perception that the obesity “problem” is insurmountable. Similar to the approach taken with tobacco, we need a comprehensive social, economic, and workplace approach to prevention and intervention for this growing epidemic.

²Bjorntorp P. Metabolic implications of body fat distribution. Diabetes Care 1991; 14:1132-1143

³ Rampersaud E, Damcott CM, Fu M, et al. Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish; evidence for replication from diabetes-related quantitative traits and from independent populations. Diabetes 2007;56:3053-3062

⁴ Hayes MG, Pluzhnikov A, Miyake K, et al. Identification of type 2 diabetes genes in Mexican Americans through genome-wide association studies. Diabetes 2007;56:3033-3044

⁵Bogardus C. Missing heritability and GWAS utility. Obesity (Silver Spring) 2009;11:209-210