How Understanding the “Metabolically Healthy Obese” Could Lead to New Comorbidity Treatments

How Understanding the “Metabolically Healthy Obese” Could Lead to New Comorbidity Treatments

An Australian study recently explored some of the crucial features in those who are “metabolically healthy obese” (individuals who are free from type 2 diabetes and other obesity-related disorders despite being obese). Their findings offer new insights into developing future treatments for type 2 diabetes, insulin resistance and obesity.

Investigators claim that two-thirds of Australian adults are overweight or obese. Quite often, excess weight triggers other health problems, such as type 2 diabetes, insulin resistance (a pre-stage of diabetes), high blood pressure and an abnormal blood lipid profile. But some obese people are the exception to the rule, remaining danger-free from these metabolic disorders, in spite of being overweight or obese. Understanding the differences about these metabolically healthy obese individuals could give researchers a better idea of what causes type 2 diabetes, ultimately leading to the development of more personalized treatments.

The Australian researchers have now contributed to our understanding of how the metabolically healthy obese differ from other individuals who suffer from obesity. The study was led by Associate Professor Jerry Greenfield — Head of the Department of Endocrinology at St. Vincent’s Hospital in Sydney and a clinical research lab at the Garvan Institute of Medical Research — and published in the November issue of the Journal of Clinical Endocrinology and Metabolism.

Professor Greenfield claims: “It has been known for some time that some obese individuals seem to stay metabolically healthy. However, there has been no consensus about how to define ‘metabolically healthy’ obesity- so it has not been easy to understand what underpins these individuals’ apparent protection from disease.

“Our own approach is to define metabolically healthy obesity in clearly measurable terms. We examine whether or not obese individuals also have a key complication of excess body fat: a resistance to the hormone insulin, which regulates the level of sugar in the blood after a meal. We consider that obese individuals who are not insulin-resistant, but instead remain sensitive to insulin, can be thought of as being metabolically healthy.”

Body tissues (muscle and liver, particularly) in those with insulin resistance become gradually less responsive to insulin. Muscle cells also stop removing sugar (as glucose) from the bloodstream and liver cells lose their ability to restrain their release of glucose into the blood. Over time, the mechanism of insulin production becomes gradually damaged and eventually is exhausted, causing type 2 diabetes.

This recent study to research insulin resistance in obesity recruited 64 obese people. The team used a technique that measures how each participant’s blood glucose levels responded to insulin over several hours.

Dr. Samocha-Bonet, who co-led the study, said, “The power of this technique is that you can simultaneously look at whether the muscle and the liver act in an insulin-sensitive way. So, for the first time, we were able to look both at whether the participants’ livers and their muscle tissue were responsive to insulin. We were intrigued to find that some participants were sensitive to insulin at muscle but were resistant at liver – whilst others had the opposite profile (sensitive to insulin at the liver but resistant at muscle).

“So, we now know it’s not enough to label an individual as ‘insulin-resistant’ or ‘insulin-sensitive’. Instead, they can be insulin-resistant at liver, at muscle, at both sites, or at neither.”

The next step in the study was to test how each participant’s insulin response profile related to other crucial readouts of metabolic health. “What we found is that obese individuals who are sensitive to insulin in muscle only or liver only are metabolically healthier in many respects than the group that is insulin-resistant at both sites,” explained Dr. Samocha-Bonet. “Not only do they have lower blood pressure, but they also have less deep abdominal fat and less fat within the liver. In fact, judging by these criteria, the metabolic health of these people is similar to that of individuals who are insulin sensitive at both muscle and liver.”

Professor Greenfield added that, “This novel observation — that being insulin-sensitive at either muscle or liver conferred as much metabolic protection as being insulin-sensitive at both sites — is perhaps the most fascinating finding of our study.

“Taken together, this metabolic protection, and the discovery that insulin resistance at the liver and muscle do not necessarily occur together in the same individual, provide significant insight into the complexity that is human insulin resistance. The findings suggest that there are different drivers of insulin action at liver and muscle that may be determined by specific genetic pathways. The demonstration that insulin sensitivity in the liver and muscle may occur independently in humans potentially paves the way for earlier detection and individualized treatment of people at risk of developing metabolic disease.”

Despite being an early stage study, this research could pave the way toward an optimized, personalized, and targeted approach to the treatment of obesity and type 2 diabetes.

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