Obesity Paradox and Lean Diabetes

Prof. Bellamkonda K. Kishore, M.D., Ph.D., MBA
Academician, Innovator & Entrepreneur

Most of you know that overweight and obesity as measured by body mass index (BMI) over 25 or 30 kg/m², respectively, are a risk factor for diseases, such as diabetes mellitus, high blood pressure, cardiovascular diseases, chronic kidney disease, and arthritis, among others. In fact, epidemiologically, obesity is linked to the development of several non-communicable diseases (NCDs). Thus, obesity is considered as the Mother of All Disease(Fig 1).

Obviously, by maintaining the BMI under 25 kg/m² (23 kg/m² in Asians as per WHO) one can avoid developing non-communicable diseases (NCDs) to a large extent. NCDs account for 74% ofall deaths worldwide or 41 million deaths each year. It is projected that by the year 2030, deaths due to NCDs will reach 52 million. Cardivasccular diseases, cancers, chronic respiratory diseases and diabetes contribute for over 80% of premature deaths.

Within the context of India, in 2018, 63% of all deaths (about 5 million deaths) were attributed to NCDs. Apart from healthcare costs, disability and loss of life, NCDs also affect the productivity of the people and thus negatively impact the economic growth of the nation. For instance, in 2017 India lost 226.8 million disability-adjusted life years (DALYs). One DALY represents the loss of the equivalent of one year of full health. It is computed by the sum of years of life lost due to premature mortality (Years of Life Lost or YLLs) and the years lived with a disability (Years Lost due to Disability or YLDs) due to prevalent cases of disease or health condition in a population. Thus, NCDs not only affect individual lives of the people, but also negatively impact the economic growth of a country.

Contrary to the wider belief, obesity is not a problem of the developed world. Now obesity is the problem of rapidly developing economies, such as BRICS countries as well as the developing countries. These countries are more populous than the developed world. About 2/3rds of the 600 to 800 million obese subjects in the world live in emerging economies or developing countries, where they face disproportionately more heath burden due to the lack of mature or advanced healthcare systems. Thus, obesity disproportionately cripples the people in developing countries vs. developed world. Hence, even a 10 to 20% reduction in the number of obese subjects in the world has a profound and direct impact on the overall health status of the world, in addition to saving trillions of dollars in healthcare costs.

Thus,it sounds reasonable from the epidemiological point of view to decrease the new cases of NCDs. However, in recent years a paradoxical phenomenon was reported by several researchers, which was namedObesity Paradox. While obesity has the potential for the development of NCDs, once a subject develops NCDs, being obese as measured by BMI appears to be beneficial as it protects against mortality due to the NCDs. Obesity paradox refers to the clinical observation that when acute cardiovascular decompensation occurs, obese patients may have a survival benefit. It was first observed by Dr. Kalantar-Zadeh in patients suffering with advanced chronic kidney disease (Fig 2). Subsequently, obesity paradox has been reported in patients with heart failure, myocardial infarction, acute coronary syndrome, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, and in older residents in nursing homes. It should be noted that obesity paradox does not contradict the epidemiological data that obesity predisposes people to the development of NCDs. However, once obese people develop NCDs, somehow they are protected against death as compared to the non-obese people with NCDs.

The scientific community is split on obesity paradox, while some support it, others brush it aside calling it BMI paradox. However, several studies showed obesity is a complex disorder and there are metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO). Furthermore, it has been shown that it is the cardiorespiratory fitness (CRF) or lack of it that determines mortality, but not just obesity itself. That means being fit is more important than shedding weight.These intriguing findings are shedding new light on the complex subject of obesity.

While obesity paradox is a complex subject to understand with our current knowledge, another interesting phenomenon is emerging. It is called Lean Diabetes or diabetes mellitus in lean or non-obese subjects (BMI < 25 kg.m2). It was originally observed in men of Asian or African ancestry with a history of nutritional insults in the childhood. But now it is prevalent in these communities, including Asian Americans or African Americans. Asians, especially, Indians have relatively less lean body mass vs. fat giving a spurious appearance of normal BMI, as compared to Caucasians. Lean diabetes is the rapidly rising form of diabetes in the United States as compared to diabetes in obese subjects (17.8% vs. 2.1% increase in prevalence between 2015 and 2020, respectively). This is mostly due to increased prevalence of lean diabetes among women and colored people. What is alarming is, clinically and pathophysiologically, lean diabetes is more severe in nature and is often intractable to treatment by conventional methods. Lean diabetes also carries much severe complications and mortality as compared to type 2 diabetes mellitus. Lean diabetes appears to be a hybrid of type 1 and type 2 diabetes mellitus (T1DM & T2DM). It seems cardiometabolic risk leading to conditions like lean diabetes, is programmed during the fetal or early neonatal development of the subject, and it is influenced by maternal and/or infant nutrition, or both. Obviously, more in depth studies are needed to address this potential possibility. Such findings will hold the key for prevention of the development of lean diabetes.

One logical question that arises, is there a link between obesity paradox and lean diabetes? While more in-depth studies are needed to address that question, the Invited Review article by this author titled Reverse Epidemiology of Obesity Paradox: Fact of Fiction? Published recently in the Physiological Reports, a joint publication of the Physiological Society of United Kingdom and the American Physiological Society, sheds new light on this subject. It appears that this is the first review article that dealt with both Obesity Paradox and Lean Diabetes on one platform offering potential links between these two. Here is the graphical abstract of that review article with details to access the invited review in the open access journal, Physiological Review.

Graphic Abstract:Obesity paradox is a clinical observation that when acute cardiovascular decompensation occurs, patients with obesity may have survival benefits. Development of insulin resistance, decrease in insulin secretion, and body fat distribution in obesity varies considerably based on ethnicity and dietary habits of people. Maternal factors may program fetal cardiovascular risk, which often leads to development lean diabetes, which has higher prevalence of complications and mortality than in obese diabetics. Cardio-respiratory fitness (CRF) has emerged as an independent risk factor for death, irrespective of the obesity status of the subject. CRF may also influence mortality in obesity paradox.

The article by BK. Kishore can be accessed athttps://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.70107

About the Author: Prof. Bellamkonda K. Kishore is an academician and innovator, who recently turned to entrepreneurship. He did innovative research on kidney diseases, obesity and metabolic syndrome and related systems. Currently he is an Adjunct Professor of Internal Medicine at the University of Utah Health in Salt Lake City, Utah while being the Co-Founder, CEO & CSO of ePurines, Inc., a therapeutic drug development startup launched by him and his academic colleagues in the University of Utah Research Park in Salt Lake City, Utah. Website:www.bkkishore.online