Determinants of obesity and diabetes are strongly linked to genetic and epigenetic variations. With the increasing prevalence of diabetes and obesity, it is imperative to understand the various factors that influence metabolic function in the body, neural pathways, and appetite centers. These changes can further influence insulin resistance leading to diabetes, dyslipidemia, inflammation, hypertension, and ectopic fat deposition, which are the markers of obesity.

Genetic variants can be inherited, and several genetic mechanisms, such as deletion, genetic imprinting, and translocation can play a role. However, epigenetic modifications that are more closely related to obesity are more complex and occur at any time and they still can be passed on from generation to generation to cause obesity.

Both diabetes and obesity can be caused by monogenic (single-gene variant) and polygenic (multi-gene variant). Monogenic variants are responsible for rare forms of disease that occur at a young age compared with polygenic variants that constitute type 2 diabetes mellitus (more common) and obesity.

People with obesity and diabetes can have multiple genes that can predispose them to insulin resistance, which is a common determinant between the two and can cause weight gain. One gene is the fat mass and obesity-associated gene, which is found in up to 43% of the population, posing challenges in calorie control in the presence of readily accessible food. Such genes can further increase hunger and caloric intake, reduce satiety, and increase sedentary behavior, all of which foster body fat storage.

Rare single-gene defects (monogenic) can cause severe obesity beginning in early childhood and are correlated with extremely high levels of hunger. People who developed severe obesity before the age of 2 should be screened for leptin deficiency, proopiomelanocortin deficiency, and melanocortin 4 receptor deficiency.

Two of the most common monogenic forms of diabetes are maturity-onset diabetes of the young, which usually develops during the teen years or young adulthood, and neonatal diabetes mellitus, which is most common in newborns and infants. Type 1 diabetes (autoimmune disease) is associated with HLA-DR3 and HLA-DR4 variants.

Type 2 diabetes is associated with the TCF7L2 variant, which affects insulin secretion and glucose production. ABCC8 helps regulate insulin. Even though genetic testing is not commonly done in practice and usually associated with high cost, awareness about the genes can be beneficial in understanding the genetic correlation of the disease. Genetic variants take many years to spread and remain stable for many generations. However, environmental factors, social determinants, political consequences, and economic surroundings can influence and play a key role in triggering the ongoing surge of diabetes and obesity.

The US FDA has approved two drugs that target patients with genetic causes of obesity: metreleptin and setmelanotide. The other more widely used antiobesity medications (ie, semaglutide, liraglutide, phentermine-topiramate, and naltrexone-bupropion) are approved for weight loss in the general population and may also be used to treat patients with genetic obesity. Among these, semaglutide is approved to treat diabetes and obesity, and studies have shown promising results in weight management.

Having a better understanding of genetic contributions to diabetes and obesity can provide a promising strategy for prevention and treatment. The reversible nature of epigenetic markers is a more promising outcome and provides clinicians with a chance to suggest changes in lifestyle with healthy eating and physical activity.

However, it is important to understand that in the growing epidemic of diabetes and obesity, the contribution of genetic factors is small, but the impact of environmental factors is immense. People who possess genes that cause insulin resistance or obesogenic genes do not necessarily become overweight, and adapting to a healthy lifestyle can prevent the genetic consequences.

Patients and healthcare providers can use multiple resources from the Obesity Medicine Association including blogs, podcasts, research articles, and many other resources. In addition, the OMA conference is a great opportunity to learn and network with obesity medicine specialists to expand our knowledge of obesity medicine.