Determinants of obesity and diabetes are strongly linked to genetic and epigenetic variations. It is imperative to understand the factors influencing metabolic function, neural pathways, and appetite centers. These changes can influence insulin resistance, leading to diabetes, dyslipidemia, inflammation, hypertension, and ectopic fat deposition.
Genetic variants can be inherited, and several genetic mechanisms play a role. Epigenetic modifications, which are complex and more closely related to obesity, can occur at any time and can span generations.
People with obesity and diabetes can have multiple genes predisposing them to insulin resistance, a shared factor facilitating weight gain. The fat mass and obesity-associated gene is found in up to 43% of the population, posing challenges in calorie control. Such genes increase hunger and caloric intake, decrease satiety, and promote sedentary behavior, all of which can foster body fat storage.
Genetic testing, despite limited use due to cost, can illuminate disease genetics. For those with severe early-onset obesity (before age 2), screening for leptin deficiency, proopiomelanocortin deficiency, and melanocortin 4 receptor deficiency is advisable due to rare monogenic defects. Maturityonset diabetes, which tends to emerge in teens and young adults, and neonatal diabetes mellitus are two of the most common monogenic forms, whereas type 1 diabetes mellitus 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. These variants remain stable for generations, while environmental, social, political, and economic factors have triggered a diabetes and obesity surge.
The US FDA approved two drugs for genetic obesity: metreleptin and setmelanotide. Other common antiobesity medications (ie, semaglutide, liraglutide, phentermine-topiramate, naltrexonebupropion) are approved for weight loss in the general population and may also treat genetic obesity. Semaglutide, in particular, is approved to treat diabetes and obesity, with promising results in weight management. A better understanding of genetic contributions to diabetes and obesity can inform prevention and treatment strategies. The reversible nature of epigenetic markers empowers clinicians to advise lifestyle changes (eg, healthy eating, physical activity) for their patients. In the diabetes and obesity epidemic, genetic factors play a small role, but the impact of environmental factors is immense. Possessing insulin resistance or obesogenic genes does not guarantee obesity; a healthy lifestyle remains key to preventing genetic consequences.
