The Role of Obesity in Type 2 Diabetes Mellitus-An Overview

Abstract

Obesity or excessive weight gain is identified as the most important and significant risk factor in the development and progression of type 2 diabetes mellitus (DM) in all age groups. It has reached pandemic dimensions, making the treatment of obesity crucial in the prevention and management of type 2 DM worldwide. Multiple clinical studies have demonstrated that moderate and sustained weight loss can improve blood glucose levels, insulin action and reduce the need for diabetic medications. A combined approach of diet, exercise and lifestyle modifications can successfully reduce obesity and subsequently ameliorate the ill effects and deadly complications of DM. This approach also helps largely in the prevention, control and remission of DM. Obesity and DM are chronic diseases that are increasing globally, requiring new approaches to manage and prevent diabetes in obese individuals. Therefore, it is essential to understand the mechanistic link between the two and design a comprehensive approach to increase life expectancy and improve the quality of life in patients with type 2 DM and obesity. This literature review provides explicit information on the clinical definitions of obesity and type 2 DM, the incidence and prevalence of type 2 DM in obese individuals, the indispensable role of obesity in the pathophysiology of type 2 DM and their mechanistic link. It also discusses clinical studies and outlines the recent management approaches for the treatment of these associated conditions. Additionally, in vivo studies on obesity and type 2 DM are discussed here as they pave the way for more rigorous development of therapeutic approaches.

Keywords: clinical trials; in vivo studies; incidence; management; obesity; pathophysiology; prevalence; therapeutic approach; type 2 diabetes.

Figure 1

Prevalence of type 2 diabetes mellitus (in 2019), obesity (in 2016) and overweight (in 2016) in selected countries. This figure has been redrawn in a modified form from [19].

Figure 2

Prevalence of diabetes worldwide in 2021. A total of 573 million people suffered from diabetes in 2021. The figure has been redrawn and modified based on information from [26].

Figure 3

Multifactorial pathophysiology of obesity and type 2 diabetes. Genetic and epigenetic factors, along with an unhealthy lifestyle play significant roles in the development of both obesity and type 2 diabetes. Various factors, including adipokines, pro-inflammatory cytokines, non-esterified fatty acids (NEFA) and others contribute to visceral fat accumulation, β-cell dysfunction, changes in gut microbiota and gut barrier leakage. In addition, inflammatory reactions in the hypothalamus might contribute to the onset of diabetes and vice versa. Diabetes impacts energy homeostasis and hyper-activates regulatory neurons as well as the surrounding microglia in the hypothalamus.

Figure 4

Adipokines released by adipose tissue are central in the control of endocrine and secretory functions of many organs. The adipose tissue secretes various molecules known as adipokines which act as powerful signal molecules. The activity of these adipokines impacts biological processes in liver, pancreas, gut, brain, skeletal muscles and many other organs.

Figure 5

Pro-inflammatory cytokines in the pathogenesis of metabolic inflammation and insulin resistance. In the development of insulin resistance and type 2 diabetes, several cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), IL-6 and others released by activated tissue macrophages and by adipocytes play a significant role. These pro-inflammatory molecules provoke important responses in liver, skeletal muscle, fat tissue and pancreas, resulting in endocrine dysfunction, impaired glucose disposal, impaired β-cell function and reduced suppression of glucose production. The abbreviations used are as follows: AKT, protein kinase B; IRS, insulin receptor substrate; PKCζ, protein kinase Cζ; PKC𝜃, protein kinase C𝜃; PP2A, protein phosphatase 2A.

Figure 6

Fats and lipids in the pathogenesis of type 2 diabetes. An overabundance of fatty acids and lipids, resulting from a high-caloric diet enriched in fat (which cannot be stored in adipocytes), lead to increased levels of circulating fat that accumulate in peripheral tissues such as the liver, muscles and pancreas. This accumulation triggers numerous molecular changes that result in increased glucose production, lowered glucose disposal and impaired insulin secretion. These factors are hallmarks of diabetes. This figure was adapted in a modified form from [65].