The rapid development of global urbanization and modernization has lasting effects on lifestyle aspects such as unhealthy eating habits, lack of exercise, increased stress and environmental factors. These factors contribute to the alarming growth of obesity and type 2 DM worldwide. Obese individuals develop insulin resistance, which is characterized by impaired insulin action in the liver and reduced glucose uptake in fat and muscle [1]. While lifestyle changes and medications are recommended for prevention, they have not been successful in suppressing the increasing incidence conditions. Therefore, it is crucial to gain a deeper understanding of the molecular mechanisms linking obesity and type 2 DM in order to address this global healthcare challenge effectively.

The intricate connections and sharing of pathophysiological mechanisms between obesity and type 2 DM amplify the prevalence and incidence of insulin resistance, dyslipidemia, NAFLD and a constellation of metabolic abnormalities in obese individuals. Increased body mass index (BMI) and abdominal fat distribution linearly increases the risk of type 2 DM due to alterations in adipose tissue biology that links obesity with insulin resistance and beta cell dysfunction [1]. Abdominal obesity, commonly determined by waist-to-hip ratio, is an independent factor for the development of hypertension and elevated fasting glucose, even if the overweight individual with predominant abdominal fat does not meet the BMI criteria for obesity [2]. Multiple in vivo and clinical studies have demonstrated a cause-and-effect relationship between obesity and type 2 DM, unraveling their intimate connections. It is shocking to note that according to the WHO fact sheet, at least 41 million children under the age 5 are overweight or obese (BMI ≥ 35 kg/m²) as of 2016. If this trend continues, 60% of the world’s population will be obese or overweight by 2030 [3]. According to WHO, obesity accounts for 44% of diabetes and the incidence of obesity-related diabetes is expected to double to 300 million by 2025 [4].

It is interesting to note that during starvation, adipose tissue, which serves as a major fuel reserve, provides a critical energy source for survival. Additionally, adipose tissue modifies various physiological functions, including appetite, reproduction and insulin action, through the secretion of adipokines and exosomes [1]. In obese individuals, non-esterified fatty acids play a crucial role in the development of insulin resistance and beta cell dysfunction [1].

The close relationship between obesity and diabetes has led to the term “diabesity”, which highlights that the majority of individuals with diabetes are obese or overweight [5]. While type 2 DM is influenced by genetic predisposition and ethnicity which are non-modifiable risk factors, it can still be prevented or managed by addressing modifiable risk factors such as obesity. Despite recent advancement in management strategies, obesity and diabetes remain a significant interconnected public health challenge worldwide.

2. Obesity and Type 2 DM

Obesity is defined as the excessive accumulation of fat in various parts of the body or organs, known as ectopic fat or throughout the body. It is a chronic, progressive, relapsing condition with multiple factors that lead to adverse metabolic and psychosocial health consequences [6]. One of the main causes of obesity is an imbalance between the excess energy stored and the energy utilized by the body, which can disrupt nutrient signals and result in insufficient energy expenditure [6]. Assessing the risk factors for adiposity involves measuring height, weight, BMI, waist circumference and body fat percentage. The diagnosis of obesity relies on the BMI cut off and the relationship between body weight, fat distribution pattern and visceral fat [7]. BMI alone is no longer sufficient to evaluate obesity, as it is a diverse condition. Table 1 displays the classification of obesity based on BMI and waist circumference [7]. The anthropometric assessment of percentage body fat is a more accurate measure of adiposity than BMI [8]. The Obesity Medicine Association classification of percentage body fat is shown in Table 2 [8]. It is interesting to note that by 2030, an estimated 14% of men and 20% of women in the world’s total population will develop clinical obesity. Additionally, it is estimated that 18% of individuals will have a BMI greater 30 kg/m², 6% will have a BMI greater than 35 kg/m², and 2% will have a BMI greater than 40 kg/m² [9]. According to the World Obesity Federation, countries with high socioeconomic status and per capita income are at a greater risk of experiencing an increased prevalence of obesity [9]. It is alarming to note that approximately two-thirds of the adult population in the United States is either obese or overweight [10]. The prevalence of obesity in the United States has alarmingly increased over the past decade. According to published data from 2017 to 2020, 42.4% of adults have a BMI ≥ 30 kg/m², while 20.9% of youth have a BMI ≥ 30 kg/m². Additionally, the age-adjusted prevalence of severe obesity, defined as BMI ≥ 40 kg/m², is 9.2% [11]. Currently, only around 30% of the adult population in the US has a normal BMI between 18–25 kg/m² [12]. When considering race and ethnicity, the highest rates of obesity are found among black women, Native Americans and Hispanics [13]. It is projected that by 2023, approximately 50% of the US adult population will be obese with around 25% developing severe obesity [14]. From a global perspective, the obese population worldwide has risen steadily over the past few decades with a six-fold increase in adults with obesity between 1975 and 2016. This increase is driven by socioeconomic advances, which pose a significant healthcare burden and contribute to the rise in mortality complications associated with obesity, such as DM and cardiovascular diseases [15]. Obesity plays an inevitable role in the increased prevalence of type 2 DM, a chronic condition where the body fails to produce sufficient insulin or cannot efficiently utilize insulin resulting in elevated blood glucose levels as its primary manifestation. Type 2 DM is characterized by low insulin secretions from β-cells and peripheral insulin resistance, leading to elevated levels of fatty acids. This causes a decrease in glucose transport into muscle cells, increased fat breakdown and hepatic glucose production [16]. This is the fastest-growing pandemic and health emergency globally. According to the latest estimates by the International Diabetes Federation, the number of diagnosed cases of DM is predicted to reach 643 million by 2030 and 783 million by 2045 [17]. Additionally, the majority of undiagnosed type 2 DM cases are concentrated in Africa, Southeast Asia and the Western Pacific. In 2021, there were 541 million adults diagnosed with impaired glucose tolerance and 319 million adults with impaired fasting glucose. These numbers are predicted to increase to 730 million and 441 million, respectively, by 2045 [17]. Previous studies have shown that the relative risk of developing type 2 DM is 4.6-fold higher for woman and 3.5-fold higher for men with a BMI greater than 29.9 kg/m² compared to their same-sex peers with a BMI less than 24.9 kg/m² [18]. It is important to note that the associations between central obesity and comorbidities vary among different races and ethnicities (Figure 1). For instance, in Asian populations with type 2 DM, central obesity is a more accurate predictor than BMI [20]. Interestingly, for individuals of European ancestry, the thresholds for central obesity are determined by a waist circumference greater than 94 cm (37 inches) for men and greater than 80 cm (31.5 inches) for women. These thresholds for individuals of South Asian, Chinese and Japanese origin are greater than 90 cm (35.5 inches) for men and greater than 80 cm (31.5 inches) for women ^[21][22][21,22]. Diabetes is a chronic metabolic disorder with multiple causes, characterized by consistently high blood glucose levels due to defects in insulin secretion, action or both. Type 2 DM is more common than type 1 DM, accounting for 90–95% cases. It is strongly influenced by genetics and involves resistance to insulin action and inadequate compensatory insulin secretion [23]. Most patients with type 2 DM are obese, with a higher percentage of body fat or abnormal distribution, which is related to the pathophysiology of DM. Adipose tissue promotes insulin resistance by releasing more free fatty acids [24]. Other contributing factors include peripheral insulin resistance, dysregulation of hepatic glucose production, decreased beta cell function and beta cell failure [1]. The diagnosis of type 2 DM is made when the patient meets one of the following criteria: glycated hemoglobin (HbA1_C) ≥ 6.5%, fasting blood glucose ≥ 126 mg/dL or 2-h post-prandial glucose ≥ 200 mg/dL. Diabetes-related morbidity and complications can be substantially reduced with tight glycemic control, aiming for an HbA1c of less than 7% [25]. According to the International Diabetes Federation (IDF), 415 million adults aged 20–79 years were diagnosed with DM in 2015 and the number of people suffering from diabetes increase in that group rose to about 573 million adults in 2021 (Figure 2). The global population with DM is predicted to increase to another 200 million by 2040 [27]. In the United States, Native Americans, Hispanics and Asian Americans are the most affected population by type 2 DM [28]. It is estimated that 70% of individuals with pre-diabetes will eventually develop type 2 DM by 2030 [27]. Interestingly, certain regions such as Fiji and American Samoa have reported the highest prevalence of the disease. Southeast Asian countries have also seen an increase in the last two decades. The top spots with the greatest total number of individuals with type 2 DM include China (88.5 million), India (65.9 million) and the US (28.9 million), which can be attributed to their large population size [29].

3. Management

Weight loss is the most efficient strategy for reducing the complications and comorbidities of type 2 DM. A moderate weight loss of 5 to 10% is sufficient to achieve normal blood pressure, glycemic control and increased HDL cholesterol levels ^[30][118]. Gradual weight loss leads to a decrease in adipocyte size, which in turn downregulates pathways involved in lipogenesis and oxidative stress ^[30][118]. Exercise is a key component of lifestyle interventions to achieve healthy weights and improve blood glucose levels, insulin sensitivity and lipid profiles. Most scientific guidelines recommend at least 150 min per week of moderate aerobic exercise combined with three weekly sessions of muscle strength resistance exercises. While exercise is crucial for weight loss, a combined approach of exercise and an energy-restricted diet such as a low-fat, low-carbohydrate and high-protein diet delivers better results ^[31][119]. The essential pillars in managing obesity and type 2 DM are dietary modifications and lifestyle interventions, although these can be challenging to maintain over time. Recently, different drugs have been approved to improve type 2 DM and promote weight loss such as GLP-1 receptor agonists and SGLT2 inhibitors [4]. Given the association between obesity and type 2 DM, a suitable anti-diabetic treatment for obese patients with diabetes should focus on preventing further weight gain while also using glucose-lowering agents that support weight reduction such as metformin therapy ^[32][120]. In the United States, a commonly used combination for type 2 DM and obesity management is Liraglutide with naltrexone and bupropion ^[33][121]. Metformin is the most prescribed FDA-approved medication for lowering blood sugar levels, as it increases insulin sensitivity and reduces glucose production in the liver. It also promotes weight loss and decreases food intake ^[34][122]. Bariatric surgery is highly beneficial for patients who are morbidly obese with a BMI of40 kg/m² or higher or for patients with type 2 DM and a BMI of 35 kg/m² or higher. This surgery effectively reduces cardiovascular events associated with morbid obesity and type 2 DM ^[35][123]. Other areas of therapeutic interest include “prebiotics”, which have been shown to improve glucose tolerance. This was demonstrated in mice on a high-fat diet that were fed prebiotics ^[36][124]. Another approach is the use of “probiotics”, which are enriched with live bacterial strains such as Bifidobacteria and Lactobacilli. These alter the gut microbiota and have been proven to be beneficial in type 2 DM by improving lipid profiles and reducing endotoxemia ^[37][125]. Several studies have reported a lower prevalence of type 2 DM and a healthy BMI in populations that consume significant amounts of polyunsaturated fatty acids, primarily found in fish ^[38][126]. Recently, intermittent fasting has been proven to be beneficial for weight reduction and improving glucose tolerance. It does this by selectively stimulating the activation of beige adipocytes in white adipose tissue (WAT) to promote “WAT browning” and by regulating the composition of intestinal microbial products, such as acetate and lactate which are known inducers of WAT browning ^[39][127].