Introduction
Obesity, a global concern, has surged to epidemic levels in the last three decades. This surge can be attributed to unhealthy lifestyle choices, including excessive consumption of processed foods and inactivity, which became more common in the latter half of the 20th century. In 2014, almost 39% of adults worldwide were considered overweight or obese, a doubling since 1975 [1]. A global study predicted that by 2030, 5.0% of Indians would be obese, and 27.8% of them would be overweight [2]. By 2030, almost 20% of adults in rural India are expected to be overweight or obese [3]. Type 2 Diabetes Mellitus (T2DM), which significantly raises morbidity and mortality, is the most serious metabolic consequence of obesity. Within the global healthcare system, T2DM is a major concern. By 2030, it is anticipated that the prevalence of T2DM will rise to 7,079 cases per 100,000 people worldwide [4]. In India, the percentage of people with diabetes increased from 7.1% in 2009 to 8.9% in 2019 [5]. India has 77 million diabetics, ranking second globally in the diabetes epidemic, just behind China. Among them, 12.1 million are over 65 years of age, and by 2045, that number is expected to rise to 27.5 million [5]. Worldwide, the prevalence of diabetes is rising. In developing economies like India, it is primarily fueled by the increasing prevalence of overweight and obesity. In this context, Sims EA et al., were the first to report the interrelationship between weight gain and impaired glycaemic control, coining the term “diabesity” [6]. The term “diabesity” refers to the contemporary state in which obesity and diabetes mellitus co-exist, suggesting a pathophysiological cause-and-effect relationship. An overview of the pathogenesis and management of diabesity discussed here.
Pathophysiology
Numerous pathophysiological mechanisms have been postulated to explain how diabetes develops in obese individuals. The development of insulin resistance due to chronic inflammation is considered the primary pathophysiological mechanism.
The “inflammation hypothesis” suggests that obesity causes low-grade, chronic inflammation. As a result, visceral adipocytes secrete adipose-specific cytokines like adiponectin and leptin, as well as inflammatory cytokines such as Interleukin-6 (IL-6) and Tumour Necrosis Factor-α (TNF-α) [7]. Additionally, the production of other metabolic regulators, such as the Fibroblast Growth Factor (FGF) family-which includes FGF 19 and FGF 21-as well as bioactive lipids like sphingolipids, may play a role in the development of systemic inflammation and, eventually, insulin resistance [8]. The secretion of these substances increases in obese individuals [9]. Increased release of Non-Esterified Fatty Acids (NEFAs) is observed in both T2DM and obesity, and it is associated with insulin resistance in both conditions [10].
The “lipid overflow hypothesis” posits that insulin sensitivity and β-cell function decline in obesity [11]. A high-fat diet that leads to an excess of circulating lipid substrates, such as fatty acids, also contributes to oxidative stress and chronic inflammation. Ectopic lipid reserves may increase with obesity, and potentially harmful lipid components and metabolites can cause cytotoxicity in peripheral cells, such as β-cells and the liver, hindering their ability to regenerate, survive, and function [12]. Lipotoxicity causes β-cell death in pancreatic islets by promoting the accumulation of high levels of triglycerides [12].
The “adipokine hypothesis” indicates that various hormones and chemicals produced by adipose cells, known as adipokines, play a role in initiating inflammatory and metabolic cascades that lead to T2DM and insulin resistance [13]. These hormonal and metabolic processes, along with an aberrant genetic background and lifestyle choices, trigger complex molecular cascades resulting in diabesity. White adipose tissue functions as an endocrine organ by secreting a variety of hormones such as leptin, adiponectin, and resistin, which have auto- and paracrine functions. The expansion of fat reserves in obesity has been linked to defective secretion of these endocrine components, impairing the metabolism of insulin target tissues and ultimately leading to the failure of insulin-producing β-cells [14].
Additionally, recent literature has highlighted the effect of gut flora on obesity and insulin resistance. The gut microbiome significantly impacts nutrient metabolism, and individuals with less variation in their gut flora are at a higher risk of being obese and insulin-resistant [15].
Management
Diabesity is a complex phenomenon involving both obesity and impaired glycaemic control. Therefore, the management of this condition requires a multidisciplinary approach that includes lifestyle modifications, pharmacotherapy, and surgical intervention.
Lifestyle Measures
Obesity and T2DM have similar pathophysiological pathways, particularly concerning adverse lifestyle choices. Thus, lifestyle modifications should be the initial step in managing diabesity, prior to any medical intervention. Lifestyle modifications involve making dietary and exercise adjustments to facilitate weight loss [9].
Dietary modification: Remission of T2DM can be induced by weight loss. According to several studies, approximately 70% of people with T2DM can experience remission with a weight loss of 15 kg [16,17]. Weight losses of up to 5 kilograms have been shown to lower fasting blood glucose levels and enhance sensitivity in the liver, skeletal muscle, and adipose tissues. The literature suggests that stepwise incremental weight loss leads to progressive improvements in HbA1c [18]. A study by Ajala O et al., examined the advantages of potential dietary changes for overweight diabetic patients [19]. Their research showed that a high-protein, Mediterranean-style diet, reduced carbohydrate intake, and a lower glycaemic index diet significantly improved glycaemic control. More recent research by Ozsoy S et al., investigated the potential effect of dietary modifications on gut flora, which could alter the neurotransmitter pathways associated with insulin sensitivity and satiety [20].
Physical activity: Exercise has many advantages, such as lowering blood pressure, cholesterol levels, and visceral adipose tissue, all of which reduce the risk of cardiometabolic diseases [6,7]. Exercise alone does not lead to a reduction in diabetes, despite improvements in biochemical indicators; therefore, a combination of exercise and dietary changes is recommended for optimal results [21-24]. This is supported by findings from the Malmö study, which showed that patients on a combined diet and activity modification program experienced long-term, sustainable benefits, with remission in half of the T2DM patients after five years. The degree of weight loss (r-value=0.19, p-value <0.02) and the change in fitness levels (r-value=0.22, p-value <0.02) significantly correlated with improvements in glycaemic management [25]. According to a meta-analysis by Umpierre D et al., diabetic patients benefit from concurrent dietary counselling and structured aerobic, resistance, or mixed exercise training, leading to improvements in glycaemic management and significantly lower HbA1c levels [26]. Exercise is linked to enhanced insulin sensitivity even in cases of modest weight reduction (weight loss ≥3% to <5% from baseline) [27]. This observation suggests that the relationship between exercise and improved glycaemic control is independent of weight loss.
The DIRECT experiment recently demonstrated that a systematic weight-management program integrated within a medical care setting could induce diabetic remission [28,29]. In the Diabetes Remission Clinical Trial (DiRECT), remission of diabetes was achieved by 57% of participants who lost 10%-15% of their body weight, and 86% of those who lost ≥15% of their body weight [28]. Insulin action is significantly influenced by weight loss; even a 5% reduction in weight can enhance insulin sensitivity in multiple organs, including skeletal muscle, liver, and adipose tissue [30,31].
Recommendations: The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” for 2024 includes the following recommendations regarding diet and physical activity for managing diabesity [32]:
- Patients with T2DM who are overweight or obese should be advised to follow a diet, exercise regimen, and behavioural therapy aimed at achieving a 5% weight loss.
- Such interventions should focus on creating an energy deficit of 500-750 kcal/day.
- Diets should be customised, as different diets with the same calorie restriction but varying protein, carbohydrate, and fat intake can be equally effective for weight loss.
- Patients who meet their short-term weight loss goals should be offered comprehensive weight maintenance programs for at least one year. These programs should promote regular body weight monitoring (either weekly or more frequently), a continuing low-calorie diet, and high levels of physical exercise (200-300 minutes per week) with at least monthly contact.
- To achieve a 5% weight loss, short-term (3-month) therapies utilising very low-calorie diets (800-1000 kcal/day) and complete meal replacements may be recommended. Such programs must include long-term, comprehensive weight maintenance counselling to sustain weight loss.
Pharmacotherapy
For T2DM, drug therapy generally includes weight loss medications and antihyperglycaemic drugs that have weight loss or weight-neutral effects.
Weight loss medication: Several short-term and long-term weight management medications have been approved by the US Food and Drug Administration (FDA).
Phentermine: Phentermine, a short-term medication for weight loss, is a sympathomimetic anorexigenic agent. It was approved by the FDA in 1959 [33]. It exerts its effects primarily through indirect sympathomimetic action by increasing Nor epinephrine levels. Additionally, it has been reported that phentermine inhibits neuropeptide Y, a principal signaling pathway for the induction of hunger [34]. In a meta-analysis by Haddock CK et al., a mean weight loss of 3.6 kg was achieved with phentermine 30 mg/day over 8-24 weeks [35]. In a clinical trial conducted by Aronne LJ et al., it was concluded that after 28 weeks, a weight loss of 6.1% was observed with monotherapy of phentermine 15 mg/day, compared to 1.7% for a placebo [36]. Common side effects of phentermine include constipation, insomnia, and dry mouth [37].
Orlistat: Orlistat reduces intestinal fat absorption by inhibiting pancreatic and gastric lipase. Numerous studies have been conducted to assess the effects of Orlistat on both obesity and diabesity. Participants taking Orlistat experienced a significantly greater mean percentage of weight loss compared to those in the placebo group [38-41].
Lorcaserin: Lorcaserin, a 5-hydroxytryptamine (5-HT2C) agonist, was approved by the FDA in 2012 for the promotion of weight loss as an adjunct to diet and exercise [42]. The BLOOM DM (Behavioural Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus) study concluded that the percentage of patients who lost at least ≥5% of their body weight was more than double in the lorcaserin group compared to the placebo group [43]. However, Smith SR et al., found in their Randomised Controlled Trial (RCT) that only 28% of obese patients achieved a 5% weight loss after 12 weeks of treatment with lorcaserin 10 mg [44], raising concerns about the utility of this drug in clinical practice. Therefore, if a weight loss of at least 5% is not achieved, the FDA recommends discontinuing lorcaserin after 12 weeks [45]. However, in 2020, the FDA alerted the public about a possible increased risk of cancer associated with lorcaserin [46].
Glucagon-like Peptide 1 (GLP-1) receptor agonist (Liraglutide): An injectable glucagon-like peptide-1 agonist, Liraglutide, enhances satiety and decreases appetite via its effects on the Central Nervous System (CNS). It was approved for the treatment of T2DM (T2D) in 2010 at a dose of 1.8 mg daily [47]. One of the four studies in the Satiety and Clinical Adiposity Liraglutide Evidence (SCALE) program concluded that after three years of treatment with Liraglutide 3.0 mg, an average weight loss of 6.1% was observed in comparison to the placebo group, which had only 1.9%. However, 15% of the study population reported serious adverse events, particularly gastrointestinal disorders [48]. Nausea was the most common adverse event associated with Liraglutide, with an incidence of almost 40% [42].
Combination drug therapy:i) Sympathomimetic amine anorectic/Antiepileptic combination (Phentermine/Topiramate): Phentermine was the first drug approved by the FDA for weight loss. However, in 2012, its approval in Europe was withdrawn due to safety concerns [49]. Topiramate, an anticonvulsant agent, has been shown to promote weight loss in obese patients; however, its mechanism for weight loss is unclear. A combination of phentermine and topiramate received FDA approval in 2012 for the treatment of obesity [42]. In a recent meta-analysis by Lei XG et al., significant weight loss was observed in the phentermine/topiramate group compared to the placebo group; however, the percentage of weight loss was dose-dependent. The meta-analysis also concluded that there was an increased risk of nervous system-related adverse events in the intervention group [50]. Paresthesia, insomnia, dysgeusia, dry mouth, constipation, and dizziness were reported as the most frequently observed adverse effects of phentermine/topiramate [51]. The incidence of psychiatric and cognitive adverse events was two to three times higher with phentermine/topiramate compared to a placebo [52].
ii) Opioid antagonist/Aminoketone antidepressant combination (Naltrexone/Bupropion): Bupropion, a drug used for smoking cessation is an antidepressant [42]. Naltrexone is an opioid antagonist that decreases food cravings in obese individuals [42]. In the three clinical trials included in the Contrave Obesity Trials (COR), the effect of naltrexone/bupropion on total body weight loss in patients with obesity was investigated. It was concluded that a weight reduction of 4-5% more was reported in the intervention group compared to the control group [53-55]. Similar findings were also reported in a clinical trial involving diabetic patients with obesity [56]. Naltrexone/bupropion is associated with a high incidence of gastrointestinal adverse effects (nausea, vomiting, constipation, dry mouth), in addition to headache, dizziness, insomnia, and anxiety [42].
iii) Cagrilintide-Semaglutide (CagriSema): A long-acting amylin analogue called cagrilintide is being studied for weight management. In a phase two clinical trial by Lau DCW et al., it was concluded that cagrilintide treatment for overweight and obese individuals resulted in significant weight loss and was well tolerated [57]. Combining cagrilintide with the GLP-1 receptor agonist semaglutide also offers weight-loss benefits. In another phase 2 trial by Frias JP et al., it was found that cagrilintide-semaglutide enhanced glycaemic management and weight loss compared to cagrilintide alone [58].
Antidiabetic drugs with weight loss:a) Biguanides: Metformin is a first-line medication for the management of T2DM. It inhibits hepatic gluconeogenesis and improves insulin sensitivity in skeletal muscle. Metformin use has been shown to offer several health benefits, including the ability to reverse hepatic steatosis and reduce cholesterol levels. It has been proposed that the weight loss effects associated with metformin may be indirect rather than a direct impact on hepatic fat metabolism and storage. Another reported effect of metformin is the reduction of appetite, although its mechanism of action is not yet fully understood [59,60]. The concerns regarding weight gain and hypoglycaemia are minimal with metformin, as it does not increase insulin secretion from the β-cells [61]. Various studies have shown weight loss of up to 2-3 kg with metformin [62-64]. The effect of metformin on Body Mass Index (BMI) in various populations was examined in a meta-analysis by Pu R et al., which involved 21 trials and 1,004 participants. It was discovered that patients with obesity experienced a reduction in BMI of 1.3 units [62]. Wu H et al., proposed that metformin may have a beneficial effect on the composition of the gut microbiome and may enhance the gut’s ability to metabolised glucose, potentially leading to weight loss [63]. According to Day EA et al., metformin may enhance the expression of Growth Differentiation Factor 15 (GDF-15), which suppresses appetite and promotes weight loss [64,65].
b. Insulin: Patients with significantly increased HbA1c are treated with insulin to optimise glycaemic control as quickly and effectively as possible. However, compared to other hypoglycaemic medications, insulin therapy has been associated with a considerable increase in body weight. Insulin use has been linked to weight gains of between 1.56 to 5.75 kg [66]. Both the type and dosage of insulin can affect how much weight a diabetes patient gains, with higher insulin dosages being associated with increased weight gain [67]. Premixed insulin has been shown to have a greater weight-related impact than basal insulin [68]. According to Freemantle N et al., the use of glargine insulin led to a noticeably smaller change in weight compared to premixed insulin [69]. Therefore, insulin must be prescribed with caution in patients with diabesity to minimise the risk of weight gain.
c. Dipeptidyl Peptidase 4 (DPP-4) inhibitors: Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin (Trajenta), and Vildagliptin (Galvus) inhibit the degradation of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. This action amplifies the effects of incretin hormones, lowering glucagon levels and increasing insulin release in a glucose-dependent manner. These agents have minimal impact on overall body weight and are thus considered weight-neutral [66].
d. GLP-1 receptor agonists: GLP-1 receptor agonists function by inducing the secretion of insulin and inhibiting the synthesis of glucagon. Furthermore, they delay gastric emptying by modulating receptors in the gut, as well as neurons responsible for appetite regulation. This leads to improved satiety and, consequently, weight loss [66]. Semaglutide (injection) was approved by the FDA for chronic weight management in 2021, making it the first weight loss drug to be approved by the FDA since 2014 [70].
Rybelsus: GLP-1 receptor agonist, Rybelsus is recommended as an adjunct to diet and exercise for improved glycaemic control in patients with T2DM. It contains semaglutide and works by stimulating insulin secretion and decreasing glucagon production in a glucose-dependent manner to lower blood glucose levels. Rybelsus has also been reported to be associated with weight loss. In a clinical trial reported by the FDA, the mean decrease in weight from baseline to week 26 for the Rybelsus 7 mg, Rybelsus 14 mg, and placebo groups were -0.4 kg, -2.4 kg, and -3.7 kg, respectively. However, the US FDA has issued a warning regarding a potential risk of thyroid C-cell tumours associated with Rybelsus. It is also contraindicated in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) and in those with a personal or family history of Medullary Thyroid Carcinoma (MTC) [71].
SGLT-2 inhibitors: SGLT-2 inhibitors increase glucose excretion in the urine by reducing the reabsorption of glucose in the renal tubules [72]. As a result of SGLT-2 inhibition, approximately 50-70 grams of glucose are excreted in the urine, which equates to about 200-300 calories per day. A weight loss of 2-3 kg has been demonstrated with SGLT-2 inhibitors as monotherapy and in combination with metformin [73,74]. These medications have been linked to weight loss of 0.9-2.5 kg and an approximate 0.69% decrease in HbA1c levels [66]. Bailey CJ et al., reported a weight loss of around -1.10 to -1.74 kg when SGLT-2 inhibitors were used in combination with metformin [75]. Common side effects of this medication include genital mycotic infections, urinary tract infections, vulvovaginal pruritus, and increased urination. Additionally, these drugs have been shown to raise Low Density Lipoprotein (LDL) cholesterol and blood creatinine levels. In patients with renal impairment or those on potassium-sparing medications, they can also result in hyperkalemia [76].
Recommendations: For T2DM, drug therapy typically includes weight loss medications and antihyperglycaemic drugs that have weight loss or weight-neutral effects. In 2024, the ADA “Standards of Medical Care in Diabetes” provided the following recommendations for the use of drug therapy in obese patients with T2DM [32]:
- The side effects of antihyperglycaemic drugs on weight must be considered when prescribing medications to obese individuals with T2DM.
- Medications for co-morbid conditions that may cause weight gain should be minimised whenever possible.
- In selected patients with obesity and T2DM, weight loss medications may be effective as adjuncts to diet, physical activity, and behavioural counselling. Potential benefits must be weighed against the potential risks of these medications.
- In patients with “diabesity,” GLP-1 receptor agonists with greater weight loss efficacy (e.g., semaglutide or tirzepatide) should be considered due to their weight-independent benefits.
- Weight management treatment should be reevaluated for those who do not reach their goals. Furthermore, in such patients, treatment strategies should be intensified with additional pharmacotherapy or metabolic surgery.
Metabolic Surgery
Bariatric surgery is an effective treatment for obesity that results in rapid glycaemic improvement in patients with co-morbid diabetes. Bariatric surgery has both weight-dependent and weight-independent effects on diabetes control. In addition to weight loss, bariatric surgery helps treat or prevent a wide range of obesity-related co-morbidities [32]. Numerous published studies have demonstrated the effectiveness of metabolic surgery in the treatment of diabesity and its associated complications [77,78]. After undergoing metabolic surgery for two or more years, there was an 87.0% improvement and a 78.0% remission of T2DM, according to a systematic review and meta-analysis that included 4,070 obese patients from 19 studies [78]. In 2017, Adams TD et al., concluded in their study of 400 participants that metabolic surgery led to a weight loss of 35 kg compared to the non surgical group, which experienced only a 2.9 kg weight loss [79].
Schauer PR et al., compared the efficacy of bariatric surgery versus medical therapy in patients with T2DM. They concluded that three years of intense medical therapy combined with bariatric surgery resulted in glycaemic control in significantly more obese patients with uncontrolled T2DM than medical therapy alone. Additionally, there was a significant improvement in quality of life in the surgical group at three years compared to the group receiving medical therapy alone [80].
Recommendations: The ADA “Standards of Medical Care in Diabetes, 2024” has provided the following recommendations for metabolic surgery [32]:
- Metabolic surgery can be considered in adults with T2DM who have a BMI of 30.0 kg/m2 (or 27.5 kg/m2 in Asian Americans).
- Metabolic surgery must be performed in appropriate medical centers with multidisciplinary teams skilled in managing diabetes and gastrointestinal surgery.
- When a person is being considered for metabolic surgery, it is important to assess them for co-morbid psychological conditions, as well as social and situational factors that may affect the procedure.
- After surgery, routine monitoring of micronutrients and nutritional status, along with long-term lifestyle support, must be provided to patients.
- A comprehensive mental health assessment must be conducted for patients presenting for metabolic surgery. In patients with significant depression, histories of alcohol or substance abuse, or other mental health conditions, surgery should be postponed until these conditions are addressed.
- After undergoing metabolic surgery, patients should be assessed for the need for further mental healthcare to help them cope with the physical and psychological aftereffects of the procedure.
Challenges in Diabesity Management
In patients with diabesity, the priority is optimal glycaemic management due to the considerable metabolic, macrovascular, and microvascular risks posed to poor control T2DM. However, several antidiabetic medications, such as insulin, are associated with an increased risk of weight gain in T2DM patients, which could potentially exacerbate their condition [13]. Tolbutamide, pioglitazone, and glimepiride have been shown to be the hypoglycaemic agents most strongly linked to weight gain (2.1-2.8 kg) in a meta-analysis of medications frequently associated with weight change [81]. When selecting antidiabetic medication regimens, clinicians must prioritise striking a balance between the risk of diabetes and achieving sufficient glycaemic control. Therefore, establishing both short- and long-term goals, along with a multifaceted strategy, is essential for the effective management of diabetes.
Conclusion(s)
Diabesity is becoming a recognised public health concern. It is critical to understand the complex pathophysiological mechanisms underlying the interaction between diabetes and obesity in order to choose appropriate management strategies. Recent developments in the treatment of diabetes and obesity have led to the creation of drugs that specifically target the pathways affecting weight, satiety, and glucose homeostasis. Moreover, regular inspections, exercise, and a nutritious diet can help prevent and control diabesity.
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