Both adult T2DM and YODM share common risk factors, pathological changes, and clinical manifestations as they both belong to the diabetes category. Common risk factors include obesity, family history, shared pathological changes such as reduced insulin sensitivity and insufficient insulin secretion, and common clinical manifestations like polydipsia, polyuria, increased appetite, and fatigue (20). However, due to the younger age of the YODM patient population, they exhibit unique clinical features, making management more challenging, disease progression faster, and the condition more severe (21).

Critical driving factors for the prevalence of YODM include both genetic factors inherited from parents and acquired risk factors related to oneself, such as obesity, unhealthy lifestyle habits, and psychological factors.

In addition to the continuous decline in function and quantity of pancreatic β-cells, tissue-specific IR is also a typical characteristic of T2DM. When the main target tissues of insulin, such as muscles, fat, and the liver, fail to respond appropriately to insulin, insulin sensitivity decreases continuously, making glucose less likely to be cleared from the bloodstream. Tissues begin to exhibit IR, leading to increased insulin production by the pancreas or presenting as hyperinsulinemia (51). Research has confirmed that IR plays a crucial role in the occurrence and development of various metabolic disorders, including non-alcoholic fatty liver disease (NAFLD), metabolic syndrome, obesity, hypertension, and cardiovascular diseases (52, 53). Chronic hyperinsulinemia resulting from IR can also lead to a reduction in pancreatic β-cell mass (54).

Currently, the primary mechanisms of IR involve abnormalities in substance metabolism, chronic inflammation, oxidative stress, among other aspects (55). Firstly, excessive energy intake promotes an increase in free fatty acids (FFA) and lipid deposition, leading to IR (56). AMP-activated protein kinase (AMPK), as an AMP-dependent protein kinase, is a key molecule in regulating biological energy metabolism. Studies have shown that activated AMPK can enhance insulin sensitivity and promote glucose uptake (57). Protein tyrosine phosphatase 1B (PTP1B), a widely expressed prototype non-receptor tyrosine phosphatase, is a critical negative regulator in insulin signal transduction. Overexpression in adipose tissue can lead to dephosphorylation of insulin receptors and inhibit insulin signal transduction (58). GLUT4 is an insulin-dependent transmembrane carrier protein that facilitates the translocation of glucose on the cell membrane. IR leads to reduced glucose uptake and is associated with impaired GLUT4 translocation (59).

Certainly, there is ample evidence indicating that chronic inflammation is pervasive throughout the course of DM, and it also influences IR (60). Macrophages can be classified into two different subtypes based on their activation status: M1 polarization, which promotes inflammation and is associated with reduced insulin sensitivity (61), and M2 polarization, which inhibits inflammation and is associated with enhanced insulin sensitivity (62). Activation of the NF-κB and JNK pathways due to pro-inflammatory status increases the secretion of various inflammatory mediators, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), leading to the promotion of IR (63–65). Oxidative stress and inflammation often coexist and mutually influence each other in the host. Reactive oxygen species can stimulate the production of inflammatory factors, and, in turn, cellular inflammatory factors can promote the generation of oxygen free radicals (66). Oxidative stress reduces the translocation of IRS-1, decreases protein kinase B (PKB) phosphorylation, and lowers GLUT-4 expression (67, 68).

Existing clinical studies confirm that both insulin sensitivity and insulin secretion are impaired in YODM patients (69). Genetic-related β-cell dysfunction has been found in East Asian adolescents, and it is significantly associated with the development of T2DM even with mild decreases in insulin sensitivity (70). In contrast, IR is prevalent in the Indian population and may manifest as early as in neonates (71). The Restoring Insulin Secretion (RISE) study indicates that compared to adults with T2DM, YODM exhibits more severe IR, higher insulin secretion demand, and lower insulin clearance rates (15). A comparative study of YODM diagnosed within 1.5 years, matched with non-T2DM individuals in terms of BMI, showed a 75% decrease in the first-phase and a 55% decrease in the second-phase insulin secretion in YODM, accompanied by severe peripheral and hepatic IR (69). This may be attributed to hormonal changes affecting insulin sensitivity during puberty, and the more severe obesity issues in adolescent patients also affect peripheral tissue insulin sensitivity (72). IR may prompt β-cells to secrete more insulin, leading to earlier β-cell failure. Dysfunction, rather than death, is a common β-cell defect in T2D (73). Therefore, focusing on IR in the early stages of YODM and conducting intervention studies may improve β-cell function to some extent. A cross-sectional study, including 79 adolescents aged 10 to 18, assessed body composition indicators: body mass index (BMI), body fat percentage, waist circumference, and subcutaneous fat. IR was diagnosed in 29.1% of patients, and these body composition indicators were all correlated with IR (74) ( Figure 1 ).

Considering the causes of obesity-induced DM, IR plays a crucial role (75, 76). A study conducted in Japan using intravenous glucose tolerance testing revealed IR in both obese non-diabetic adolescents and YODM individuals (77). Additionally, one of the major complications of obesity is IR, leading to disturbances in carbohydrate metabolism. Compared to normal-weight children, overweight and obese children have a higher incidence of IR (78). In the early stages of the disease, pancreatic β-cells can compensate for IR by increasing insulin secretion in the pathogenesis of glucose intolerance. Compensatory hyperinsulinemia induces increased appetite and weight gain. With the decline in pancreatic β-cell function and inadequate insulin secretion, the transition from IR to impaired glucose tolerance and then to T2DM occurs (79). Androutsos and colleagues applied principal component analysis to a health growth study cohort of over 2000 Greek children aged 9–13. They observed a positive correlation between a combination of high screen time, short sleep duration, and high sugary beverage consumption with HOMA-IR, while a combination of high to moderate-intensity physical activity and frequent eating showed a negative correlation with HOMA-IR (80). Dietary imbalance is prevalent in YODM and affects obesity and psychosocial function.

In the TODAY study, 20% and 6% of young people exhibited subclinical and clinical binge eating (5). In the SEARCH study, 50.3% of youth and YODM had dietary imbalances (81). Changes in gastric redoxin secretion may be an early biomarker of impaired glucose regulation in obese children with IR (82). Relevant studies found that for each additional hour of sedentary time and screen use between ages 8–10 and 15–17, insulin sensitivity decreased by 8.2% and 6.4%, respectively, while fasting blood glucose increased by 0.03 mmol/L and 0.02 mmol/L. This emphasized the evidence of sedentary behavior and screen time as key driving factors for the high-risk development of YODM (83).

Simultaneously, numerous factors, including genetics, inflammation and immunity, lipid metabolism, and adolescent hormones, affect signaling pathways such as insulin receptors, mediating the occurrence of IR. Firstly, certain genetic variations may lead to IR during adolescence. Studies indicate that polymorphisms in specific genes may influence key molecules in insulin signal transduction pathways, resulting in the occurrence of IR. The development of IR in YODM usually involves complex regulation by various genetic mechanisms. Genes of the insulin receptor substrate (IRS) family are closely associated with IR. Proteins encoded by IRS genes are critical molecules in insulin signal transduction pathways, and their abnormal function may lead to IR. Polymorphisms in IRS genes have been found to be associated with the development of IR in YODM.

Polymorphisms in inflammatory factor genes may be associated with IR in YODM. Chronic inflammation associated with obesity can lead to IR and β-cell dysfunction (84). Abnormal expression of inflammatory factors may increase tissue inflammatory responses, thereby interfering with the normal function of insulin signal pathways, leading to IR. During adolescence, changes in hormone levels and cytokines may increase adipose tissue inflammatory responses, further exacerbating the degree of IR. Inflammatory responses lead to increased release of cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These cytokines may directly interfere with insulin signal transduction pathways, affecting the function of insulin receptors and the effectiveness of insulin. The pro-inflammatory cytokine TNF-α can induce IR by disrupting early insulin-stimulated tyrosine phosphorylation (85). The increase in inflammatory reactions may induce autoimmune reactions, activate immune cells, disrupt immune regulation, and cause immune stress, leading to increased release of inflammatory factors, thus interfering with the normal function of insulin signal pathways. Activation of autoimmune reactions may damage and destroy insulin-secreting cells. Activation of immune cells such as macrophages and lymphocytes may increase the release of inflammatory factors, affecting the normal function of insulin signal pathways. Imbalance in immune regulation may lead to an increase in inflammatory reactions and abnormal activation of immune cells. Chronic immune stress may lead to increased activation of immune cells and increased release of inflammatory factors. All these abnormal changes can affect the normal function of insulin signal pathways.

Patients with YODM often exhibit lipid metabolism disorders (86, 87), including hyperinsulinemia and lipid peroxidation. These factors lead to the release of more fatty acids from adipocytes, further worsening IR and insufficient insulin secretion. IR can also lead to abnormalities in lipid metabolism, where fatty acids are not efficiently utilized by muscle and adipose tissues, leading to the synthesis of triglycerides in the liver, resulting in a vicious cycle of fatty liver and IR. The main cause of lipid metabolism disorders may be attributed to poor lifestyle habits during adolescence. A high-sugar, high-fat, high-energy-density diet may lead to weight gain and fat accumulation. Additionally, poor dietary structure may lead to abnormal expression of key molecules in the insulin signal pathway, thereby disrupting normal insulin signal transduction. Lack of physical exercise leads to reduced energy consumption in muscles, lipid metabolism disorders, and decreased insulin sensitivity. Moderate physical exercise helps control weight, improve the function of insulin signal pathways, and thus alleviate the degree of IR. Mechanistically, adipose tissue secretes various factors, including leptin, adiponectin, etc., which may negatively impact insulin sensitivity. The IR in YODM is related to the total body fat mass, especially visceral fat. This is mediated by various fat factors, including leptin, resistin, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Additionally, non-esterified fatty acids contribute to IR by increasing hepatic glucose output and hindering glucose uptake in skeletal muscles (88, 89). Furthermore, an increase in visceral fat leads to decreased levels of adiponectin and reduced expression of adiponectin receptors on cell surfaces (90).

Adolescence is a critical period for growth and development, and changes in hormone levels during puberty have a significant impact on insulin sensitivity. During adolescence, changes in sex hormones may affect fat distribution and the growth and development of muscle tissue, influencing the function of insulin signal transduction pathways. Alternatively, hormonal changes during adolescence may affect IR through neuroendocrine regulatory mechanisms. Other factors, including changes in thyroid hormone levels and adrenal cortex hormone levels during adolescence, may also affect metabolic pathways and insulin signal transduction, thereby influencing the occurrence of IR.

Early diagnosis and intervention help control the progression of the disease. In the early stages of diabetes diagnosis, effective treatment measures can improve the patient’s condition and contribute to diabetes remission. Approximately 40% of YODM cases are asymptomatic at the time of diagnosis, as diabetes is detected through screening due to signs of obesity, other risk factors, or IR (99). Therefore, early identification is crucial and can be achieved through alternative indicators such as waist circumference, triglyceride-glucose (TyG) index, metabolites, and IR index.

A study analyzing data from 38,000 Brazilian adolescents aged 12 to 17 compared the associations between obesity, overweight, waist circumference, and IR. The results showed that waist circumference is more helpful in identifying adolescents with IR, especially in late adolescence (100). Another multicenter cross-sectional study analyzed 161 newly diagnosed T2DM children and adolescents, with 1,935 children with normal blood sugar as healthy controls. The results indicated that the increase in HOMA2-B and HOMA2-IR is associated with a higher risk of T2DM, suggesting that besides IR, impaired beta-cell function is closely related to Chinese YODM. Gender differences in susceptibility and higher complications require YODM screening and prevention strategies (101). The triglyceride-glucose (TyG) index [area under the curve (AUC) 0.839)] showed better performance in identifying T2DM patients than HOMA-IR (AUC 0.645), demonstrating a significant association between IR and T2DM (102). Respiratory metabolites, including limonene, nonane, and 2,7-dimethylundecane, are correlated with IR evaluated by the homeostasis model assessment (HOMA-IR). Given their simple and non-invasive breath-based testing, these substances have the potential to serve as effective measures for early detection of insulin resistance (103). Another study tracking 190 newly diagnosed T2DM patients for 5 years identified 12 different metabolites, with forty-two hexaenoic acid, oxygen tri-nucleotide, dihydrocholesterol, and trienoic acid being the most representative (104).

In recent years, the global prevalence of T2DM has been increasing annually, with a significant contributing factor being the rising rates of overweight or obesity due to lifestyle changes. Clinical research results indicate that whether through lifestyle, medication, or metabolic surgical interventions, it is possible to slow down the progression from prediabetes to diabetes or achieve the reversal of elevated blood sugar, leading to normal levels, as T2DM remission (105, 106). Current research indicates that only some patients can achieve diabetes remission. These conditions include the exclusion of specific types of diabetes, such as secondary diabetes or diabetes caused by certain genetic factors, as well as patients with a longer course, more severe complications, and poor pancreatic beta-cell function. For T2DM patients without autoimmune destruction of pancreatic islets, overweight or obesity (BMI ≥ 25 kg/m²), preserved beta-cell function, and a course of ≤ 5 years have a higher likelihood of remission (91, 107). However, among these conditions, early-stage obesity serves as a crucial signal for achieving diabetes remission.

The Japan Diabetes Data Management (JDDM74) analyzed data from over 4,000 patients over 30 years nationwide, with 3,454 patients achieving diabetes remission, significantly correlated with a moderate weight loss of 3.0–7.9% (108). Therefore, based on the current clinical characteristics achievable for diabetic patients, combined with ongoing interventional research, weight loss and subsequent visceral fat loss are crucial for relieving T2DM, with obesity being the central core for achieving remission. Obesity can lead to excessive growth of adipose tissue, especially abdominal fat. This adipose tissue releases various hormones and cytokines, including free fatty acids, leptin, tumor necrosis factor, etc. These substances can interfere with insulin signaling, leading to insulin resistance. In the obese population, adipose tissue releases an increasing amount of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines, and other factors involved in the development of insulin resistance (109).

Unlike adults, adolescents are more heavily influenced by external factors, making it challenging for many YODM patients to effectively control their diet, engage in physical activity, and manage blood glucose in their daily lives. Adolescents, being in a sensitive period of growth transition, often experience unstable behavioral and emotional states, hindering stable blood sugar control. However, the remission of diabetes may have more significant benefits for adolescents. Medical goals for YODM include preventing further weight gain and/or achieving weight loss (encouraging obese patients to lose 7–10% of their weight), maintaining good blood sugar control, reducing disease-related stress, and managing adolescent psychosocial issues (110).

For diabetes patients, especially adolescents, considerations should extend beyond the treatment of diabetes itself to include other conditions caused by diabetes, including the emotional disorders often associated with adolescents. Diabetes distress encompasses complications, self-management demands, unresponsive provider reactions, poor interpersonal relationships, and negative emotional responses to diabetes itself. Depression and diabetes distress screening scores are closely related to YODM, similar to adolescents with T1DM (111). YODM exposed to various stressful life events often experience reduced quality of life, depressive symptoms, and lower compliance with prescription oral medications (112). In the Pediatric Diabetes Consortium, 22% of YODM cases were found to have comorbid depression, with only 9% receiving treatment in the past 12 months (113). Compared to non-diabetic peers, YODM is more likely to experience emotional or anxiety disorders before and after diagnosis (114). Therefore, patients must possess good self-management skills, adhere to dietary controls, medication regimens, and regularly monitor blood glucose levels. Patients should comply with treatment plans, including regular medication intake, follow-up appointments, and actively collaborate with doctors in adjusting and improving treatment plans.

Controlling body weight, especially for obese diabetes patients, can improve insulin sensitivity, contributing to the remission of diabetes. Therefore, weight loss and subsequent reduction in visceral fat are key to diabetes remission (115). Compared to adolescents, pre-adolescent YODM patients face a higher risk of related incidence, emphasizing the importance of intervention measures to prevent and treat obesity in early childhood (116). Patients need to adhere to a healthy lifestyle, including regular physical exercise, maintaining healthy dietary habits, and avoiding unhealthy habits such as smoking and excessive alcohol consumption. The Population-based Panasonic cohort study in Japan, analyzing the relationship between changes and diabetes remission in 1,903 patients over a 5-year period, showed that weight loss of ≥3.9 kg or ≥5.0% in patients with BMI ≥ 25 kg/m² (obesity) may be effective in relieving new-onset type 2 diabetes, excluding patients with BMI < 25 kg/m² (117). Lifestyle changes are an important component of YODM weight management. The T2DM youth weight management guidelines recommend that adolescents reach at least a 7–10% weight reduction from their final adult height, with weight indexes below the 85th percentile for those still growing (118) ( Table 1 ).

While there is currently evidence supporting the effectiveness of certain treatments in adolescents with type 2 diabetes, we must also be mindful of the potential side effects associated with these treatments (119). These include the possibility of hypoglycemic reactions, gastrointestinal discomfort, drug allergies, and others. Additionally, weight-loss surgery may lead to postoperative malnutrition, gastric emptying disorders, abnormal insulin secretion, among other issues (120, 121). Considering the psychological sensitivity of patients, it is crucial to continuously monitor their psychological status when implementing treatment plans or making recommendations. Timely intervention for any emerging social and psychological barriers is also necessary.