Diabetes stands as one of the most prevalent and serious chronic diseases worldwide. Currently, more than 537 million people worldwide are affected by diabetes. Estimates suggest that the total number of diabetes patients will rise to 784 million by 2045. Among all countries, China has the largest diabetic population (1). Substantial evidence indicates that sustained hyperglycemia may induce a range of diabetes-related complications, particularly nephropathy and retinopathy. Inflammatory processes are implicated as a critical factor in the onset and progression of these conditions (2).

Chronic low-grade inflammation in adipose tissue connects obesity-related insulin resistance (IR) to type 2 diabetes. Numerous studies have demonstrated that adipose tissue serves not only as a critical organ for regulating energy storage and nutrient balance but also as an endocrine organ capable of secreting various adipokines involved in glucose and lipid metabolism regulation (3, 4). Collagen VI (COL6) is one of the extracellular matrix proteins secreted by adipose tissue, playing a crucial role in maintaining the structural integrity and functionality of various tissues throughout the body. Endotrophin (ETP), a signaling fragment generated during COL6 formation (5), has been shown to exhibit pro-inflammatory and pro-fibrotic properties, contributing to systemic IR and adverse metabolic outcomes, such as lipid toxicity (6–8). Recent mouse studies indicated that induced overexpression of ETP in adipocytes exacerbates IR, whereas treatment with ETP-neutralizing antibodies enhances insulin sensitivity and alleviates adipose tissue inflammation and fibrosis in obese mice. Further human studies revealed elevated serum ETP levels in patients with IR (9–11).

Short-term intensive insulin (STII) therapy has increasingly become a first-line treatment for newly diagnosed type 2 diabetes patients in recent years (12). This approach achieves non-pharmacological remission by rapidly and effectively normalizing blood glucose levels. The primary mechanism of STII involves reducing glucotoxicity and relieving the excessive workload on beta cells, which enhances metabolic control and preserves pancreatic islet function (13, 14). A hyperglycemic environment is associated with chronic inflammation, which exacerbates IR and may induce oxidative stress, leading to further damage to blood vessels and other tissues (2). By lowering blood glucose levels efficiently, STII therapy reduces inflammatory factor release, improves insulin sensitivity, and inhibits hyperglycemia-induced oxidative stress (15).Therefore, we hypothesized that STII treatment might improve the degree of IR by modulating the levels of the proinflammatory adipokine ETP.

However, no studies have specifically examined the relationship between serum ETP and newly diagnosed type 2 diabetes. Moreover, the impact of STII on ETP levels remains unexplored. In this study, we aim to investigate the effects of STII on ETP levels in newly diagnosed type 2 diabetes. Additionally, we demonstrated the anti-inflammatory effects of STII by comparing changes in ETP levels before and after STII therapy in patients with newly diagnosed type 2 diabetes.

In this study, we observed a significant elevated in serum ETP levels in patients with newly diagnosed type 2 diabetes, indicating a positive association between serum ETP and type 2 diabetes. Tougaard NH et al. also reported that serum COL6 formation marker ETP was independently associated with renal events, first major adverse cardiovascular events, mortality, and the risk of heart failure in patients with type 2 diabetes. Additionally, urinary ETP was found to be associated with the progression of proteinuria (19). These fundings may support a hypothesis that serum ETP plays a significant pathogenic role in the initiation and progression of type 2 diabetes.

The novel adipokine ETP, a signaling peptide derived from the cleavage of the COL6 α3 chain, has emerged as a critical mediator in the pathological processes of adipose tissue in obesity. Evidence linking elevated ETP levels in obese adipose tissue to diabetes development suggested that ETP not only contributes to an adverse microenvironment within obese adipose tissue but also serves as a pathologically relevant driving force. This ultimately results in systemic IR and obesity-related metabolic disorders (6, 20). Elevated expression levels of ETP promote macrophage infiltration into adipose tissue, which is a major source of circulating inflammatory factors in obesity and plays a critical role in the progression of IR. Moreover, adipose tissue with increased ETP levels rapidly disrupts the regulation of circulating TG and non-esterified fatty acids, leading to hepatic steatosis. Consequently, abnormal lipid accumulation occurs in other tissues or organs, creating a “lipid toxic” environment that further exacerbates IR (20–22).

Preclinical studies have revealed that overexpression of ETP in the adipose tissue of transgenic mice impairs normal adipocyte function, leading to systemic metabolic dysfunction, characterized by enhanced IR and reduced insulin sensitivity (6). Additionally, transgenic mice exhibited significantly elevated levels of transforming growth factor-β1 (TGF-β1) and its receptors in adipose tissue (23). Increased oxygen radical production due to glucotoxicity has been shown to stimulate TGF-β synthesis. Similar to glucotoxicity, ETP exerts pleiotropic effects by potentiating TGF-β synthesis, thereby positively regulating diverse biological processes including inflammation, angiogenesis, fibrosis, and epithelial-mesenchymal transition (24, 25). At high glucose concentrations, fibrous structures form within the extracellular matrix surrounding adipose tissue, damaging the microenvironment and inducing elevated COL6 levels. However, regulating blood glucose can inhibit macrophage and fibroblast activity, potentially reducing ETP concentrations during effective glucose control (26). Sengul et al. observed that circulating ETP levels decreased alongside reductions in glycated hemoglobin and blood glucose, suggesting that improved glycemic control may lead to lower ETP concentrations (45). Our study demonstrated a positive correlation between serum ETP and fasting blood glucose before treatment in newly diagnosed type 2 diabetic patients. However, no significant correlation was found between serum ETP and fasting blood glucose after two weeks of STII therapy, nor was there a correlation between the changes in ETP and the changes in fasting blood glucose before and after treatment. Both glucotoxicity and ETP can modulate metabolic processes by enhancing TGF-β synthesis. However, current evidence remains insufficient to elucidate the interaction between glucose and ETP. The underlying signaling pathways and mechanisms require further investigation.

This study examined the changes in serum ETP levels in patients with newly diagnosed type 2 diabetes following STII pump therapy. Our results revealed that serum ETP levels in patients with newly diagnosed type 2 diabetes, which were markedly reduced following STII pump therapy. Additionally, we observed a positive correlation between baseline serum ETP levels and HOMA2-IR in patients with newly diagnosed type 2 diabetes. Furthermore, the reduction in ETP levels following STII pump therapy was also positively correlated with HOMA2-IR, suggesting that ETP may be associated with IR. Multiple linear regression analysis demonstrated that the δ-HOMA2-IR value could effectively explain variations in δ-ETP levels. This implies that larger changes in HOMA2-IR are associated with more pronounced fluctuations in ETP levels, while smaller changes in HOMA2-IR correspond to minimal alterations in ETP levels among in patients with type 2 diabetes. A recent study revealed that circulating ETP levels are associated with insulin resistance in individuals with obesity (44). Fasting ETP was significantly higher in obese insulin-resistant subjects compared to obese insulin-sensitive individuals. Using dietary induction, it was found that the 24-hour area under the curve (AUC) for circulating ETP was 25% higher in obese insulin-resistant subjects than in obese insulin-sensitive controls. In obese patients with type 2 diabetes, significant weight loss achieved through surgical intervention or intensive dietary therapy led to a marked reduction in circulating ETP levels alongside improved insulin sensitivity. Furthermore, endotrophin has been shown to directly impair insulin-stimulated glucose uptake in human skeletal muscle myotubes, indicating a direct negative effect on insulin action. In our study, newly diagnosed type 2 diabetic patients were stratified by BMI, only three cases were classified into the obese group, and no significant relationship was observed between BMI and circulating ETP—a finding that may be attributed to the small sample size. Research by Samuel Klein’s team suggests that circulating ETP acts as both a biomarker and a causative factor of systemic insulin resistance in obese insulin-resistant populations. However, our preliminary findings indicate a strong correlation between circulating ETP and insulin resistance in newly diagnosed type 2 diabetic patients, but do not establish a causal relationship. Whether ETP directly influences insulin resistance in type 2 diabetes remains unclear, and further investigation is needed to elucidate its role and underlying mechanisms.

ETP promotes the synthesis of TGF-β. Pancreatic β-cells dysfunction or depletion constitutes a pivotal pathophysiological event in the development of diabetes mellitus. According to current evidence, TGF-β signaling is active in both developing and adult β cells, generally inhibiting β cell proliferation (25). In addition, high glucose contributes to the occurrence and progression of diabetic complications by upregulating the TGF-β signaling pathway (27). Therefore, studies investigating potential antidiabetic therapies targeting the TGF-β signaling pathway are becoming increasingly significant. Given this, the role of ETP in enhancing TGF-β synthesis warrants further exploration regarding its impact on diabetes and associated complications. Sun et al. found that in mice on a high-fat diet, ETP overexpression may mediate chronic inflammation and fibrosis by activating the TGF-β pathway, which plays a key role in insulin resistance. This suggests that activation of the TGF-β pathway is an integral component of ETP’s effects. Subsequently, neutralizing antibodies against ETP were shown to ameliorate adverse metabolic effects and effectively reverse metabolic dysfunction induced during high-fat diet exposure (20). Based on these findings, targeting ETP neutralization or blocking the ETP-enhanced TGF-β synthesis pathway may offer a novel strategic direction for developing new therapies for type 2 diabetes.

Type 2 diabetes represents a complex metabolic disorder characterized by two fundamental abnormalities: impaired pancreatic hormone secretion and reduced insulin sensitivity in target tissues. In adipose tissue, IR promotes lipolysis, resulting in elevated circulating free fatty acids. This not only exacerbates insulin dysfunction but also contributes to systemic inflammation, creating a vicious cycle that worsens metabolic health (28). Chronic hyperglycemia triggers a cascade of pathophysiological responses, including oxidative stress, chronic low-grade inflammation, and proinflammatory cytokine release, ultimately leading to diabetic complications and multi-organ dysfunction (29). In patients with type 2 diabetes, dyslipidemia may lead to increased concentrations of circulating inflammatory cytokines (30). Existing studies have shown that IR is closely linked to a chronic low-grade inflammatory state. Multiple immune cell populations, including macrophages, T cells, and B cells - synergize with adipocyte-derived inflammatory mediators to drive the initiation and progression of IR (31). Previous studies have demonstrated that various pro-inflammatory adipokines, including Apelin, Resistin, Visfatin, and TNF-α, contribute not only to the impairment of pancreatic hormone secretion and IR (32), but also to the development of chronic diabetic complications. For example, elevated levels of these pro-inflammatory adipokines can exacerbate oxidative stress induced by hyperglycemia, resulting in endothelial dysfunction and increased vascular permeability (33, 34). In our study, the results also demonstrated that serum ETP levels were significantly elevated in patients with newly diagnosed type 2 diabetes, further suggesting the presence of increased chronic inflammation in type 2 diabetes. Targeting ETP or its associated pathways may provide novel strategies for reducing inflammation and enhancing metabolic control in type 2 diabetes.

Accumulating clinical evidence demonstrates that short-term intensive insulin (STII) therapy rapidly normalizes glycemic levels and reduces lipid accumulation, effectively alleviating glucotoxicity, lipotoxicity, and insulin resistance (IR) in patients with newly diagnosed type 2 diabetes. This, in turn, protects β-cell function and enhances overall metabolic health. However, studies examining the effects of STII treatment on ETP expression in patients with diabettes remain scarce. Thus, determining whether STII therapy can suppress ETP expression in vivo would offer valuable insights into its broader therapeutic potential for reducing inflammation and improving metabolic outcomes in diabetes management.

The exact mechanisms underlying the anti-inflammatory effects of insulin therapy are still not fully understood. Nonetheless, the following evidence supports this notion: 1) Insulin can activate several signaling pathways that suppress the expression of pro-inflammatory genes, including the phosphatidylinositol 3-kinase, the protein kinase B/Akt (35). By modulating these pathways, insulin plays a crucial role in maintaining the balance between metabolic homeostasis and immune responses, thereby potentially alleviating inflammation-related complications (36–39). Moreover, insulin attenuates toll-like receptor (TLR)-mediated inflammatory damage by inhibiting TLR signaling pathways (40). 2) Insulin modulates the levels of inflammatory mediators to bridge inflammation, such as by inhibiting generation and extracellular release of pro-inflammatory factors (e.g., tumor necrosis factor-α and interleukin-6) (41), and downregulating the expression of immune mediators like monocyte chemoattractant protein-1 and nuclear factor kappa B (42). 3) Insulin therapy reduces the ratio of T helper cell type 1 to T helper cell type 2 while increasing the proportion of regulatory T cells, thereby attenuating inflammatory responses (15). 4) High blood glucose levels may stimulate leukocytes to produce reactive oxygen species (ROS) and enhance oxidative stress, thereby exacerbating inflammatory conditions. Insulin administration can inhibit ROS generation and demonstrate anti-inflammatory properties (43). 5) Insulin therapy reduces IR linked to inflammation. In this study, we found that STII pump therapy improved IR in patients with newly diagnosed type 2 diabetes. Moreover, we observed that the levels of the inflammatory marker CRP decreased as glycemic control was enhanced. Along with glycemic regulation, serum ETP levels were significantly reduced, paralleled by decreased CRP levels, suggesting ETP’s beneficial modulatory effect on systemic inflammation.

This research has certain limitations. First, it was a single-institution study with a relatively limited cohort, analyzing the relevant data of only 40 patients with newly diagnosed type 2 diabetes before and after intensive insulin therapy. Second, the relatively short duration of intensive insulin therapy, focusing solely on the dynamic changes in ETP levels during the short-term remission of hyperglycemia. Existing studies have indicated that ETP may serve as a biomarker for complications in type 2 diabetes and is associated with mortality, renal complications, and cardiovascular events. Therefore, long-term follow-up in diabetic patients is of great clinical importance. further studies would be valuable to expand the sample size and enhance follow-up investigations, exploring the changes in ETP levels at 3 months, 1 year, and beyond following STII therapy in patients with newly diagnosed type 2 diabetes.

In summary, our preliminary study demonstrated that serum ETP levels were significantly higher in patients with newly diagnosed type 2 diabetes than in the control group. Insulin treatment could decrease serum ETP expression, suggesting that STII therapy may alleviate the elevated micro-inflammatory state in patients with type 2 diabetes. However, the mechanisms underlying the anti-inflammatory effects of insulin therapy warrant further investigation. Additionally, we found that reduced ETP expression was strongly correlated with improved HOMA-IR but not with changes in FPG. This finding highlights the need for larger sample sizes and long-term studies to determine whether the anti-inflammatory effects of insulin therapy are independent of its hypoglycemic effects.