Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, primarily caused by insulin resistance (IR) and pancreatic β-cell dysfunction (1). IR is the state in which target cells exhibit reduced sensitivity to insulin, resulting in impaired glucose uptake and subsequent hyperglycemia (2). In parallel with the escalating obesity epidemic, the incidence of T2DM has risen steadily and is now regarded as one of the most pressing global public health issues. Data from the World Health Organization (WHO) indicate that as of 2022, an estimated 828 million individuals aged 18 years and older were diagnosed with diabetes, with T2DM accounting for the vast majority of cases (3). The prevalence of T2DM has risen most strikingly in developed countries and emerging economies, creating profound impacts on personal health and placing considerable strain on families and healthcare systems.

At present, management of T2DM mainly involves drug therapy, nutritional and physical activity interventions. Drug-based therapies primarily include insulin sensitizers, DPP-4 inhibitors, and SGLT2 inhibitors, all of which improve insulin efficacy and facilitate glycemic control (4–6). Nutritional interventions focus on controlling caloric and carbohydrate intake, aiming to manage body weight and enhance insulin responsiveness (7, 8). Physical activity is strongly advocated because it stimulates fat metabolism and potentiates insulin function (9). Nevertheless, despite these treatment options, a substantial proportion of patients fail to attain adequate blood glucose control, and the risk of diabetes-associated complications continues to increase over time. Consequently, discovering new biomarkers and therapeutic targets, especially those involved in metabolic pathways, has emerged as a major area of contemporary investigation.

Branched-chain amino acids (BCAAs) have recently attracted increasing attention as a class of biologically important amino acids. Comprising leucine, isoleucine, and valine, BCAAs are essential amino acids acquired from the diet, involved in intracellular protein synthesis and energy homeostasis. A growing body of research demonstrates that BCAAs significantly contribute to diabetic metabolism, closely linking them to the development and progression of IR. In individuals with T2DM, circulating BCAAs concentrations are generally higher than in healthy populations, correlating strongly with IR, obesity, and other metabolic abnormalities (10). Experimental data indicate that BCAAs function beyond metabolic intermediates, potentially influencing insulin responsiveness via diverse mechanisms and aggravating IR. The interplay between BCAAs and IR involves intricate regulatory mechanisms. BCAAs engage in cellular growth and metabolic control through mTOR signaling, with hyperactivation of mTOR being strongly associated with IR (11). Moreover, metabolites derived from BCAAs, including α-keto acids and ketone bodies, may compromise β-cell functionality, resulting in diminished insulin output. In recent years, research has increasingly focused on the gut microbiota’s involvement in BCAAs metabolism. Evidence suggests that imbalances in gut microbial composition can modulate BCAAs uptake and metabolic processing, indirectly impacting insulin signaling (12).

Although the reasons for elevated BCAAs levels and their association with IR remain unclear, dysfunctional BCAAs catabolism may represent one of the underlying factors. This review aims to provide an in-depth understanding of BCAAs metabolism and its potential role in the pathogenesis of IR in T2DM, as well as to summarize pharmacological and alternative lifestyle interventions that reduce plasma BCAAs levels and their impact on metabolic health.

IR was initially characterized in Himsworth’s seminal studies (13). Early studies demonstrated that diabetic individuals showed divergent responses to glucose and insulin administration, with some maintaining stable or declining blood glucose and thus categorized as insulin-sensitive; whereas others exhibited marked hyperglycemia, reflecting insulin insensitivity or attenuated insulin responsiveness. This phenomenon typifies IR in metabolic syndrome, characterized by the inability of peripheral tissues to elicit an appropriate glucose-lowering response at normal circulating insulin concentrations, commonly termed reduced insulin sensitivity. Such insulin action encompasses the inhibition of hepatic glucose production, suppression of lipolysis, stimulation of glucose uptake, and augmentation of glycogen synthesis (14–18). IR predominantly impacts skeletal muscle, hepatic tissue, and white adipose depots (19). IR is commonly linked to impairments across multiple insulin signaling cascades, involving ectopic lipid deposition, mitochondrial dysfunction, and enhanced activation of stress-related kinases such as c-Jun N-terminal kinase (JNK) and pro-inflammatory pathways (20).

In recent years, dysregulation of BCAAs metabolism has received increasing attention in obesity-related disorders, including IR, T2D and cardiovascular diseases. A plasma metabolomic analysis comparing obese and lean individuals revealed significant differences in BCAAs-related metabolites, suggesting that enhanced BCAAs catabolism is associated with IR. This finding has been further validated in mouse plasma metabolomic studies (21–23). Moreover, in a prospective cohort study, targeted metabolomic analysis demonstrated that elevated levels of several amino acids, including BCAAs, were significantly associated with an increased risk of developing T2D (24). These findings indicate that BCAAs may serve as both biomarkers and key mediators in obesity and related metabolic disorders. In addition, a strong correlation has been observed between circulating BCAA levels and IR (25, 26). Furthermore, high BCAAs concentrations have been shown to impair insulin sensitivity and induce IR. In animal studies, acute elevation of circulating BCAAs led to increased blood glucose and insulin levels and significantly reduced whole-body insulin sensitivity during hyperinsulinemic–euglycemic clamp experiments, whereas lowering BCAAs levels improved glucose tolerance in obese mice (27). A randomized, double-blind study investigated the effect of modulating BCAAs metabolism on insulin sensitivity in 16 patients with mild to moderate T2D using sodium phenylbutyrate (NaPB), a drug that promotes BCAAs catabolism. The results showed that NaPB treatment significantly reduced plasma BCAAs levels and improved peripheral insulin sensitivity by approximately 27%, accompanied by enhanced skeletal muscle mitochondrial oxidative capacity, increased glucose oxidation, and decreased blood glucose levels (28).

The two major mechanisms by which plasma BCAAs are related to IR are as follows: First, impaired mitochondrial BCAAs metabolism plays a critical role (29). Patients with T2DM exhibit higher plasma BCAAs levels compared to healthy individuals, while their mitochondrial oxidative capacity is markedly reduced (30). Elevated plasma BCAAs may result from diminished mitochondrial oxidative capacity, suggesting a close link between mitochondrial function and IR (31). When BCAAs metabolism is impaired, large amounts of BCAAs -derived metabolites (such as 3-hydroxyisobutyrate, 3-HIB) accumulate in plasma, which may exert toxic effects on cells and ultimately lead to IR (32). Reportedly, a community-based observational study including 15 patients with T2DM, 13 first-degree relatives (FDR), and 17 controls (CON, all overweight or obese) assessed muscle mitochondrial oxidative capacity using high-resolution respirometry, and in some participants combined hyperinsulinemic-euglycemic clamp with ¹³C-leucine tracer to measure in vivo BCAAs oxidation. Results showed that plasma BCAAs levels in T2DM patients were higher than in controls and were significantly negatively correlated with muscle mitochondrial oxidative capacity (r = -0.44, P < 0.001). Furthermore, their whole-body leucine oxidation rate was significantly reduced under basal conditions (0.202 vs. 0.275 μmol·kg⁻¹;·min⁻¹, P < 0.05), and also showed a downward trend under hyperinsulinemic conditions (30).

The second mechanism involves activation of the mTOR signaling pathway by BCAAs metabolism, thereby disrupting insulin signaling (33). In addition to their role in protein synthesis, BCAAs act as signaling molecules regulating multiple physiological activities (34). Studies have shown that plasma leucine can influence glucose metabolism by activating the mTOR signaling pathway in skeletal muscle. Linn et al. reported that during hyperinsulinemic-euglycemic clamp experiments, ingestion of whey protein or an equivalent amount of leucine led to a significant ~30% increase in muscle p-mTOR (Ser2448) levels (35). Conversely, studies with the mTOR inhibitor rapamycin provide supporting evidence from the opposite perspective: in patients with type 1 diabetes, short-term rapamycin pretreatment prior to islet transplantation significantly reduced daily insulin requirements (–8 ± 6 U/day, p < 0.001) and led to sustained improvement in hepatic insulin sensitivity one year post-transplant, as indicated by a significant decrease in hepatic glucose production (–1.1 ± 1.1 mg/kg/min, p = 0.04) (36). In addition, insulin can activate mTOR through the PI3K-Akt signaling pathway (37). When BCAAs continuously activate mTOR, the downstream effector S6 kinase (p70S6K) phosphorylates insulin receptor substrate 1 (IRS-1) on serine residues, thereby further inhibiting Akt signaling, reducing glucose transport, and promoting the development of IR (38, 39).

Therefore, BCAAs are not only metabolic biomarkers of IR but may also serve as one of the key drivers in the development of IR.

BCAAs are not only important biomarkers of IR but may also directly contribute to its development. In an acute supplementation experiment, intravenous BCAAs infusion transiently reduced blood glucose in mice, likely through stimulation of insulin secretion. However, beginning 10 minutes post-infusion, plasma insulin and glucose levels both rose and remained elevated until the end of the experiment. Hyperinsulinemic–euglycemic clamp studies further demonstrated reduced systemic insulin sensitivity, accompanied by hyperactivation of hypothalamic AgRP neurons and increased food intake. These effects were reversed when BCAAs levels were reduced (27). Thus, BCAAs can acutely impair glucose metabolism and insulin sensitivity, while dietary restriction of BCAAs has shown beneficial effects in experimental models. In a protein diet study, reducing all three BCAAs by 67% in the control amino acid (Ctrl AA) diet (Low BCAAs) exerted distinct effects on obese mice. Specifically, isoleucine restriction reprogrammed hepatic and adipose metabolism, enhanced hepatic insulin sensitivity and ketogenesis, increased energy expenditure, and activated the FGF21–UCP1 axis. Valine restriction induced similar but milder metabolic benefits, whereas leucine restriction had no significant effect (80, 81).

Mechanistically, BCAAs contribute to IR through several pathways. First, excessive BCAAs and their metabolites (e.g., BCKAs and corresponding acylcarnitines) accumulate in skeletal muscle and liver, impairing mitochondrial energy metabolism and inhibiting fatty acid oxidation, leading to by-product accumulation and further disruption of insulin signaling. Second, BCAAs activate the mTORC1 pathway, inducing serine phosphorylation of IRS-1 and weakening downstream insulin receptor signaling, thereby reducing cellular insulin sensitivity. Third, elevated BCAAs levels promote M1 polarization of adipose tissue macrophages, increasing proinflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1), which further exacerbate IR (82).

Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine protein kinase and a key member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family (83). mTOR regulates core processes of cell proliferation and growth in response to signals such as insulin, amino acids, energy status, and oxygen (84). It coordinates upstream signals with downstream effectors, including transcriptional and translational mechanisms, to modulate fundamental cellular activities such as energy utilization, protein synthesis, autophagy, cell growth, and proliferation (85). As a catalytic subunit, mTOR exists in two distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which phosphorylate different substrates and exhibit diverse physiological functions (86).

Patients with obesity and insulin-resistant T2DM exhibit significantly elevated serum BCAAs levels (87, 88). Clinical studies show that elevated BCAAs levels are positively correlated with the degree of IR (89). BCAAs, including leucine, isoleucine, and valine, are essential amino acids and potent activators of mTORC1 (90). Leucine can synergize with insulin to activate mTORC1. Persistent mTORC1 activation leads to phosphorylation of S6K1, which subsequently phosphorylates serine residues on insulin receptor substrates IRS-1 and IRS-2 impairing downstream insulin signaling and potentially targeting IRS-1 for proteasomal degradation (38, 39) (see Figure 2). For example, a study found that when rat extensor muscles were cultured with varying concentrations of leucine, AMP-activated protein kinase (AMPK) activity was suppressed, while the mTORC1/p70S6K1 signaling pathway was activated, resulting in IR (91).

Grb10 is an intracellular adaptor protein that can directly bind to multiple growth factor receptors, including the insulin receptor and the insulin-like growth factor-1 (IGF-1) receptor, and negatively regulate their actions (92). mTORC1 can stabilize Grb10 by phosphorylating its tyrosine residues, preventing its degradation and thereby continuously inhibiting the interaction between IRS and the insulin receptor. This leads to increased IR and places an additional burden on pancreatic glucose handling. Consequently, BCAAs may contribute to pancreatic dysfunction or the development of T2DM through sustained activation of mTORC1.

BCAAs, particularly leucine, directly act on downstream targets S6K1 and Grb10 via mTORC1 signaling. Activation of S6K1 promotes protein synthesis and cell growth, while Grb10 mediates negative feedback to suppress insulin signaling, helping maintain metabolic homeostasis. A deeper understanding of the roles of S6K1 and Grb10 in the mTORC1 pathway is critical for elucidating the contribution of BCAAs to T2DM-associated IR and provides potential targets for therapeutic strategies based on mTOR signaling.

Insulin promotes the translocation of GLUT4 in adipocytes through activation of the PI3K/AKT signaling pathway (see Figure 3), facilitating glucose uptake into fat cells. Intracellular glucose is metabolized via glycolysis to glycerol, which participates in triacylglycerol (TAG) synthesis and de novo lipogenesis (93). Adipocyte IR is an early hallmark of obesity and T2DM. BCAAs can impair insulin action through sustained activation of mTORC1, with leucine being a key activator. mTORC1 is involved in multiple physiological processes, including cell growth, metabolism, and glucose homeostasis (94). Studies have shown that in rats fed a high-fat (HF) diet supplemented with BCAAs, IR can be reversed by the mTORC1 inhibitor rapamycin (22). Additionally, the microbiota-dependent tryptophan metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) can enhance hepatic insulin signaling by directly activating the aryl hydrocarbon receptor (AhR), stimulating TSC2 transcription, and suppressing mTORC1 signaling, thereby alleviating HF diet-induced IR (95).

In obese and diabetic rodents and humans, the downstream molecule of mTORC1, ribosomal S6K1, is activated (96). S6K1 is regarded as a negative regulator of IRS signaling (38, 39) (96–98). Experimental evidence indicates that high concentrations of BCAAs stimulate mTOR, subsequently inducing IR through serine phosphorylation of IRS-1 (99). In addition, dysregulated BCAAs metabolism can cause BCAAs accumulation in the aorta, leading to mitochondrial reactive oxygen species (ROS) damage and inflammatory responses via excessive mTOR activation (100). Recent studies have further demonstrated that BCAAs metabolic defects may result in local leucine accumulation, which promotes α-cell proliferation through the mTOR pathway (101). Activation of the BCAAs/mTORC1 axis is also associated with insulin sensitivity (11, 102, 103). Mitochondrial BCAAs aminotransferase (BCATm) markedly elevates plasma BCAAs levels, but is not affected by high-fat diet–induced obesity and IR (104, 105), suggesting that BCAAs-mediated effects such as mTOR activation alone are insufficient to induce IR.

Furthermore, activation of mTORC1 stabilizes Grb10, reducing its degradation. Grb10 inhibits the interaction between insulin receptor substrates (IRS) and the insulin receptor via tyrosine phosphorylation, thereby impairing insulin signaling. Studies have shown that eight weeks of treadmill training in T2DM rats effectively reduced elevated Grb10 levels in the hippocampus, restored the mTOR/AMPK signaling pathway, alleviated spatial learning and memory deficits, and enhanced GLUT4 translocation, ultimately improving diabetes-associated cognitive impairment (106). Moreover, evidence shows that β-cell mass and function are increased in diabetic mice with β-cell–specific Grb10 knockout (107), and transcriptome analysis of diabetic mouse liver revealed significant downregulation of Grb10 expression (108). It has also been reported that the food additive carrageenan can impair insulin signaling through two mechanisms: on the one hand, inducing inflammation that elevates Ser(P)307-IRS1 and suppresses insulin signaling; on the other hand, enhancing the GRB10 promoter, whereby GRB10 inhibits Tyr(P)-IRS1, further reducing Ser(P)473-AKT activation. Together, these changes alter IRS1 phosphorylation status and insulin sensitivity (109). Therefore, BCAAs may activate mTORC1 by increasing Grb10 expression, disrupt insulin signaling pathways, and ultimately lead to IR.

Overactivation of the mTORC1 signaling pathway is considered a key mechanism in this process. mTORC1 plays a central role in regulating cell growth and metabolism, while simultaneously inhibiting insulin signaling, thereby affecting glucose uptake and utilization. This inhibitory effect reduces cellular insulin responsiveness and promotes the development of IR. Consequently, modulation of mTORC1 activity may provide a potential therapeutic strategy for diabetes.

BCAAs are closely associated with T2DM and IR, making them a promising therapeutic target for alleviating these conditions. In the field of BCAAs-targeted drug development, several potential candidates have attracted research attention. One class of drugs comprises BCAAs synthesis inhibitors, such as BT2 (3,6-dichloro-2-carboxybenzo[b]thiophene) (110), which block endogenous BCAAs synthesis, thereby reducing circulating levels. Another class of drugs aims to lower BCAAs levels by promoting their oxidation and clearance, including NaPB (28) and fibrate compounds (111), which reduce plasma BCAAs concentrations by enhancing their metabolism and excretion.

studies have shown that dietary restriction of BCAAs can enhance insulin sensitivity through multiple mechanisms and may play a role in diabetes management (131). In an obese mouse model, dietary BCAAs restriction without altering total protein or energy intake resulted in reduced body weight and improved insulin sensitivity and glucose tolerance (132). Another study found that feeding obese mice a diet selectively low in BCAAs improved metabolic health, enhanced glucose tolerance, and reduced fat accumulation (80). These findings indicate that BCAAs restriction can improve insulin sensitivity through multiple mechanisms, thereby alleviating IR (133).

In a 4-week isocaloric intervention with protein intake fixed at 1 g/kg body weight, 12 patients with T2DM consumed diets in which approximately 60% of the protein was provided as an amino acid mixture during weeks 2 and 4. The intervention group received a BCAAs-depleted formula, whereas the control group received a complete amino acid formula. BCAAs restriction reduced fasting, clamp, and postprandial BCAAs levels by 17%, 13%, and 62%, respectively, and was associated with a 24% increase in the oral glucose sensitivity index, a 28% reduction in postprandial insulin secretion, and a 21% increase in circulating Fibroblast Growth Factor 21 (FGF21) levels. In addition, BCAAs restriction was accompanied by downregulation of mTOR signaling in white adipose tissue, an increased mitochondrial respiratory control ratio, and alterations in gut microbiota composition, characterized by an increase in Bacteroidetes and a decrease in Firmicutes. However, under hyperinsulinemic–euglycemic clamp conditions, no significant changes in whole-body or hepatic insulin sensitivity were observed (134).

it is important to note that numerous studies have revealed a close association between elevated BCAAs levels and IR, providing mechanistic support for the theory that “lowering BCAAs levels may improve metabolic disorders.” Nevertheless, at the intervention level, there is currently a lack of direct evidence demonstrating that simply reducing dietary BCAAs intake can reverse IR. Since BCAAs are essential amino acids, excessive restriction may lead to nutritional imbalance, making it a pressing challenge to “meet physiological needs while avoiding excessive accumulation.” Therefore, future research should explore alternative strategies, such as modulating the gut microbiota or developing small-molecule drugs that selectively inhibit BCAAs synthesis or metabolism, to achieve more precise regulation of BCAAs levels.

IR is one of the central features of T2DM and is closely associated with BCAAs metabolic dysregulation. Increasing evidence indicates that impaired BCAAs metabolism is tightly linked to the metabolic abnormalities and IR observed in T2DM. As essential amino acids, BCAAs play critical roles in protein synthesis and energy metabolism. Multiple studies consistently demonstrate that elevated circulating BCAAs levels are closely associated with the development and progression of IR in T2DM (135–137) supporting the involvement of BCAAs metabolic dysregulation in T2DM pathogenesis.

Moreover, a brief review of BCAAs metabolic pathways reveals that BCAAs catabolism is mediated by multiple enzymes and transporters, generating various intermediates. These intermediates have been shown to regulate key pathways related to glucose and lipid homeostasis as well as insulin sensitivity. Notably, BCAAs not only play a pivotal role in the pathogenesis of T2DM but also represent potential therapeutic targets. Modulating BCAAs metabolism and its associated pathways may improve IR and glycemic control in T2DM patients. Furthermore, elucidating the precise molecular mechanisms by which BCAAs influence IR could facilitate the development of novel interventions and personalized therapeutic strategies, enhancing T2DM management.

In summary, BCAAs metabolic dysregulation is closely associated with metabolic dysfunction and IR in T2DM. A deeper understanding of the complex relationship between BCAAs and IR will provide valuable insights into T2DM pathophysiology and may open new avenues for the treatment of this prevalent metabolic disorder.