Immune activation induced by dysregulated lipid metabolism in the pathogenesis of type 2 diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by two core pathological features: Insulin resistance and β-cell dysfunction, with dyslipidemia and immune dysregulation playing critical roles in its pathogenesis. Ectopic lipid deposition and lipotoxicity, resulting from dysregulated lipid metabolism, drive T2DM progression by reshaping immune microenvironments across multiple organs. Over the past two decades, the concept of “immune-metabolic coupling” has gained widespread recognition: Lipotoxicity activates immune cells through pattern recognition receptors, eliciting chronic low-grade inflammation and systematically disrupting insulin signaling pathways. This process involves key metabolic tissues including adipose tissue, liver, skeletal muscle, pancreatic islets, and the intestine. Free fatty acids, inflammatory mediators, extracellular vesicles, and immune cell trafficking collectively form a cross-organ communication network that perpetuates the progression of T2DM. This review systematically summarizes organ-specific immune alterations and their interactive mechanisms, and emphasizes that future research should focus on elucidating the mediators and pathways of inter-organ crosstalk, as well as the origins and migration routes of immune cells. These insights will provide a theoretical foundation for advancing from mere management of T2DM toward the restoration of immunometabolic homeostasis.

Key Words: Type 2 diabetes mellitus; Insulin resistance; Lipid metabolism disorders; Cross-organ communication; Immunity

Core Tip: Type 2 diabetes mellitus (T2DM) is driven by insulin resistance and β-cell dysfunction. This review highlights the innovative concept of “immune-metabolic coupling”, where dysregulated lipid metabolism (dyslipidemia) causes lipotoxicity, activating immune cells and triggering chronic inflammation that disrupts insulin signaling across multiple organs. We focus on the cross-organ communication network that perpetuates T2DM and argue that future research must target this immunometabolic crosstalk to move beyond managing the disease and toward restoring long-term immunological and metabolic homeostasis.

INTRODUCTION

The global prevalence of diabetes presents a growing public health challenge. According to the most recent International Diabetes Federation Diabetes Atlas, nearly one in nine adults aged 20-79 is affected by diabetes, with projections indicating a significant increase by 2050[1]. Type 2 diabetes mellitus (T2DM) is the most prevalent form of diabetes worldwide, accounting for 90%-95% of all diabetes cases[2]. The fundamental pathological hallmarks of T2DM include insulin resistance (IR) and dysfunctional β-cells, yet the underlying mechanisms extend beyond impaired glucose metabolism. Dyslipidemia is increasingly recognized as a critical contributor to the initiation and progression of T2DM. Intracellular ectopic lipid deposition leads to chronic organ damage and represents a key event in T2DM pathogenesis[3]. Lifestyle factors, including high-calorie diets and physical inactivity, are major drivers of the rising T2DM prevalence[4]. In healthy states, surplus energy is stored as triglycerides in adipose tissue to maintain metabolic equilibrium. However, chronic overnutrition disrupts this balance, precipitating dyslipidemia[5]. Under these conditions, the storage capacity of adipose tissue becomes overwhelmed, promoting not only weight gain and obesity but also aberrant lipid accumulation in non-adipose tissues such as the liver, skeletal muscle, and pancreatic β-cells ultimately compromising insulin secretion[6,7].

Over the past two decades, the concept of “immune-metabolic coupling” has garnered broad acceptance[8,9]. Dyslipidemia and associated lipotoxic signals activate pattern recognition receptors, reshaping the immune microenvironment in crucial metabolic organs including visceral adipose tissue, liver, skeletal muscle, pancreatic islets, and the intestines. This triggers a transition from local to systemic chronic low-grade inflammation and impairs insulin signaling, synergistically accelerating IR and dysglycemia[10,11]. Research indicates that lipid accumulation induces adipocyte hypertrophy and dysfunction, prompting infiltration by macrophages, T cells, and B cells, and establishing a state of persistent low-grade inflammation. An increase in pro-inflammatory immune cells [such as M1 macrophages, cluster of differentiation (CD) 8⁺ T cells, and T-bet⁺ B cells], coupled with a decline in regulatory populations [regulatory T cells (Tregs) and regulatory B cells (Bregs)], disrupts insulin signal transduction and promotes IR[12,13]. Furthermore, lipotoxicity activates the Toll-like receptor (TLR) 4/myeloid differentiation primary response 88 (MyD88) pathway in β-cells, inducing chemokine release that recruits pro-inflammatory macrophages into pancreatic islets. These islet macrophages exacerbate β cell dysfunction and insulin deficiency through the secretion of inflammatory cytokines and phagocytosis of insulin vesicles[14].

Notably, immune microenvironment alterations in adipose tissue, islets, liver, skeletal muscle, and gut are interlinked via a cross-organ communication network mediated by free fatty acids (FFAs), inflammatory cytokines, and immune cell trafficking. However, the precise molecular mechanisms governing these interactions remain poorly understood. This review aims to delineate how dyslipidemia activates immune cells within key metabolic tissues including adipose tissue, pancreatic islets, the liver, skeletal muscle, and the gut and to examine the interorgan signaling crosstalk that underpins the pathogenesis of T2DM.

LIPID ACCUMULATION-INDUCED ADIPOSE TISSUE IMMUNE DYSREGULATION DRIVES IR

During obesity, excess lipid storage causes adipocyte hypertrophy the onset of adipocyte dysfunction. Hypertrophic adipocytes fail to balance lipid storage with lipolysis, activating adipose immune responses and provoking systemic low-grade inflammation that promotes IR[14]. This chronic, sterile inflammatory state is a key basis for immune activation in obesity and related IR, with one molecular mechanism involving high-fat diet (HFD)-induced activation of the NLRP3 inflammasome[15]. Saturated FFAs act as key signaling molecules that trigger inflammasome activation. This, in turn, promotes the maturation of pro-inflammatory cytokines such as interleukin (IL)-1β and IL-18, which are subsequently released by immune cells infiltrating the adipose tissue of obese individuals thereby exacerbating both local and systemic inflammation[16]. Early rodent studies showed markedly increased adipose tumor necrosis factor (TNF)-α, and blocking TNF-α improved glucose tolerance and insulin sensitivity[17], establishing chronic tissue inflammation as a core driver of IR[18,19]. Progressive lipid overload enlarges adipose depots, enhances immune-cell infiltration, and sustains chronic low-grade inflammation involving macrophages, T cells, and B cells hallmarks of immune dysregulation[20,21].

Macrophages

Macrophage-mediated adipose inflammation is a principal mechanism linking obesity to IR and T2DM[22]. In obesity, adipocytes release large amounts of FFAs and monocyte chemoattractant protein-1 (MCP-1)[23,24]. Elevated FFAs favor macrophage accrual[25]. Recruited adipose tissue macrophages (ATMs) become lipid-laden, buffering local lipid excess. In parallel, monocyte CCR2 engagement by MCP-1 promotes trafficking into adipose tissue[26], making the MCP-1/CCR2 axis a major source of ATMs. CCR2 high monocytes respond strongly to MCP-1, display heightened chemotaxis, and are preferentially recruited[27]. Other chemokine systems, including CCR5, contribute to monocyte recruitment[28]. Upon infiltration into adipose tissue, these monocytes differentiate into macrophages.

Lipolysis and adipocyte death expose ATMs to abundant fatty acids[29]. These lipids ligate macrophage receptors including TLRs and CD36 initiating pro-inflammatory signaling. Saturated fatty acids (SFAs) indirectly activate TLR4 via fetuin-A, leading to nuclear factor kappa-B (NF-κB) activation and cytokine production[30]. TLR4 inhibition ameliorates IR. CD36, a scavenger receptor for SFAs, drives inflammatory cytokine expression in ATMs and impairs insulin signaling[31]. Lipotoxic stress polarizes infiltrating ATMs toward an M1 phenotype that releases TNF-α, IL-1, IL-6, and MCP-1, thereby disrupting insulin signaling[32,33]. IL-1β, IL-6, and TNF-α further activate mitogen-activated protein kinase (MAPK) and NF-κB cascades, which inhibit insulin signaling by altering insulin receptor substrate (IRS)-1 phosphorylation and reduce adipocyte glucose uptake[34]. Conversely, ω-3 fatty acids are anti-inflammatory: G protein-coupled receptor 120, highly expressed on pro-inflammatory macrophages, serves as their receptor and suppresses TLR2/3/4 and TNF-α pathways, promoting insulin sensitization[35]. Ces1d regulates triacylglycerol/diacylglycerol metabolism and restrains lipid-driven macrophage activation; its expression declines during monocyte-to-M1 transition. Ces1d deficiency causes enlarged lipid droplets and triacylglycerol/diacylglycerol accumulation, fostering an M1-like state. These pro-inflammatory macrophages recruit CD3⁺ CD8⁺ T cells to adipose tissue, amplifying local inflammation and aggravating IR[36].

T cells

Evidence indicates that obesity reshapes T-cell composition in adipose tissue, with increases in pro-inflammatory CD4⁺ helper T (Th) 1 and CD8⁺ T cells and a concomitant decline in Tregs, changes closely linked to IR[37].

FFAs rapidly reprogram both visceral adipose tissue and peripheral CD4⁺ T cells: Adipocyte-derived FFAs expand and enrich interferon-gamma (IFN-γ) producing CD4⁺ T cells within fat, intensifying local inflammation[38]. Systemically elevated FFAs activate the phosphatidylinositol 3-kinase (PI3K) p110δ protein kinase B (AKT) pathway, skewing CD4⁺ T cells toward effector memory like phenotypes that home to adipose tissue and amplify inflammation[39]. CD8⁺ T cells are key initiators and sustainers of adipose inflammation and directly promote obesity-related IR by modulating macrophage activity. In diet-induced obese mice, CD8⁺ T cells infiltrate visceral fat before macrophage accumulation and, through MCP-1 secretion, recruit and activate macrophages[40]. Genetic or antibody-mediated depletion of CD8⁺ T cells reduces macrophage infiltration, lowers TNF-α and IL-6 expression, and improves insulin sensitivity; adoptive transfer of CD8⁺ T cells into CD8-deficient mice aggravates inflammation and IR[41]. A reduction of adipose-tissue Tregs also contributes to obesity-associated inflammation, partly via IFN-α induced apoptosis that diminishes their numbers[42].

B cells

Adipose-tissue B cells are active drivers of IR. In HFD induced obesity, B cells infiltrate visceral fat and aggravate IR and glucose intolerance by activating pro-inflammatory macrophages and T cells and by producing pathogenic IgG. Consistently, B-cell deficient mice remain metabolically protected despite weight gain, and anti-CD20 mediated depletion improves IR[43]. T-bet, a transcription factor shaping B-cell effector programs[44], marks a subset that is enriched in visceral adipose tissue of obese humans and mice; these T-bet⁺ B cells secrete IgG2c and the chemokine CXCL10, thereby worsening IR. Selective deletion of T-bet in B cells ameliorates HFD-induced IR[45]. The lipid mediator leukotriene B4 (LTB4) recruits B2 lymphocytes into obese adipose tissue and directly programs them toward a pro-inflammatory phenotype. Activated B2 cells, in turn, potentiate Th1 and macrophage inflammatory activity, collectively exacerbating IR; blockade of the LTB4/LTB4 receptor 1 pathway limits B2-cell infiltration and activation[46]. Additionally, adipose Bregs produce IL-10 and support tissue homeostasis. Through IL-10 dependent suppression, Bregs counteract obesity-associated adipose inflammation and IR. Niche factors such as CXCL12 and FFAs sustain Breg number and function, whereas obesity-related alterations in these cues diminish Breg abundance and immunoregulatory capacity, facilitating IR[47].

Additionally, both innate lymphoid cells (ILCs) and neutrophils are implicated in obesity-associated IR. Adipose-resident ILCs contribute to obesity-related IR by secreting IFN-γ[48]. Moreover, in the visceral adipose tissue of obese individuals, neutrophil numbers are increased and are associated with specific gut microbiota characteristics. A transient rise in neutrophils drives an increase in pro-inflammatory Th1 cells and a decrease in Tregs within adipose tissue, thereby triggering inflammation[49].

In summary, HFD-driven dyslipidemia and lipotoxicity establish chronic low-grade inflammation that remodels the adipose immune microenvironment via activation and imbalance across macrophages, T cells, and B-cell subsets disrupts insulin signaling, and ultimately promotes the onset and progression of IR (Figure 1).

Figure 1 Mechanisms of lipid accumulation-induced adipose tissue immune microenvironment disruption and insulin resistance. Mechanisms including: (1) Adipocyte hypertrophy and macrophage activation: Hypertrophied adipocytes release excessive free fatty acids (FFAs), which promote macrophage recruitment and differentiation into adipose tissue macrophages. FFAs activate macrophages via receptors such as Toll-like receptor (TLR) 4 and cluster of differentiation (CD) 36, driving polarization toward the pro-inflammatory M1 phenotype. This leads to the secretion of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Additionally, fetuin-A binds to TLR4 and indirectly activates the nuclear factor kappa-B signaling pathway, further enhancing TNF-α and IL-6 production. These cytokines collectively impair insulin signal transduction; (2) Monocyte recruitment and infiltration: FFAs and the chemokine monocyte chemoattractant protein-1 (CCL2) recruit circulating monocytes to adipose tissue via the CCR2 pathway. Upon infiltration, these monocytes differentiate into macrophages, amplifying the inflammatory response; (3) T cell activation and cytokine secretion: Under the influence of FFAs, both CD4⁺ and CD8⁺ T cells become activated and proliferate. They secrete cytokines such as interferon-gamma, which enhance inflammatory responses and promote further macrophage recruitment and activation; and (4) B cell involvement in inflammation: B cells accumulate in adipose tissue, where they contribute to inflammation by activating T cells and secreting pathogenic IgG antibodies and the chemokine CXCL10. These actions exacerbate both local and systemic inflammation, further impairing insulin sensitivity. IL: Interleukin; TNF: Tumor necrosis factor; NF-κB: Nuclear factor kappa-B; TLR: Toll-like receptor; FetA: Fetuin-A; ATM: Adipose tissue macrophage; CD: Cluster of differentiation; FFAs: Free fatty acids; IFN: Interferon; MCP-1: Monocyte chemoattractant protein-1.

LIPID METABOLISM DISORDER MEDIATES ISLET MACROPHAGE INFILTRATION AND Β CELL FAILURE

Under obese conditions, HFD, and IR, circulating levels of FFAs are elevated. These increased FFAs serve as endogenous danger-associated molecular patterns. Evidence suggests that excessively high fatty acid concentrations constitute a critical factor that promotes islet inflammation, activates islet immune responses, and contributes to β cell dysfunction[50]. Several studies indicate that inflammation within the islet microenvironment is mediated, at least partially, by FFAs. Elevated FFAs are sensed by TLRs on β cells, which promotes islet inflammatory responses and immune activation, ultimately leading to β cell failure. Numerous studies have documented increased macrophage infiltration in the islets of individuals with T2DM. The extent of macrophage accumulation often correlates with the severity of β cell dysfunction. In contrast to the predominant T-lymphocyte infiltration observed in T1DM islets, islet inflammation in T2DM is chiefly mediated by macrophages[51].

One study demonstrated that SFAs activate the TLR4/MyD88 signaling pathway within β cells. Activation of TLR4/MyD88/NF-κB signaling cascade prompts β cells to produce and release specific chemokines, which recruit CD11b (+) Ly-6C (+) M1-type pro-inflammatory monocytes/macrophages to the islets[52]. Macrophages also express TLR4. Upon engagement by SFAs, macrophage TLR4 activates the NF-κB pathway, triggering the secretion of IL-1β and TNF-α. These cytokines subsequently act on β cells to activate their NF-κB and Janus tyrosine kinase (JNK) pathways while exacerbating endoplasmic reticulum stress[13]. The synergistic action of these responses ultimately impairs the glucose-stimulated insulin secretion (GSIS) capacity of β cells. Concurrently, these inflammatory cytokines derived from islet macrophages enhance the lipotoxic effects of SFAs, leading to suppressed expression of genes associated with β cell differentiation and function. Beyond inflammatory cytokines, islet macrophages directly interfere with β cell function via extracellular vesicle (EV) phagocytosis and platelet-derived growth factor (PDGF) secretion pathways. Immunostaining has revealed insulin within macrophage filopodia, and electron microscopy has confirmed the phagocytosis of characteristic β cell insulin secretory granules by adjacent macrophages. This phenomenon was more pronounced in the islets of HFD mice[53]. Phagocytosis of β cell secretory vesicles by intra-islet macrophages may represent one mechanism underlying the reduction in GSIS. Furthermore, binding of macrophage-derived PDGF to PDGFR on β cells promotes compensatory β cell proliferation[53] (Figure 2).

Figure 2 Mechanisms of macrophage-mediated islet inflammation and β-cell dysfunction induced by disordered lipid metabolism. Elevated circulating free fatty acids initiate islet inflammation by activating the Toll-like receptor (TLR) 4/nuclear factor kappa-B (NF-κB) pathway in pancreatic β-cells, prompting them to secrete chemokines that recruit circulating monocytes. Upon infiltration and under lipotoxic conditions, these monocytes polarize into pro-inflammatory M1 macrophages, which are further activated via the TLR4/NF-κB pathway to secrete abundant inflammatory cytokines. These cytokines in turn impair β-cell function by activating intracellular Janus tyrosine kinase and NF-κB signaling and inducing endoplasmic reticulum stress, collectively suppressing glucose-stimulated insulin secretion and insulin gene expression. Additionally, the activated M1 macrophages directly phagocytose insulin secretory granules and release platelet-derived growth factor to engage platelet-derived growth factor receptors on β-cells, stimulating a compensatory proliferative response that ultimately fails to prevent β-cell failure and inadequate insulin secretion. FFAs: Free fatty acids; TLR: Toll-like receptor; NF-κB: Nuclear factor kappa-B; JNK: Janus tyrosine kinase; ER: Endoplasmic reticulum; MyD88: Myeloid differentiation primary response 88; PDGF: Platelet-derived growth factor; PDGFR: Platelet-derived growth factor receptor.

However, the primary origin of the increased islet macrophages remains debated. Some studies propose that SFAs-stimulated β cells attract circulating monocytes, which subsequently differentiate into pro-inflammatory macrophages after entering the islets. Other reports indicate that although monocytes are detectable in the pancreas, they do not migrate into the islets; instead, the accumulation of intra-islet macrophages results from local proliferation of resident macrophages[13]. Elucidating the dominant mechanism is essential for developing precise therapeutic strategies to mitigate islet inflammation-associated damage in obesity and diabetes.

Abnormal lipid metabolism also directly influences β cell function. The low-density lipoprotein receptor-related protein 1 (LRP1) is a key regulator of β cell function in dyslipidemic T2DM. One of its primary roles is to bind and internalize extracellular lipoproteins, and it is expressed in various cell types, including β cells. Under HFD conditions, β cell-specific LRP1 knockout mice showed that lipid metabolic improvements mediated by the master transcriptional regulator peroxisome proliferators-activated receptor (PPAR) γ2 reduced the accumulation of lipotoxic sphingolipids but concurrently impaired β cell function, indicating that LRP1 acts as a central node integrating lipid metabolism and β cell function[54].

In summary, lipotoxicity promotes the functional decline of pancreatic β-cells. Elevated FFAs directly impose metabolic stress and, concurrently, activate the TLR4/NF-κB signaling pathway, initiating an immune-inflammatory response within the islets. This process is characterized by macrophage infiltration and pro-inflammatory polarization, which also impairs the transport of insulin secretory vesicles in β-cells. Ultimately, these events lead to severely compromised insulin secretion and a reduction in functional β-cell mass. Therapeutic strategies targeting this metabolic-immune crosstalk are of significant importance for preserving β-cell function in T2DM.

LIPID OVERLOAD INDUCES HEPATIC MACROPHAGE SUBSET REMODELING AND T CELL POLARIZATION IMBALANCE

Macrophages

In the adult liver, embryonic-derived Kupffer cells (KCs) and circulating monocyte-derived macrophages (MoMFs) cooperate to sustain immune-metabolic homeostasis. Sensing portal microbial and nutrient cues, KCs via the liver X receptor alpha (LXRα)/complement receptor of the immunoglobulin family (CRIg)/T-cell immunoglobulin and mucin domain-containing protein 4 (TIM4) axis and a lipid-metabolism transcriptional network promote cholesterol efflux, clear bile pigments, and secrete IL-10/transforming growth factor-β (TGF-β), thereby acting as metabolic immune sentinels[55]. HFD or IR induces a “triple imbalance” lipid droplet overload, phenotypic decline, and chemotactic amplification. KCs accumulate free cholesterol/ceramides with downregulated LXRα/CRIg/TIM4, while releasing CCL2 and CXCL10 to recruit CCR2⁺ Ly6C high monocytes and establish a resident extrinsic rela[56,57]. In metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), embryonic-derived KCs decrease, and MoMFs refill the niche along two fates: Replenishment as TIM4⁺ KCs or conversion to triggering receptor expressed on myeloid cells 2 (TREM2⁺) lipid-associated macrophages (LAMs)[58-60]. TREM2⁺ LAMs are enriched for extracellular-matrix remodeling and lipid-handling programs; they can aid fibrosis resolution through collagen phagocytosis yet also aggravate liver injury through an MS4A7-NLRP3 pathway[61,62]. Multi-omics studies further show that early metabolic fatty liver is marked by expansion of CD14⁺/CCR2⁺ MoMFs proportional to hepatic lipid load, with far denser lipid droplets than in residual KCs, underscoring MoMFs/LAMs as a core lipotoxic–inflammatory node[63]. HFD-induced, phosphatidylcholine-rich exosomes simultaneously blunt hepatocyte IRS-2/PI3K-AKT-glycogen synthase kinase 3-beta signaling and activate KCs through TLR4-NF-κB-NLRP3, whereas blocking exosome biogenesis or silencing Pcyt1a mitigates IR and KC hyperactivation[64]. Additional hepatocyte-macrophage communication via ITGβ1-enriched vesicles, the miR-30a-3p/ABCA1 axis, MSR1-JNK signaling, and p38α-driven M1 polarization promotes foam-cell like macrophage accumulation and fibrosis[65-68]. Palmitic acid and peroxidized lipids act as endogenous pathogen-associated molecular patterns that engage TLR4/myeloid differentiation protein 2 and, together with a TLR2 “first signal”, trigger NLRP3 caspase-1 and reactive oxygen species-NF-κB/JNK pathways, amplifying inflammation and IR[69-73]. Necrotic hepatocytes further impede efferocytosis through the CD47-signal regulatory protein α “don’t-eat-me” axis, prolonging damage-associated molecular patterns exposure and worsening fibro-metabolic injury[74]. Pathway plasticity also shapes disease course: Notch-immunoglobulin kappa J region (RBPJ) restrains CD36-dependent lipid clearance and maintains a pro-inflammatory MoMF dominance, while genetic/pharmacologic RBPJ blockade unleashes a high-CD36 clearance network that alleviates lipotoxicity and inflammation[75,76]. In parallel, the IL-15/acetate/extracellular adenosine triphosphate-P2RX7 axis pre-programs circulating CXCR6⁺ CD8 T cells (FOXO1 low factor-related apoptosis ligand/TNF high), reinforcing feedback with the macrophage lipid inflammatory circuit, whereas foam-like macrophages can transiently dampen inflammation via an IL-10/annexin A1 autocrine loop after engulfing steatotic hepatocytes[77].

T cells

Disordered hepatic lipid homeostasis reflects not only innate immune imbalance but also tight control by multiple T-cell lineages. Through cytokine circuits, T cells feed back to the KC-macrophage axis and influence the transition of MASLD toward T2DM. KCs also function as professional antigen-presenting cells that prime T-cell responses, an essential step for adaptive immunity[78]. Th1 cells, characterized by T-bet expression, produce IFN-γ, IL-2, and TNF-α[79]. Under lipid excess, Th1 expansion and IFN-γ secretion drive the insulin-resistance inflammation cascade[80]. Conversely, IFN-γ deficiency mitigates steatosis and fibrosis, indicating a direct pro-steatotic role for the Th1 axis[81]. The Th17/IL-17 pathway closely couples to lipotoxicity: IL-17 can raise CXCL10, promote hepatic macrophage recruitment and inflammation, and potentiate palmitate-induced hepatocyte injury[82-84]. Consistently, clinical and experimental data link Th17 elevation to diabetes progression; exogenous IL-17 aggravates steatohepatitis, whereas IL-17 neutralization alleviates disease[85-87]. In contrast, Th22/IL-22 exerts metabolic protection by restraining lipogenesis. IL22RA1 is required for hepatic lipid control; hepatocyte-specific IL22RA1 knockout mice develop greater diet-induced steatosis, IR, glucose intolerance, inflammation, and fibrosis[88]. Short-term IL-22 reduces hepatic PPARα, PPARγ, and sterol regulatory element binding protein (SREBP)-1c expression, while longer treatment decreases fatty acid synthase and ELOVL6[89], restores glycemic control, and diminishes steatosis, inflammation, and fibrosis[90]. Treg cells are pivotal for immune homeostasis. In visceral adipose tissue their function depends on PPARγ; PPARγ-deficient Tregs display an insulin-resistant phenotype, and pioglitazone fails to rescue insulin sensitivity in Treg-specific PPARγ-/- mice[91]. During high-fat feeding, depletion of intrahepatic Foxp3⁺ CD4⁺ CD25⁺ Tregs provokes steatosis, whereas Treg reconstitution attenuates the MASLD/MASH phenotype and lowers intrahepatic TNF-α[92]. Induced Tregs also improve IR and adipose inflammation in obese mice[93] (Figure 3).

Figure 3 Lipid overload drives innate-adaptive immune imbalance and promotes hepatic insulin resistance. High-fat diet-derived exosomes and pathogen-associated molecular patterns are recognized through cluster of differentiation (CD) 36-mediated uptake and Toll-like receptor 4/myeloid differentiation protein 2 signaling, respectively, leading to Kupffer cell (KC) activation and initiation of nuclear factor kappa-B priming. Under the influence of Notch/immunoglobulin kappa J region-mediated lineage commitment, monocyte-derived macrophages differentiate toward a triggering receptor expressed on myeloid cells 2 lipid-associated macrophage phenotype, whereas the liver X receptor alpha-complement receptor of the immunoglobulin family-T-cell immunoglobulin and mucin domain-containing protein 4 axis supports the maintenance of homeostatic KC identity. Pro-inflammatory stimuli facilitate NLRP3 inflammasome assembly and caspase-1 activation, resulting in interleukin (IL)-1β maturation and secretion, along with increased production of tumor necrosis factor-α and IL-1β. The CD47-signal regulatory protein α checkpoint serves to modulate phagocytic activity and prevent excessive clearance. These inflammatory factors collectively inhibit the hepatocyte insulin signaling cascade, spanning from the insulin receptor to insulin receptor substrate-2, phosphatidylinositol 3-kinase, and protein kinase B, thereby promoting insulin resistance. Simultaneously, shifts in the cytokine milieu favor T-cell differentiation away from regulatory T cells/helper T (Th) 22 subsets toward Th1/Th17 dominance, characterized by elevated interferon-gamma and IL-17 and reduced IL-10 and IL-22, which further exacerbates hepatic insulin resistance and inflammation. HFD: High-fat diet; EV: Extracellular vesicle; IRS: Insulin receptor substrate; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; CD: Cluster of differentiation; TLR: Toll-like receptor; MD2: Myeloid differentiation protein 2; SIRPα: Signal regulatory protein α; NF-κB: Nuclear factor kappa-B; PAMP: Pathogen-associated molecular patterns; LXRα-CRIg-TIM4: Liver X receptor alpha-complement receptor of the immunoglobulin family-T-cell immunoglobulin and mucin domain-containing protein 4; RBPJ: Immunoglobulin kappa J region; MoMF: Monocyte-derived macrophage; TREM: Triggering receptor expressed on myeloid cells; LAM: Lipid-associated macrophage; IL: Interleukin; TNF: Tumor necrosis factor; IFN: Interferon; Treg: Regulatory T cell; Th: Helper T.

Overall, Th1/Th17 subsets reinforce a “lipotoxicity-inflammation-fibrosis” feedback loop, whereas Th22/Treg subsets confer metabolic protection through anti-lipogenic and anti-inflammatory actions. Their dynamic disequilibrium is a key immune driver of MASLD/MASH progression toward T2DM[94]. Obesity-associated hepatic lipid metabolic disruption initiates a self-reinforcing immune-metabolic vicious cycle. This cycle begins with the loss of KC homeostasis and the accumulation of pro-inflammatory macrophages, then expands to a Th1/Th17-dominated T-cell response. Ultimately, through crosstalk between innate and adaptive immunity, localized inflammation is systematized into persistent IR and systemic metabolic dysfunction. Interrupting this process represents one of the most promising strategies for intervening in the MASLD-T2DM disease continuum.

ECTOPIC LIPID DEPOSITION IN SKELETAL MUSCLE IMPAIRS INSULIN SENSITIVITY THROUGH IMMUNE MICROENVIRONMENT DYSREGULATION

High circulating FFAs are readily taken up by skeletal muscle, where ectopic fat appears as intermuscular and intramuscular adipose depots and as intramyocellular lipid droplets. Because skeletal muscle accounts for most insulin-stimulated glucose disposal, lipid overload blunts insulin signaling and glucose uptake, fostering IR. The local immune compartment further shapes this trajectory.

Individuals with type 2 diabetes display reduced muscle mass, strength, and performance; muscle mass inversely correlates with diabetes incidence and IR[95]. Under homeostatic conditions, satellite cell mediated repair restores damaged muscle with support from immune cells, but regeneration is compromised in lipid-laden and diabetic milieus[96]. Single-cell analyses identify tissue-resident macrophages in skeletal muscle distinct from counterparts in other organs as functionally diverse subsets that maintain homeostasis and promote regeneration[97]. In severe obesity/diabetes models (ob/ob, db/db), muscle becomes a major sink for ectopic lipids, and post-injury repair is markedly delayed, with reduced angiogenesis, impaired cell proliferation, and diminished myoblast activity. These defects parallel weakened macrophage infiltration and inefficient clearance of necrotic fibers and debris[98].

Inflammatory mediators and EVs released by non-resident immune cells also act as major brakes on muscle regeneration in T2DM. IL-6 exerts context-dependent effects on muscle homeostasis, determined by its cellular source, receptor engagement (classic vs trans-signaling), and the surrounding microenvironment. Lipid overload drives adipose hypertrophy and inflammation, thereby stimulating macrophages to produce pro-inflammatory IL-6[99,100]. During physical inactivity, IL-6 trans-signaling via the soluble IL-6 receptor drives metabolic dysfunction and atrophy[101]. Conversely, intense exercise induces autocrine muscle IL-6 that signals through membrane IL-6R to activate anti-inflammatory programs, enhance nutrient utilization, and promote hypertrophy[100]. In vitro, hyperglycemia increases triglyceride and cholesterol loading in macrophages. Whereas small EVs and large EVs from normal macrophages carry distinct lipid cargos, high glucose abolishes these differences, yielding “pathological” EVs that disrupt macrophage macrophage communication, raise lipid burden in recipient macrophages, and skew them toward an M2 phenotype. Uptake of such EVs by myofibers directly elevates intramyocellular triglycerides and impairs insulin sensitivity[102]. We therefore posit that macrophage-derived EVs generated under hyperglycemia contribute to muscle lipid accumulation and IR. Collectively, dysregulated lipid metabolism perturbs the skeletal-muscle immune microenvironment, promoting atrophy and defective regeneration; the underlying causal links warrant further investigation.

LIPID METABOLISM DISORDERS INDUCED BY OBESITY CAN DISRUPT GUT IMMUNITY, COMPROMISE THE INTESTINAL BARRIER, AND TRIGGER SYSTEMIC INFLAMMATION

Accumulating evidence indicates that dyslipidemia driven by obesity compromises intestinal immune function via multiple pathways, promoting gut inflammation and accelerating the onset and progression of T2DM. Gut-associated immunity is increasingly recognized as a key factor in obesity-related IR, involving mechanisms of both innate and adaptive immunity.

Macrophages

The gut, as a primary interface organ with the external environment, is also a crucial immune organ. The gut immune system must precisely distinguish between harmful and beneficial antigens to mount appropriate responses for each, defending against pathogen invasion[103]. Macrophages act as first-line immune responders, serving as key innate immune effector cells that play a central role in intestinal immunoregulation[104]. Recent studies indicate that the activation and infiltration of intestinal macrophages are strongly correlated with metabolic disorders. In mice fed an HFD, intestinal epithelial cells secrete CCL2, thereby recruiting F4/80⁺ CD11b⁺ CD11c^- pro-inflammatory macrophages via the CCR2 receptor. This recruitment and subsequent inflammasome activation trigger the release of cytokines such as IL-1β and TNF-α, which impair the intestinal barrier and increase its permeability. This facilitates the translocation of bacterial products such as lipopolysaccharide (LPS) and other inflammatory mediators into the portal circulation, promoting adipose tissue inflammation and IR. Importantly, macrophage-specific CCR2 knockout reduces macrophage infiltration in the colon, enhances intestinal barrier integrity, and improves insulin sensitivity[105]. Another study demonstrated that a HFD expands the population of pro-inflammatory macrophages, particularly the P1 and P2 subsets, in the colon. These cells exhibit upregulated mammalian target of rapamycin (mTOR) and IFN signaling pathways, coupled with enhanced mitochondrial metabolism, which collectively contribute to β-cell dysfunction and impaired insulin secretion. Targeted ablation of colonic macrophages or inhibition of mTOR reduces the abundance and activity of these pro-inflammatory macrophages, leading to improved insulin sensitivity and restored β-cell function[106]. Moreover, HFD-fed KK-Ay mice develop pronounced dyslipidemia, marked by elevated total cholesterol and triglycerides. Concomitant increases in Staphylococcus and Proteobacteria within the gut microbiota enhance endotoxin LPS production. LPS binding to TLR4 activates NF-κB through the MyD88-dependent pathway, inducing the secretion of pro-inflammatory cytokines TNF-α and IL-6 and damaging the intestinal barrier. Systemic LPS dissemination ultimately promotes IR. Modulating gut microbiota composition and inhibiting the TLR4/MyD88 signaling pathway can effectively attenuate inflammatory cytokine release, alleviating IR and diabetic manifestations[107].

The innate intestinal immune system, particularly through macrophage activity, is essential for maintaining gut homeostasis and metabolic health. Studies demonstrate that HFD perturbs this equilibrium, mainly by activating pro-inflammatory macrophages via the CCL2-CCR2 axis and mTOR signaling. This leads to compromised intestinal barrier function and systemic inflammation, culminating in IR and β cell dysfunction. Furthermore, gut microbiota dysbiosis, such as expansion of Staphylococcus and Proteobacteria, amplifies inflammatory responses through the LPS-TLR4-MyD88-NF-κB pathway, further driving IR. These insights uncover new mechanisms in metabolic disease pathogenesis and support therapeutic approaches targeting intestinal macrophages.

B cells and T cells

Immunoglobulin A (IgA) serves as a critical mediator between gut microbiota and intestinal immunity. Produced mainly by B1 cells, IgA plays a role in modulating IR[108]. Research shows that HFD-fed mice exhibit reduced IgA⁺ plasma cells in the colon and downregulated expression of IgA-promoting factors including TGF-β1, IL-5, and the retinoic acid synthetic enzyme ALDH1A1. IgA-deficient (IgA-/-) mice developed more severe glucose intolerance and IR after HFD challenge. Adoptive transfer of intestinal B cells from IgA-/- mice into B cell-deficient recipients reproduced these metabolic defects, indicating that intestinal IgA⁺ B cells directly influence systemic glucose regulation[109].

The chemokine receptor CCR9 and its ligand CCL25 are physiologically important in immune development and maintaining intestinal immune homeostasis. They help regulate early T cell differentiation in the thymus and guide immune cell homing to the small intestinal mucosa[110]. One study indicated that HFD feeding promotes infiltration of IFN-γ-producing CD4⁺ T cells and γδ T cells in the small intestine, inciting local inflammation and barrier injury. This permits leakage of bacterial products such as LPS, which then instigate inflammation in visceral adipose tissue and the liver via the portal vein, ultimately inducing IR. Adoptive transfer studies confirmed that CCR9⁺ T cell homing to the small intestine aggravates local inflammation and systemic IR. In contrast, CCR9 deficiency impaired T cell homing to the intestine, reduced CD4⁺ T cell infiltration, and significantly improved glucose tolerance and insulin sensitivity[111]. Another study observed that HFD feeding reduces Th17 cells in the intestine, attenuating the protective effects of IL-17 and IL-22, while increasing Th1 cells and enhancing IFN-γ-driven inflammation. This imbalance disrupts intestinal immune homeostasis, weakens the epithelial barrier, and increases permeability, permitting endotoxins and bacterial antigens to enter circulation. The resulting endotoxemia initiates systemic low-grade inflammation, aggravating IR. Transfer of gut-tropic Th17 cells into obese mice markedly improved glucose tolerance and insulin sensitivity[112]. Similarly, other work has shown that HFD-induced dysbiosis particularly a reduction in segmented filamentous bacteria suppresses antigen-presenting cell activity, thereby inhibiting Th17 cell differentiation. Diminished Th17 responses impair intestinal immune defense, leading to bacterial translocation and inflammation in metabolic tissues, which promotes IR and obesity[113].

The adaptive immune network in the gut, including IgA antibodies, T cell subsets such as Th17 and Th1, and chemokine receptors like CCR9, is essential for maintaining intestinal immune equilibrium and systemic metabolic regulation. HFD disrupts this finely balanced system by reducing IgA⁺ B cells and related factors such as TGF-β1 and IL-5, weakening mucosal immunity, and intensifying intestinal inflammation and barrier dysfunction through CCR9-mediated aberrant T cell homing and Th17/Th1 imbalance. These changes promote endotoxin translocation and systemic IR. These results elucidate molecular connections between intestinal adaptive immunity and metabolic disease, and suggest the therapeutic potential of targeting IgA⁺ B cells, modulating T cell subsets, or interfering with the CCR9/CCL25 axis to alleviate metabolic disorders. Future studies should further delineate the interactions between gut immune cells and microbiota to advance immunotherapeutic strategies for metabolic diseases.

CROSSTALK BETWEEN ORGANS

An HFD induces gut microbiota dysbiosis, characterized by an expansion of Proteobacteria and a decline in segmented filamentous bacteria, which triggers a cascade of pathological events[107]. Elevated intestinal permeability facilitates the leakage of endotoxins, which travel through the portal vein to the liver and activate the TLR4/MyD88/NF-κB pathway in KCs. This leads to increased production of TNF-α and IL-1β, provoking a severe hepatic inflammatory response. Concurrently, CCL2 released by intestinal epithelial cells recruits circulating monocytes via the CCR2 axis; these differentiate into pro-inflammatory macrophages, some of which migrate to the liver and contribute to amplifying inflammatory processes. Lipid overload in the liver further remodels the local immune microenvironment: Embryonically derived KCs exhibit functional impairment due to lipid droplet accumulation, while MoMFs differentiate into TREM2⁺ LAMs that exacerbate liver damage via the MS4A7-NLRP3 pathway[61,62]. Moreover, HFD-induced intestinal immune dysregulation marked by decreased IgA⁺ B cells and Th17/Treg imbalance sustains LPS leakage. LPS activates innate immune cells, accelerates hepatic inflammation, and skews intrahepatic T cell polarization toward Th1 and Th17 phenotypes, thereby reinforcing a cycle of lipotoxicity and inflammation. The functions of protective Th22/IL-22-which suppresses PPARγ/SREBP-1c-mediated lipogenesis and Treg cells are also compromised, weakening metabolic protection[62]. Under HFD conditions, exosomes derived from intestinal epithelial cells are preferentially transported to the liver, where they suppress IRS-2/PI3K-AKT signaling in hepatocytes and activate the TLR4-NLRP3 inflammasome in KCs, stimulating TNF-α and IL-6 release and promoting IR[64]. Inflammatory mediators (including TNF-α and IL-1β) and lipotoxic agents (such as palmitic acid and oxidized lipids) from the liver can return to the intestine via circulation, inhibiting Breg cell differentiation and Th17 development, reducing IL-10 production, and further compromising intestinal immunity. The damaged intestinal barrier and ongoing dysbiosis perpetuate LPS delivery to the liver, establishing a vicious feedback loop.

In obesity, adipose tissue expansion surpasses its storage capacity, resulting in enhanced lipolysis and release of FFAs, which enter the liver directly via the portal vein. Concurrently, adipocyte-derived inflammatory factors such as MCP-1, TNF-α, IL-6 and lipotoxic molecules including SFAs and ceramides enter the liver through systemic circulation, activating hepatic immune responses. Polarized pro-inflammatory M1-type ATMs and T/B cell imbalances characterized by an increase in CD8⁺ T cells and a reduction in Treg cells within fat tissue not only intensify local inflammation but also promote infiltration of CCR2⁺ Ly6C high monocytes into the liver via secretion of chemokines such as CCL2 and CXCL10[57]. These monocytes differentiate into lipid-laden macrophages in the liver, displacing functionally impaired KCs and forming a pro-inflammatory TREM2⁺ CD9⁺ subset that aggravates liver injury through MS4A7-NLRP3 activation[62]. In turn, expansion of Th1/Th17 cells within the inflammatory hepatic milieu and their secreted cytokines such as IFN-γ, IL-17 feedback onto adipose tissue, recruiting additional immune cells and activating pro-inflammatory signaling including MAPK/NF-κB pathways in adipocytes, ultimately suppressing glucose uptake via IRS-1 phosphorylation.

FFAs and inflammatory mediators released from adipose tissue also disseminate to the pancreas and skeletal muscle via systemic circulation. In pancreatic islets, FFAs activate the TLR4 pathway in β cells, prompting chemokine release that recruits monocytes differentiating into M1 macrophages. These macrophages exacerbate β cell failure through TNF-α/IL-1β secretion and phagocytosis of insulin vesicles, resulting in insufficient insulin secretion and hyperglycemia[52]. In skeletal muscle, ectopic FFAs deposition impedes insulin signaling. Additionally, IL-6 and inflammatory EVs derived from ATMs are internalized by muscle cells, worsening lipid accumulation, IR, and impairing regenerative capacity[100,102]. IR in skeletal muscle diminishes glucose utilization, exacerbating hyperglycemia and dyslipidemia. Ultimately, hyperglycemia and lipid metabolic disorders mutually reinforce each other, contributing to the establishment of irreversible type 2 diabetes.

HFD impairs the intestinal barrier and increases permeability, permitting gut-derived endotoxins like LPS and bacterial metabolites to enter the portal circulation[105]. LPS reaches adipose tissue via the bloodstream, where it activates the TLR4/MyD88/NF-κB signaling pathway. This activation stimulates the release of inflammatory cytokines, including TNF-α and IL-6, from ATMs. Consequently, insulin signaling is suppressed, contributing to the development of IR[107]. CCR9⁺ T cells homing to the small intestine enhance infiltration of IFN-γ-producing CD4⁺ T cells, driving an inflammatory shift in the gut and worsening inflammation in both the intestine and visceral adipose tissue[111]. FFAs, inflammatory factors such as TNF-α, IL-6, and chemokines originating from adipose tissue enter the intestine, altering microbial composition, recruiting and activating intestinal immune cells, promoting local inflammation, and further disrupting barrier integrity. Through these immune-inflammatory and metabolic interactions, these processes jointly exacerbates systemic low-grade inflammation and IR (Figure 4).

Figure 4 Inter-organ crosstalk drives metabolic inflammation and insulin resistance. Intestinal dysbiosis and barrier impairment allow lipopolysaccharide and extracellular vesicles (EVs) to enter the liver via the portal vein, triggering hepatic inflammation [tumor necrosis factor-α, interleukin (IL)-1β] and synergizing with lipotoxic mediators such as palmitic acid and oxidized lipids to amplify inflammatory responses. Liver-derived inflammatory cytokines and helper T (Th) 1/Th17 skewing further exacerbate intestinal mucosal immune dysregulation. Under lipid overload, adipose tissue releases free fatty acids, ceramides, and chemokines/cytokines including monocyte chemoattractant protein-1, IL-6, CCL2, and CXCL10, promoting hepatic immune remodeling and inflammation (reduced Kupffer cells, increased triggering receptor expressed on myeloid cells 2⁺ lipid-associated macrophages, Th1/Th17 polarization, and Th22 suppression). Adipose-derived free fatty acids concurrently contribute to lipid deposition in skeletal muscle, reduced insulin sensitivity, and impaired glucose uptake, while also inducing M1 macrophage accumulation and β-cell dysfunction in the pancreas. Skeletal muscle-derived IL-6 and inflammatory EVs can further circulate to the liver, aggravating hepatic insulin resistance. These interactions form a positive feedback loop that collectively drives the progression of systemic insulin resistance and hyperglycemia. IL: Interleukin; IgA: Immunoglobulin A; Treg: Regulatory T cell; Th: Helper T; EV: Extracellular vesicle; TNF: Tumor necrosis factor; LPS: Lipopolysaccharide; IFN: Interferon; FFAs: Free fatty acids; LAM: Lipid-associated macrophage; KC: Kupffer cell; MCP-1: Monocyte chemoattractant protein-1.

FUTURE PERSPECTIVES

This review has summarized the mechanisms by which dyslipidemia activates immune cells and facilitates complex multi-organ crosstalk, thereby driving the onset and progression of T2DM. Among these interactions, the gut-liver-adipose axis warrants particular attention as a pivotal hub in this network. Although current studies have begun to reveal alterations in the immune microenvironments of adipose tissue, liver, pancreatic islets, skeletal muscle, and intestine under dyslipidemic conditions, as well as their mutual communication, the potential contribution of the central and autonomic nervous system to this immune-metabolic network has been largely overlooked. The current understanding of lipotoxicity-induced immune cell activation and polarization remains largely centered on classical pathways such as TLR4/NF-κB and CCL2/CCR2. Moreover, the precise mechanisms through which organ-specific microenvironments, including potential neural regulation, fine-tune immune responses are still unclear. The majority of existing evidence derives from animal models, and although pharmacological agents targeting key nodes such as CCR2/CCR5 and TREM2 demonstrate therapeutic efficacy in preclinical studies, their clinical translatability remains to be established. The mediators and pathways responsible for inter-organ signal transmission also require further elucidation. In Table 1, we summarize the effects of representative lipid-lowering drugs on inflammatory and immunomodulatory biomarkers. Evidence from human clinical studies partially corroborates findings from animal models. A randomized controlled trial demonstrated that a germinated brown rice diet can balance the Treg/Th17 cell ratio, reduce serum levels of inflammatory factors such as IL-6, IL-8, and LPS, and consequently improve gut mucosal permeability. This resulted in positive improvements in fasting blood glucose levels in T2DM patients, which is attributed to the restoration of intestinal immune homeostasis[114]. The randomized, double-blind study of the IL-1β-targeted drug canakinumab confirmed that inhibiting immune inflammation significantly reduces the risk of concurrent cardiovascular events. Additionally, it may exert beneficial effects on glucose metabolism, potentially through the improvement of β-cell function[115,116], this directly supports the central role of inflammation-immunity in T2DM and its complications. Furthermore, classic glucose-lowering drugs have also demonstrated potential in modulating lipid metabolism beyond their primary hypoglycemic effects. Pioglitazone, a PPAR-γ agonist, not only improves insulin sensitivity but also exerts additional beneficial effects on lipid metabolism[117]. The sodium-dependent glucose transporters 2 inhibitor canagliflozin has been shown to contribute to weight loss and modulate lipid metabolism[118]. These effects collectively contribute to the amelioration of systemic low-grade inflammation. However, the successful translation of findings from animal models into clinically targetable interventions still faces multiple challenges, with species differences being a key bottleneck. Significant distinctions exist between humans and laboratory animals in terms of immune system composition, regulation of metabolic pathways, and interactions with gut microbiota. Consequently, targets that prove effective in mouse models may fail to demonstrate expected efficacy in human trials due to the activation of compensatory mechanisms or differences in target expression. Additionally, target safety and the timing of intervention pose further difficulties for clinical translation.

Table 1 Representative lipid-lowering agents effects on inflammatory and immunomodulatory biomarkers.

Lipid-lowering ingredient	Lipid-modifying	Inflammation and immunomodulation
Curcumin-piperine[119]	TG (decrease)	Serum CRP (decrease)
Pan-PPAR agonist (lanifibranor)[120]	TG (decrease); LDL-C (decrease); apolipoprotein A1 (decrease); HDL (increase)	CRP (decrease)
Aqueous extract of Cichorium intybus seeds[121]	TG (decrease)	Glutathione catalase (decrease); superoxide dismutase (decrease); malondialdehyde (decrease); adiponectin (decrease); TNF-α (decrease); IL-1β (decrease)
Aqueous extract of Terminalia chebula[122]	TG (decrease); LDL-C (decrease); TC (decrease); VLDL-C (decrease); HDL (increase)	NO (decrease); GSH (decrease); MDA (decrease); hsCRP (decrease)
Rutin flavonoid supplement[123]	TG (decrease); LDL-C (decrease); TC (decrease); HDL (increase)	MDA (decrease); IL-6 (decrease)
L-citrulline supplementation[124]	TG (decrease); HDL (increase)	TNF-α (decrease); hs-CRP (decrease)
Nano-curcumin[125]	Lipoprotein (a) (decrease)	hs-CRP (decrease)
Ellagic acid[126]	TG (decrease); LDL-C (decrease); TC (decrease)	MDA (decrease); CRP (decrease); TNF-α (decrease); IL-6 (decrease); TAC (increase); GPx (increase); SOD (increase)
GLP1RA (exenatide)[127]	TG (decrease); HDL (increase)	CRP (decrease); IL-6 (decrease); TNF-α (decrease)
GLP1RA (orforglipron)[128]	TG (decrease); LDL-C (decrease); ApoB (decrease); ApoC3 (decrease)	hs-CRP (decrease)
Rosuvastatin/ezetimibe[129]	LDL-C (decrease)	Senescent CD8+ T cells (decrease); Treg (decrease); Naive to memory CD8+ T cell (increase)

PPAR: Peroxisome proliferators-activated receptor; GLP1RA: Glucagon-like peptide-1 receptor agonist; TG: Triglycerides; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol; HDL: High-density lipoprotein; VLDL-C: Very low density lipoprotein cholesterol; ApoB: Apolipoprotein B; ApoC3: Apolipoprotein C3; CRP: C-reactive protein; IL: Interleukin; TNF: Tumor necrosis factor; NO: Nitric oxide; GSH: Glutathione; MDA: Malondialdehyde; hsCRP: Hypersensitive C-reactive protein; TAC: Total antioxidant capacity; GPx: Glutathione peroxidase; SOD: Superoxide dismutase; CD: Cluster of differentiation; Treg: Regulatory T cell.

CONCLUSION

In summary, advancing beyond a single-organ perspective and integrating multi-dimensional immune metabolic signaling networks will be essential for deciphering the pathophysiology of T2DM and developing targeted therapeutic strategies. Future interventions for T2DM should embrace combinatory approaches that simultaneously address multiple organs. Treatments focusing on a single organ may be undermined by compensatory mechanisms arising from systemic crosstalk. Thus, future research should pursue integrated strategies aimed at restoring intestinal barrier integrity, alleviating hepatic lipotoxicity, reprogramming ATMs, and protecting pancreatic β cells, and harnessing neuro-immune interactions, ultimately shifting the therapeutic goal from symptom mitigation to the restoration of immune-metabolic homeostasis.