KEY FIGURE

Highlights

• Insulin resistance is a central, multisystem driver of type 2 diabetes.

• Type 2 diabetes evolved from organ defects to a systems-level network disease.

• Insulin resistance is dynamic, tissue-specific, and stage-dependent.

• Targeting insulin resistance enables precision, organ-protective therapy.

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disease characterized by coordinated impairments in insulin action and secretion across multiple organs, including the heart, liver, skeletal muscle, adipose tissue, pancreas, kidney, and central nervous system [1]. In 2021, an estimated 529 million people worldwide were living with diabetes, corresponding to a global age-standardized prevalence of 6.1% [2]. Importantly, the clinical burden of T2DM extends well beyond hyperglycemia to encompass cardiovascular disease (CVD), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD), conditions that share insulin resistance as a central pathophysiological driver through mechanisms involving ectopic lipid deposition, chronic low-grade inflammation, endothelial dysfunction, and maladaptive organ crosstalk. These observations have shifted the conceptual framework of diabetes from a predominantly glucocentric disorder to a system-level disease characterized by widespread insulin resistance and organ dysfunction.

Advances in the understanding of insulin signaling, mitochondrial metabolism, and interorgan communication have refined contemporary views of T2DM pathophysiology, highlighting insulin resistance, including its impact on insulin secretion, as a dynamic and heterogeneous process that varies across tissues and disease stages. In parallel, therapeutic innovations—particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors and incretin-based agents—have reinforced the importance of targeting mechanisms beyond glucose lowering.

Against this background, this review aims to synthesize current mechanistic insights into insulin resistance across key metabolic organs, emphasizing its central role in the development, progression, and clinical heterogeneity of T2DM. By integrating molecular, organ-specific, and system-level perspectives, we propose a unifying framework that positions insulin resistance as a central determinant of disease heterogeneity and a strategic therapeutic target for future research and precision-based therapy.

EVOLUTION OF PATHOPHYSIOLOGY OF TYPE 2 DIABETES MELLITUS

The conceptual framework of T2DM has evolved substantially over the past three decades, reflecting recognition of the disease as a complex, multi-organ disorder rather than a simple defect in insulin secretion or action. In 1988, DeFronzo [3] proposed the “triumvirate” model, identifying insulin resistance in skeletal muscle and liver, together with β-cell dysfunction, as the core defects driving hyperglycemia. This model established the reciprocal interaction between insulin resistance and β-cell failure as central to T2DM pathogenesis. Subsequently, the “ominous octet” expanded this framework to include adipose tissue, the gastrointestinal tract, pancreatic α-cells, the kidney, and the brain, reframing T2DM as a multi-organ disorder of dysregulated signaling pathways [4]. This shift redirected therapeutic strategies toward non–β-cell targets. More recently, the “deleterious dozen” incorporated inflammation, immune dysregulation, gut microbial dysbiosis, and islet amyloid deposition [1]. Building on this, the “Tumultuous thirteen” further integrates mitochondrial dysfunction, impaired interorgan communication, neuroendocrine dysregulation, and stress-related hormonal pathways, conceptualizing T2DM as a dynamic and progressively maladaptive network across interconnected organ systems (Fig. 1) [5]. Together, these models reflect a paradigm shift from a glucose-centric view to a systems-based understanding of T2DM, emphasizing the interconnected metabolic, inflammatory, immune, and neuroendocrine mechanisms that drive disease progression.

Within this evolving framework, insulin resistance remains a defining feature of T2DM, predominantly affecting the liver, skeletal and cardiac muscle, and adipose tissue. Once viewed solely as a defect in insulin signaling, insulin resistance is now understood as an adaptive response to nutrient excess that in part limits intracellular substrate overload through activation of stress and inflammatory pathways. With chronic metabolic stress, this adaptive response becomes maladaptive, resulting in persistent inflammation, adipokine imbalance, and ectopic lipid accumulation. These processes manifest as increased hepatic gluconeogenesis, impaired skeletal and cardiac muscle glucose uptake, and exaggerated adipose tissue lipolysis, collectively reinforcing systemic insulin resistance.

INSULIN RESISTANCE IN MAJOR ORGANS AND RELATED FACTORS

Insulin resistance in liver and metabolic dysfunction-associated steatotic liver disease

The liver represents a central metabolic hub that integrates nutrient flux, hormonal signaling, and inflammatory cues to regulate systemic glucose and lipid homeostasis. Hepatic insulin resistance—defined as the failure of insulin to suppress gluconeogenesis despite hyperinsulinemia—is a core abnormality that drives fasting and post-absorptive hyperglycemia in T2DM.

At the molecular level, disruption of insulin receptor-mediated signaling along the insulin receptor substrate (IRS)–phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt) axis underlies impaired suppression of gluconeogenesis and dysregulated lipid metabolism. Excess intrahepatic lipid accumulation, particularly diacylglycerols (DAGs) and ceramides, activates protein kinase Cɛ (PKCɛ), impairing insulin receptor kinase activity and attenuating downstream IRS-dependent signaling [6–8]. As illustrated in Fig. 2, reduced Akt activation fails to phosphorylate and inactivate forkhead box O1 (FoxO1), resulting in persistent nuclear FoxO1 activity and sustained transcription of gluconeogenic genes such as glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1), thereby maintaining inappropriate hepatic glucose production despite hyperinsulinemia [6–9]. In contrast, selective preservation of insulin signaling through lipogenic and mitogenic pathways, including sterol regulatory element binding protein 1c (SREBP1c) activation, promotes de novo lipogenesis, triglyceride synthesis, and very-low-density lipoprotein secretion [9,10]. These signaling defects are amplified by convergent cellular stress pathways. Mitochondrial redox imbalance, oxidative stress, and endoplasmic reticulum (ER) stress activate inflammatory cascades, including c-Jun N-terminal kinase (JNK), nuclear factor κB (NF-κB), and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome signaling, which reinforce hepatic insulin resistance through serine phosphorylation and degradation of IRS proteins [7,11]. Notably, lipid- and stress-induced hepatic insulin resistance can develop early in metabolic disease, preceding overt hyperglycemia and contributing to systemic metabolic dysfunction.

One influential model proposed to explain the coexistence of hyperglycemia and hepatic steatosis in T2DM is the concept of selective insulin resistance, whereby insulin-mediated suppression of gluconeogenesis is impaired while lipogenic signaling remains relatively preserved. Hepatocyte zonation studies demonstrate that this paradox reflects differential regulation of IRS isoforms across the liver lobule. Hyperinsulinemia preferentially downregulates IRS2 in periportal hepatocytes, the dominant site of gluconeogenesis, while IRS1 expression in perivenous hepatocytes—critical for SREBP1c–mediated lipogenesis—remains intact or enhanced [10,12]. Consequently, Akt–FoxO1 signaling is selectively impaired in periportal regions, whereas Akt–SREBP1c signaling in perivenous regions remains active, driving hepatic steatosis despite ongoing glucose overproduction. This zonated IRS1/IRS2 model provides one plausible mechanistic explanation for the coexistence of hyperglycemia and MASLD in T2DM. However, alternative mechanisms—including ectopic lipid accumulation and substrate-driven lipogenesis, hyperinsulinemia-mediated signaling through parallel pathways, and complex interactions among nutrient-sensing networks such as mechanistic target of rapamycin (mTOR) and adenosine monophosphate (AMP)-activated protein kinase (AMPK)—have also been proposed, and the relative contribution of these pathways remains incompletely understood [7].

Hepatic insulin resistance is further shaped by interorgan crosstalk within a broader metabolic network. Adipose tissue insulin resistance increases lipolysis and enhances delivery of free fatty acids (FFAs), glycerol, and lactate to the liver, while adipokine imbalance, including elevated tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and reduced adiponectin, further exacerbates hepatic lipid accumulation and inflammation [6,11]. Although de novo lipogenesis contributes to hepatic steatosis, increased flux of FFAs from insulin-resistant adipose tissue is considered the major source of hepatic triglyceride accumulation in many individuals with obesity and T2DM [13]. Skeletal muscle insulin resistance limits peripheral glucose disposal and increases release of gluconeogenic amino acids, thereby augmenting hepatic substrate supply for glucose production and reinforcing systemic hyperglycemia and metabolic inflexibility [6,7]. In addition, disruption of the gut–liver axis—characterized by gut microbial dysbiosis, increased intestinal permeability, and translocation of microbial products—promotes hepatic inflammation and impairs insulin signaling, further amplifying hepatic and systemic insulin resistance [7,14]. Beyond classical hormones and cytokines, extracellular vesicles have been recognized as additional mediators of metabolic interorgan communication, contributing to the propagation of insulin resistance and steatotic liver disease [15]. Together, these processes establish a self-reinforcing network linking hepatic insulin resistance to the progression of T2DM and cardiometabolic complications.

The recently adopted term MASLD replaces nonalcoholic fatty liver disease and emphasizes the presence of hepatic steatosis in conjunction with at least one cardiometabolic risk factor, including obesity, dysglycemia, hypertension, or dyslipidemia [16,17]. This revised definition reflects the central role of metabolic dysfunction in disease pathogenesis and recognizes MASLD as the hepatic manifestation of systemic cardiometabolic disease rather than an isolated liver disorder [16–20]. Its global prevalence has risen in parallel with obesity and T2DM, reaching nearly 38% by 2019 [21]. Mechanistic and epidemiological studies support a bidirectional relationship between MASLD and T2DM, whereby insulin resistance promotes hepatic steatosis, while MASLD further exacerbates systemic insulin resistance and increases the risk of incident T2DM, CVD, and mortality [19,22–27]. These associations are mediated through interconnected pathways involving chronic low-grade inflammation, atherogenic dyslipidemia, ectopic lipid deposition, and prothrombotic alterations [28–30].

Insulin resistance and decreased glucose uptake in skeletal and cardiac muscle

Skeletal and cardiac muscle insulin resistance represent a central metabolic defect that converges with adipose tissue dysfunction, hepatic insulin resistance, ectopic lipid deposition and inflammation to accelerate hyperglycemia. As the body’s largest insulin-sensitive organ, skeletal muscle accounts for the majority of postprandial glucose disposal [31,32]; thus, even modest impairments in muscle insulin responsiveness exert disproportionate effects on systemic glycemic control. High-quality muscle—characterized by preserved oxidative capacity and minimal lipid infiltration—supports whole-body insulin sensitivity and mitigates glucolipotoxic stress, whereas poor-quality muscle predisposes to insulin resistance and cardiometabolic disease [33,34].

At the molecular level, skeletal muscle insulin resistance is primarily characterized by impaired insulin-stimulated glucose transport and glycogen synthesis, reflecting defects in distal insulin signaling pathways that regulate glucose transporter 4 (GLUT4) trafficking and glucose utilization (Fig. 3) [7,35,36]. Under physiological conditions, insulin activates the IRS1–PI3K–Akt pathway, leading to phosphorylation of TBC1 domain family member 4 (TBC1D4; AS160), activation of Rab and Rac family small GTPase 1 (RAC1) GTPases, and translocation of GLUT4-containing vesicles to the plasma membrane, thereby facilitating glucose uptake [7,35]. In insulin-resistant muscle, chronic lipid oversupply and elevated circulating FFAs directly impair insulin-stimulated glucose uptake and promote accumulation of intramyocellular DAGs and ceramides, which activate PKC isoforms and stress-responsive kinases, resulting in impaired Akt signaling and defective GLUT4 translocation [36–38]. In parallel, insulin-mediated inhibition of glycogen synthase kinase 3 (GSK3) α/β is attenuated, leading to reduced activation of glycogen synthase and diminished glycogen storage despite preserved glucose availability [7,36]. Mitochondrial dysfunction and reduced oxidative capacity further exacerbate these abnormalities by promoting incomplete fatty acid oxidation, oxidative stress, and metabolic inflexibility [11,39]. Importantly, recent human studies indicate that skeletal muscle insulin resistance reflects not only reduced insulin sensitivity but also diminished maximal insulin responsiveness, such that even high insulin concentrations fail to fully restore GLUT4 translocation and glucose uptake [36,38]. Collectively, these coordinated defects establish skeletal muscle as a dominant site of impaired postprandial glucose disposal and a central driver of systemic hyperglycemia in T2DM [7,35,36,40].

Ectopic fat accumulation within skeletal and cardiac muscle (“myosteatosis”) provides a mechanistic link between lipid overflow from dysfunctional adipose tissue and impaired muscle insulin signaling. Lipid infiltration correlates with loss of muscle strength and physical performance [41] and is consistently associated with metabolic impairment, including glucose dysregulation [42], higher incidence of heart failure in older individuals [43] and increased cardiovascular events [44]. Excess triglyceride deposition in myocardium has been associated with impaired cardiac energetics, diastolic dysfunction, and lipotoxic cardiomyopathy [45,46]. Advanced imaging studies using proton magnetic resonance spectroscopy provide compelling mechanistic insight: intramyocellular lipid, particularly saturated species, disrupts insulin signaling via DAG-PKCθ activation, mitochondrial stress and impaired oxidative flux, thereby establishing a cycle of metabolic inflexibility and insulin resistance [47].

Intervention studies further reinforce the dynamic interplay between muscle lipid content and insulin action. Caloric restriction reduces intramuscular fat and improves insulin sensitivity, highlighting the reversible component of muscle lipid deposition [48]. In contrast, experimental limb disuse induces rapid accumulation of intramuscular adipose tissue and concomitant loss of strength, demonstrating how inactivity can activate the muscle-fat axis in the direction of metabolic deterioration [49]. Thus, ectopic fat deposition not only reflects systemic metabolic injury but also constrains the efficacy of lifestyle and pharmacological interventions. Collectively, skeletal muscle insulin resistance acts as both a driver and amplifier, linking adipose-driven lipid spillover, mitochondrial dysfunction, inflammatory signaling and declining physical function to progressively impaired glucose disposal.

Insulin resistance in adipose tissue and adipocyte dysfunction

Adipose tissue insulin resistance represents a core metabolic defect that both drives and is reinforced by the broader network of pathogenic processes underlying T2DM and metabolic syndrome [36,50]. Beyond passive energy storage, adipose tissue functions as an active endocrine and immunometabolic organ that regulates systemic substrate partitioning, insulin sensitivity, and inflammatory response. In the context of nutrient excess, early impairment of insulin action in adipocytes may initially function as a protective adaptation, activating inflammatory and stress-responsive pathways—including NF-κB, JNK, and ER stress signaling—to limit further substrate influx and cellular overload [50,51]. However, chronic overnutrition converts this adaptive response into a maladaptive state characterized by progressive adipocyte dysfunction, loss of insulin-mediated metabolic control, and propagation of systemic metabolic injury [36,50].

At the molecular level, adipose tissue insulin resistance arises from the convergence of ER stress, mitochondrial dysfunction, and innate immune activation (Fig. 4) [6,11,50]. Nutrient excess triggers the unfolded protein response and activates stress kinases such as JNK and inhibitor kappa-B kinase β (IKKβ), leading to serine phosphorylation and degradation of IRS proteins and attenuation of downstream IRS–PI3K–Akt signaling. These signaling defects impair insulin-stimulated glucose uptake and, critically, blunt insulin-mediated suppression of lipolysis—one of the most insulin-sensitive metabolic actions in adipocytes—resulting in excessive release of FFAs and glycerol [6,11,52]. In parallel, adipocyte hypertrophy, local hypoxia, and extracellular matrix remodeling promote recruitment and phenotypic reprogramming of adipose tissue macrophages toward a pro-inflammatory state [51,53]. While macrophages are pro-phagocytic and may initially contribute to lipid buffering and tissue homeostasis, persistent lipid spillover and cellular stress drive chronic meta-inflammation. Cytokines such as TNF-α and IL-6 not only suppress insulin signaling but also directly stimulate adipocyte lipolysis, further amplifying FFA flux and adipose dysfunction. Concurrent reductions in adiponectin and distortion of the adipokine milieu exacerbate systemic insulin resistance [51,54].

Loss of adipocyte insulin sensitivity is therefore closely coupled to impaired lipid-buffering capacity. Failure of insulin to restrain lipolysis increases FFA flux to the liver, directly stimulating hepatic gluconeogenesis, and plays a major role in promoting hepatic steatosis, while excess glycerol further fuels glucose production [6,52,55]. In parallel, altered adipokine signaling and inflammatory mediators impair skeletal and cardiac muscle glucose uptake and insulin action, while chronic low-grade inflammation contributes to β-cell stress and functional decline [6,36,54]. Through these interconnected mechanisms, adipose tissue insulin resistance interfaces directly with meta-inflammation, immune dysregulation, hepatic insulin resistance, and ectopic lipid deposition, thereby amplifying whole-body metabolic dysfunction [36,50,55].

Functionally, dysfunctional adipose tissue evolves from a passive energy reservoir into an active amplifier of metabolic disease. By linking substrate overload to inflammatory signaling, endocrine imbalance, and interorgan crosstalk—particularly along the adipose–liver–muscle axis—adipose tissue insulin resistance acts not as an isolated defect but as a powerful driver of multi-organ insulin resistance [39,56]. This process accelerates the transition from compensated insulin resistance to overt hyperglycemia and contributes to the progression of T2DM and its cardiometabolic complications [6,36,50].

Insulin resistance and pancreatic β-cell dysfunction

Pancreatic β-cell dysfunction represents the critical event that transforms compensated insulin resistance into overt T2DM. While insulin resistance may be present for many years before the onset of diabetes, hyperglycemia develops only when pancreatic β-cells can no longer secrete sufficient insulin to meet the increased metabolic demand. Thus, the natural history of T2DM is determined not only by the severity of insulin resistance but also by the capacity of β-cells to adapt and sustain compensatory insulin secretion [36,57]. In the early stages of insulin resistance, β-cells undergo a series of adaptive responses aimed at maintaining glucose homeostasis. Increased insulin demand stimulates enhanced insulin biosynthesis and secretion, β-cell hypertrophy, and, in some experimental models, expansion of β-cell mass. These compensatory mechanisms result in hyperinsulinemia, which may preserve normoglycemia despite substantial insulin resistance in peripheral tissues. However, this adaptive state imposes a considerable metabolic burden on β-cells and may ultimately become unsustainable.

Chronic exposure to nutrient excess and increased secretory demand initiates a process of β-cell decompensation characterized by progressive loss of insulin secretory capacity. Persistent hyperglycemia and elevated circulating FFAs induce glucolipotoxicity, which disrupts multiple aspects of β-cell function [58]. Excess intracellular glucose metabolism increases production of reactive oxygen species, while chronic lipid exposure promotes accumulation of toxic lipid intermediates, including ceramides and DAGs. Together, these processes impair glucose-stimulated insulin secretion, reduce insulin gene expression, and disrupt mitochondrial adenosine triphosphate (ATP) generation, a critical determinant of stimulus-secretion coupling. Because β-cells possess relatively limited antioxidant defenses, they are particularly vulnerable to oxidative stress-induced injury [59].

ER stress represents another major mechanism linking insulin resistance to β-cell failure [60]. The increased demand for insulin biosynthesis places substantial stress on the ER protein-folding machinery, leading to activation of the unfolded protein response. Although initially adaptive, prolonged ER stress promotes activation of apoptotic pathways involving CCAAT/enhancer-binding protein homologous protein (CHOP), JNK, and caspase signaling. In parallel, mitochondrial dysfunction impairs cellular energy production and further amplifies oxidative stress and inflammatory responses. These interconnected pathways contribute to progressive deterioration of β-cell function and survival. Inflammation and immune activation within pancreatic islets also play important roles in β-cell dysfunction [61]. Metabolic stress induces local production of inflammatory mediators including IL-1β, TNF-α, and IL-6, which impair insulin secretion and promote β-cell apoptosis. Activation of the NLRP3 inflammasome has emerged as a key mechanism linking nutrient excess and islet inflammation. In addition, recruitment of macrophages and other immune cells to pancreatic islets contributes to a chronic inflammatory microenvironment that further accelerates β-cell dysfunction [62]. These findings highlight the close interplay between metabolic stress, inflammation, and β-cell failure in T2DM.

Loss of functional β-cell mass is increasingly recognized as a consequence not only of apoptosis but also of β-cell dedifferentiation [63,64]. Under conditions of chronic metabolic stress, β-cells may lose their mature phenotype and revert toward a less differentiated endocrine state characterized by reduced expression of key transcription factors such as pancreatic and duodenal homeobox 1 (PDX1), musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA), and NK6 homeobox 1 (NKX6.1). This process diminishes insulin secretory capacity without necessarily causing immediate cell death and may contribute substantially to the progressive decline in β-cell function observed in T2DM. Furthermore, deposition of islet amyloid derived from islet amyloid polypeptide (IAPP) is commonly observed in T2DM and has been associated with β-cell toxicity, local inflammation, and loss of β-cell mass [65].

Collectively, β-cell dysfunction and insulin resistance are best viewed as interconnected and mutually reinforcing processes rather than independent abnormalities. Insulin resistance increases the demand for insulin secretion, whereas β-cell failure limits the ability to compensate for metabolic stress. Understanding the mechanisms linking insulin resistance and β-cell failure therefore remains central to the development of preventive and therapeutic strategies aimed at altering the natural history of T2DM.

Insulin resistance in the kidney: renal contribution to hyperglycemia

The kidney is increasingly recognized as an insulin-sensitive organ that actively regulates systemic glucose homeostasis, and renal insulin resistance represents an important mechanism contributing to hyperglycemia in T2DM and CKD [66–68]. Under physiological conditions, insulin suppresses renal gluconeogenesis, modulates tubular glucose handling, and coordinates cellular energy metabolism along the nephron. In insulin-resistant states, these regulatory actions are blunted, leading to inappropriate endogenous glucose production and enhanced renal glucose conservation [66,69].

Renal gluconeogenesis, localized predominantly to proximal tubular epithelial cells in the renal cortex, accounts for approximately 20%–25% of fasting endogenous glucose production and utilizes substrates such as lactate, glutamine, and glycerol [66,68]. Experimental and translational studies demonstrate that insulin suppresses this pathway via insulin receptor–PI3K–Akt signaling; however, in diabetes and CKD, post-receptor insulin signaling is impaired, resulting in persistent expression of key gluconeogenic enzymes, including PCK1 and G6PC, despite systemic hyperinsulinemia [66,70]. Dysregulation of nutrient- and energy-sensing pathways, including impaired Akt signaling and altered downstream metabolic control, further contributes to defective insulin-mediated regulation of renal glucose production and transport [66,71].

Beyond gluconeogenesis, insulin resistance within proximal tubular cells is accompanied by profound alterations in cellular metabolism and bioenergetics. CKD is characterized by mitochondrial dysfunction, reduced oxidative phosphorylation, and diminished fatty acid oxidation, with a compensatory shift toward glycolytic metabolism [67,68]. Human metabolomic and clamp-based studies demonstrate attenuated insulin-induced changes in amino acid handling and intermediary metabolism in CKD, consistent with impaired mitochondrial flexibility and reduced insulin responsiveness at the tissue level [67]. This maladaptive metabolic reprogramming increases tubular oxygen demand and promotes local hypoxia, oxidative stress, and inflammatory signaling, thereby accelerating tubulointerstitial injury and fibrosis [66,67].

Renal insulin resistance is further reinforced by activation of the intrarenal renin–angiotensin system, accumulation of uremic toxins, and chronic inflammation, all of which converge on post-receptor insulin signaling defects [68,72–74]. Angiotensin II and aldosterone impair IRS–PI3K–Akt signaling, while inflammatory mediators and advanced glycation end (AGE) products promote degradation of IRS proteins and blunt downstream metabolic responses [71–73]. Clinically, CKD is associated with reduced renal insulin clearance, resulting in fasting hyperinsulinemia that may obscure tissue-level insulin resistance when assessed using static indices [68].

Importantly, renal insulin resistance is detectable early in the course of kidney disease, even in the absence of overt diabetes, and is associated with albuminuria, systemic insulin resistance, and increased cardiometabolic risk [67,69]. However, in advanced CKD, progressive loss of functioning renal mass, reduced renal gluconeogenic capacity, impaired insulin clearance, reduced nutritional intake, and catabolic states may lower insulin requirements and alter glycemic patterns, creating a more complex metabolic phenotype. Collectively, impaired insulin suppression of renal gluconeogenesis, metabolic inflexibility of proximal tubular cells, and dysregulated intrarenal signaling establish the kidney as an active contributor to hyperglycemia and a key pathogenic organ in insulin-resistant diabetes.

Gut dysbiosis

The gut microbiota, a complex assembly of microorganisms residing in the gastrointestinal tract, plays an essential role in host metabolism, immune regulation, and nutrient processing [75]. Dysregulation of this microbial ecosystem, known as dysbiosis, is strongly associated with systemic insulin resistance and the development and progression of metabolic disorders, including T2DM [76,77]. Notably, dysbiosis can compromise gut barrier integrity, increase intestinal permeability, and facilitate the translocation of microbial components into the bloodstream. This cascade leads to chronic low-grade inflammation, termed metabolic endotoxemia, that contributes to insulin resistance and T2DM pathogenesis [78].

Gut microbes are key mediators of dietary fiber fermentation, producing short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate. These metabolites play pivotal roles in maintaining gut integrity, regulating energy metabolism, and modulating immune responses [79]. The microbiota also modulates bile acid (BA) metabolism, which in turn influences glucose homeostasis and insulin signaling pathways [80]. Other microbiota-derived metabolites, such as beneficial tryptophan (TRP) metabolites and succinate, as well as the toxic metabolite trimethylamine N-oxide (TMAO), derived from trimethylamine, have been associated with the pathophysiology of T2DM [81]. More recently, additional microbially influenced metabolites, including branched-chain amino acids (BCAAs) and imidazole propionate, have been implicated in insulin resistance and disrupted glucose metabolism [82,83].

Individuals with T2DM often exhibit reduced abundance of beneficial microbes such as Akkermansia muciniphila and Faecalibacterium prausnitzii, alongside enrichment of pro-inflammatory taxa [77]. Microbial metabolites including SCFAs, such as butyrate and propionate, enhance intestinal barrier integrity, stimulate glucagon-like peptide-1 (GLP-1) secretion, and improve insulin sensitivity [77]. In contrast, increased production of TMAO and BCAAs has been associated with inflammation, insulin resistance, and elevated cardiovascular risk in T2DM [84]. Gut-derived secondary BAs and TRP metabolites also modulate glucose metabolism and host immunity via activation of farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5), and aryl hydrocarbon receptor signaling [77,84]. Diet strongly influences microbial ecology, with fiber, polyphenols, and fermented foods promoting eubiosis, while high-fat, low-fiber diets exacerbate dysbiosis [77]. Through these metabolite-driven and immune-mediated pathways, gut dysbiosis integrates dietary exposures with systemic insulin resistance.

Genetic and environmental factors

Genetic susceptibility contributes substantially to interindividual variation in insulin resistance and T2DM risk, with over 600 independent loci identified through large-scale genome-wide association studies across diverse ancestries [85,86]. Although many risk variants map to regulatory elements active in pancreatic islets, genetic architecture also implicates pathways governing adiposity, lipid partitioning, hepatic metabolism, and energy balance—key determinants of systemic insulin sensitivity [87,88]. Loci such as fat mass and obesity-associated gene (FTO) and melanocortin 4 receptor (MC4R) influence central appetite regulation and adiposity, while glucokinase regulator (GCKR) and related variants modulate hepatic glucose and lipid metabolism, thereby shaping insulin resistance at the level of liver and adipose tissue [89–91].

Genetic variants associated with insulin resistance frequently cluster in pathways regulating adipocyte differentiation, mitochondrial function, lipid-storage capacity, and ectopic fat deposition [88,92]. Impaired subcutaneous adipose tissue expandability—partly genetically determined—predisposes to visceral and hepatic fat accumulation, promoting lipotoxicity and systemic insulin resistance [88]. Shared genetic architecture between T2DM, body mass index (BMI), dyslipidemia, and MASLD further highlights pleiotropic mechanisms linking energy storage, inflammation, and insulin signaling.

While common variants individually exert modest effects and collectively explain approximately 20% of estimated T2DM heritability, rare coding variants provide mechanistic insights into insulin signaling and metabolic regulation. Monogenic disorders affecting insulin receptor signaling or adipose tissue development illustrate that primary insulin resistance can independently drive hyperglycemia [93]. Thus, genetic susceptibility to T2DM reflects a spectrum in which β-cell dysfunction and insulin resistance coexist, with their relative contributions varying across individuals and populations.

Environmental exposures interact dynamically with inherited risk throughout the life course. Overnutrition, sedentary behavior, in utero growth restriction, and exposure to endocrine-disrupting chemicals alter chromatin accessibility, DNA methylation, and transcriptional responses in insulin-responsive tissues [94,95]. These epigenetic modifications may impair insulin signaling pathways, mitochondrial oxidative capacity, and inflammatory regulation in adipose tissue, liver, and skeletal muscle, thereby amplifying genetically mediated susceptibility [96]. Such gene-environment interactions contribute to substantial heterogeneity in insulin resistance severity and cardiometabolic risk across populations.

Inflammation and inflammasome activation

Chronic low-grade inflammation is a key driver of insulin resistance and hyperglycemia in T2DM. Elevated circulating levels of C-reactive protein (CRP), IL-6, and TNF-α serve as biomarkers of metabolic inflammation and predict incident T2DM and CVD [97,98]. CRP reflects systemic inflammatory tone and is associated with hepatic insulin resistance and endothelial dysfunction [99–101]. IL-6 promotes hepatic gluconeogenesis and impairs insulin signaling via signal transducer and activator of transcription 3 (STAT3)–suppressor of cytokine signaling 3 (SOCS3) activation, while TNF-α inhibits insulin receptor signaling through serine phosphorylation of IRS-1 and reduces GLUT4 translocation [97,102]. Together, these cytokines form a pro-inflammatory network that amplifies metabolic dysfunction and β-cell stress.

At the molecular level, metabolic stressors such as hyperglycemia, lipotoxicity, and mitochondrial reactive oxygen species activate the NLRP3 inflammasome, leading to caspase-1–mediated maturation of IL-1β and IL-18 [97,103]. These cytokines propagate inflammation and impair insulin signaling across metabolic tissues. Non-canonical inflammasome pathways further induce gasdermin D-dependent pyroptosis, linking metabolic endotoxemia to sterile inflammation [104]. Amplification by mitochondrial stress, ER stress, and thioredoxin-interacting protein sustains this inflammatory state. Collectively, inflammasome-driven cytokine signaling represents a central axis linking nutrient excess to persistent insulin resistance in T2DM.

Immune dysfunction

Beyond innate inflammation, T2DM is characterized by maladaptive remodeling of adaptive immunity, leading to impaired host defense, persistent meta-inflammation, and heightened cardiometabolic and neural complications. Chronic metabolic stress—driven by hyperglycemia, hyperinsulinemia, dyslipidemia, and altered adipokines—disrupts the balance between effector and regulatory immune responses [105].

T-cell dysregulation is central to this process. Individuals with T2DM show expansion of pro-inflammatory Th1 and Th17 cells with concomitant loss of regulatory T cells (Tregs) in circulation and metabolic tissues [105,106]. Aberrant basal activation of CD4⁺ T cells, characterized by constitutive STAT3 phosphorylation and excessive secretion of TNF-α, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-17, reflects a chronically inflamed immune phenotype. Hyperglycemia and dyslipidemia further reprogram T-cell metabolism toward glycolysis and oxidative stress, promoting Th17 polarization, impaired Th1 differentiation, and Treg dysfunction [107]. These adaptive immune shifts amplify macrophage activation and cytokine production within adipose tissue, liver, and vascular beds, thereby reinforcing systemic insulin resistance.

B-cell and humoral immunity are also perturbed. Exaggerated antibody class switching and expansion of autoreactive B cells increase immune complex formation and cytokine release, while reduced IL-10–producing B-regulatory cells and elevated immunoglobulin G1 (IgG1)/IgA titers reflect sustained immune activation [106]. Endocrine–immune crosstalk exacerbates this imbalance. Insulin and leptin signaling enhance interferon γ (IFN-γ), TNF-α, and IL-17 production, whereas diminished adiponectin weakens anti-inflammatory control, collectively driving macrophage activation and vascular injury [105]. Together, these abnormalities depict immune dysfunction in T2DM as a convergence of metabolic, endocrine, and neural stressors.

Hypercortisolism and adrenal dysregulation

Hypercortisolism is increasingly recognized as an underappreciated contributor to refractory hyperglycemia and systemic insulin resistance in individuals with T2DM, particularly in those requiring multiple medications. Excess endogenous cortisol disrupts glucose homeostasis by increasing hepatic glucose production, impairing β-cell function, promoting insulin resistance, and blunting the insulinotropic effects of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) [108]. In the CATALYST study, hypercortisolism was present in 23.8% of individuals with inadequately controlled T2DM, suggesting that subtle cortisol excess may be more prevalent than previously appreciated [108]. In a subsequent randomized trial, treatment with mifepristone, a glucocorticoid receptor antagonist, significantly reduced glycosylated hemoglobin (HbA1c; –1.47%), body weight, and waist circumference over 24 weeks, independent of adrenal imaging findings [109]. These findings highlight the importance of considering hypercortisolism as a modifiable pathophysiological contributor to T2DM and suggest that targeted cortisol-lowering therapy may improve glycemic outcomes in a subset of patients.

INSULIN RESISTANCE AND COMPLICATIONS OF DIABETES

In T2DM, chronic hyperglycemia is a key mediator of diabetic complications; however, insulin resistance represents an upstream driver that initiates and perpetuates metabolic and hemodynamic injury. Insulin resistance promotes glucotoxicity, lipotoxicity, oxidative stress, AGE product formation, PKC activation, and inflammatory signaling, all of which impair endothelial function and accelerate tissue fibrosis [110]. Landmark observational follow-ups of intensive glycemic control, including Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and United Kingdom Prospective Diabetes Study (UKPDS), demonstrated a sustained “legacy effect,” whereby early metabolic control confers long-term reduction in both microvascular and macrovascular complications [111]. These findings suggest that early reversal of insulin resistance and metabolic stress may have durable vascular benefits.

Microvascular complications such as retinopathy, nephropathy, and neuropathy correlate with cumulative glycemic burden and tissue-specific susceptibility to insulin resistance. In the retina, oxidative stress and basement membrane thickening drive neovascularization and vision loss [112]. In diabetic kidney disease (DKD) associated with T2DM, systemic and intrarenal insulin resistance contributes to glomerular hyperfiltration, mesangial expansion, and podocyte dysfunction. Progressive DKD is characterized by endothelial injury, tubulointerstitial inflammation, and fibrosis. Single-nucleus RNA sequencing from DKD samples has revealed upregulation of inflammatory (e.g., NF-κB, JAK-STAT) and profibrotic pathways across glomerular and tubular compartments [113–115]. Diabetic neuropathy involves metabolic, vascular, and inflammatory injury to peripheral nerves and affects both large and small fibers. Hyperglycemia-induced sorbitol accumulation via the polyol pathway promotes Schwann cell dysfunction and demyelination, while microvascular insulin resistance further compromises neural perfusion and repair capacity [116].

Macrovascular disease remains the leading cause of mortality in T2DM and is strongly linked to systemic insulin resistance. These complications are driven by accelerated atherosclerosis, initiated and propagated by a constellation of metabolic abnormalities: hyperglycemia, insulin resistance, dyslipidemia, hypertension, and pro-inflammatory cytokines [117]. Insulin resistance promotes atherogenic dyslipidemia, endothelial dysfunction, and vascular smooth muscle cell proliferation, thereby facilitating plaque development and instability. In large population studies, elevated levels of high-sensitivity C-reactive protein (hsCRP), IL-6, and TNF-α have been predictive of both cardiovascular and renal outcomes [118,119]. Endothelial dysfunction represents a pivotal early event in macrovascular disease. Impaired insulin signaling in endothelial cells reduces nitric oxide synthase activation and nitric oxide bioavailability, enhances oxidative stress, and promotes leukocyte adhesion and vascular inflammation [120]. Concurrent hyperinsulinemia may exert mitogenic effects through mitogen-activated protein kinase (MAPK) pathway activation, further contributing to vascular remodeling and plaque vulnerability [110]. Together, these mechanisms position insulin resistance not only as a metabolic abnormality but also as a direct mediator of vascular disease in T2DM.

ANTIDIABETIC AGENTS TARGETING INSULIN RESISTANCE

Metformin

Metformin remains the cornerstone of pharmacologic therapy for T2DM and the prototypical insulin-sensitizing agent. The principal action of metformin is inhibition of hepatic gluconeogenesis [121]. Metformin accumulates in hepatocyte mitochondria and partially inhibits complex I of the electron transport chain, reducing ATP production and increasing AMP/adenosine diphosphate levels. This shift activates AMPK, a central regulator of energy homeostasis [122]. AMPK activation suppresses gluconeogenic gene expression and reduces hepatic glucose output, directly targeting hepatic insulin resistance. Metformin also exerts AMPK-independent effects, including inhibition of mitochondrial glycerophosphate dehydrogenase, which alters hepatic redox balance and limits conversion of lactate and glycerol into glucose [123,124]. Together, these mechanisms position metformin as a direct modulator of hepatic metabolic flux. In skeletal muscle, metformin enhances insulin-mediated glucose uptake by improving IRS signaling and promoting GLUT4 translocation [125]. Concurrently, AMPK activation stimulates fatty acid oxidation and suppresses lipogenesis via inhibition of acetyl-coenzyme A carboxylase, reducing ectopic lipid accumulation in liver and muscle—key drivers of systemic insulin resistance [122,126]. Metformin attenuates adipose tissue inflammation by reducing macrophage infiltration and shifting immune polarization toward an anti-inflammatory phenotype [127]. Circulating pro-inflammatory mediators such as TNF-α and IL-6 are reduced, partly through inhibition of NF-κB and suppression of NLRP3 inflammasome activation [128]. A substantial component of metformin’s action appears to originate in the intestine. Metformin increases intestinal glucose utilization, enhances GLP-1 secretion, and modulates BA signaling [129–131]. It also reshapes gut microbiota composition, increasing SCFA-producing species and improving gut barrier integrity, thereby reducing endotoxemia and systemic inflammation [132,133].

Clinically, metformin lowers HbA1c by approximately 1.0%–1.5%, is weight neutral or modestly weight reducing, and improves atherogenic dyslipidemia [134]. In MASLD, it improves hepatic insulin resistance and aminotransferase levels, although histologic effects are modest. Collectively, metformin acts as a direct hepatic insulin sensitizer that integrates mitochondrial energy sensing, suppression of gluconeogenesis, attenuation of inflammation, and gut-mediated metabolic remodeling, thereby targeting multiple core mechanisms of insulin resistance.

Thiazolidinediones

Thiazolidinediones (TZDs), particularly pioglitazone, improve insulin resistance in adipose tissue, skeletal muscle, and liver through peroxisome proliferator-activated receptor γ activation [135–139]. By enhancing adipocyte differentiation and expanding subcutaneous lipid-storage capacity, TZDs reduce circulating FFAs and promote healthier lipid partitioning, leading to reductions in visceral and ectopic fat and mitigating adipose dysfunction and lipotoxicity [137–139]. TZDs also increase insulin sensitivity in liver and skeletal muscle via coordinated correction of lipid-induced defects in insulin signaling. Reduced FFA flux to liver and muscle lowers intracellular DAG and ceramide content, diminishing PKC-mediated inhibition of IRS (IRS-1/2) serine phosphorylation and restoring PI3K–Akt signaling [135,140,141]. In skeletal muscle, this promotes GLUT4 translocation and improves insulin-stimulated glucose disposal, consistent with hyperinsulinemic–euglycemic clamp studies showing substantial increases in whole-body glucose uptake with pioglitazone therapy [135,136]. In the liver, decreased DAG accumulation attenuates PKCɛ activation, thereby enhancing insulin-mediated suppression of hepatic glucose production and improving hepatic insulin sensitivity [136,140, 141]. TZDs also improve mitochondrial biogenesis and fatty acid β-oxidation, further reducing lipid intermediates that impair insulin action [140,142].

Pioglitazone confers cardiometabolic benefits beyond glycemic control. In PROactive and Insulin Resistance Intervention after Stroke (IRIS) trials, it reduced stroke and myocardial infarction risk, including insulin-resistant individuals without T2DM [143,144]. TZDs also improve MASLD and steatohepatitis via reductions in hepatic steatosis, inflammation, and adipose–liver crosstalk dysregulation [139,145].

GLP-1–based agents

GLP-1–based therapies improve glycemic control while exerting favorable effects on body weight, blood pressure, and cardiometabolic risk factors [146]. GLP-1 receptor agonists (GLP-1RAs), including liraglutide and semaglutide, enhance glucose-dependent insulin secretion, suppress glucagon, delay gastric emptying, and promote satiety. Beyond their pancreatic effects, GLP-1RAs reduce visceral adiposity and ectopic fat accumulation, thereby indirectly improving hepatic and peripheral insulin sensitivity. Their cardioprotective efficacy is well established, with reductions in major adverse cardiovascular events among individuals with established atherosclerotic CVD [146]. GLP-1RAs also favorably modulate lipid metabolism and inflammatory signaling [147]. Treatment is associated with reductions in triglycerides, modest increases in high-density lipoprotein cholesterol, attenuation of systemic inflammatory markers, and improvement in MASLD. Emerging evidence further suggests that GLP-1–based therapies may influence gut microbiota composition and BA metabolism, contributing to broader metabolic reprogramming [148].

Semaglutide

Semaglutide, a long-acting GLP-1RA with 94% homology to native GLP-1, is approved at a 2.0 mg weekly dose for the treatment of T2DM. Semaglutide 1.0 mg once weekly has demonstrated superior reductions in HbA1c levels and body weight compared to dulaglutide 1.5 mg weekly in people with T2DM [149]. The glucose-lowering efficacy of semaglutide 1.0 mg has been established for T2DM in the SUSTAIN trials. These studies consistently showed that semaglutide outperforms older GLP-1RAs and basal insulin in reducing HbA1c, with added benefits of weight loss and reduced hypoglycemia risk [150].

At higher doses, semaglutide exerts substantial weight-reducing effects. The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial program evaluated semaglutide 2.4 mg weekly in individuals with overweight or obesity. STEP 1 showed a 14.9% weight loss over 68 weeks in individuals with obesity, with 86% achieving ≥5% and 69% ≥10% weight loss [151]; STEP 2 and STEP 3 confirmed weight reductions of 6.2% and 10.3%, respectively, in people with T2DM or with behavioral therapy [152,153]. The newly reported STEP 11 trial evaluated semaglutide 2.4 mg in an Asian population (BMI ≥25 kg/m²) and showed a 16.0% weight loss over 44 weeks [154]. Across trials, adverse events were mostly gastrointestinal and mild to moderate; serious events were infrequent but slightly more common with semaglutide than placebo [155]. A recent phase 3 trial with semaglutide 2.4 mg therapy has proven its beneficial effect on MASLD [156].

Tirzepatide

Tirzepatide is a novel dual GIP and GLP-1 receptor agonist designed as a 39-amino acid peptide with a C20 fatty diacid moiety that enables weekly subcutaneous dosing by extending its half-life through albumin binding [157,158]. Although GIP was once considered obesogenic, tirzepatide’s weight-reducing effects have reinvigorated interest in its therapeutic role; it is now hypothesized to modulate appetite via central receptors, reduce GLP-1-related gastrointestinal side effects, and prevent GLP-1R desensitization [159]. Initiated at 2.5 mg weekly and titrated to a maximum of 15 mg, tirzepatide has demonstrated dose-dependent reductions in HbA1c (up to 2.5%) and body weight (up to 13%) across the SURPASS trials [160]. In the SURMOUNT-1 trial, weight loss reached –20.9% with the 15 mg dose; gastrointestinal side effects were most common but generally tolerable [161]. SURMOUNT-2 confirmed substantial weight loss (13.4%–15.7%) in people with T2DM and obesity, with accompanying HbA1c and cardiometabolic improvements [162]. In SURMOUNT-3 and SURMOUNT-4, mean weight reductions exceeded 26% over 84–88 weeks [163,164].

Beyond weight reduction, tirzepatide improves multiple components of insulin resistance–related cardiometabolic dysfunction. Across phase 3 trials, significant reductions in blood pressure, triglycerides, and atherogenic lipoproteins were observed [161]. Post hoc analyses of SURPASS-4 demonstrated reductions in hsCRP and improvement in cardiovascular risk biomarkers, supporting anti-inflammatory and vascular benefits [165]. In the SURPASS-3 magnetic resonance imaging substudy, tirzepatide reduced hepatic fat content more effectively than insulin degludec, suggesting amelioration of hepatic insulin resistance and ectopic lipid accumulation [166]. In addition, pooled analyses of SURPASS 1–5 demonstrated improvements in albuminuria and attenuation of estimated glomerular filtration rate (eGFR) decline, suggesting potential renoprotective effects [167]. Long-term data from SURMOUNT-1 showed a 94% reduction in the risk of progression to T2DM in most participants with prediabetes [168]. In SURPASS-CVOT with 13,165 adults with T2DM and atherosclerotic cardiovascular disease (ASCVD), tirzepatide therapy decreased composite cardiovascular events by 8%, but it was not significantly different with dulaglutide therapy (hazard ratio, 0.92) [169]. Collectively, tirzepatide represents a potent indirect insulin sensitizer, primarily through marked reductions in visceral and ectopic fat, improvements in hepatic and peripheral insulin resistance, and attenuation of inflammatory and cardiometabolic risk pathways.

SGLT2 inhibitors

SGLT2 inhibitors have transformed the therapeutic landscape by providing consistent cardiovascular and renal protection beyond glucose lowering [146,170]. Clinical trials have demonstrated robust reductions in heart failure hospitalization and progression of CKD in individuals with T2DM [171]. Notably, these benefits emerge within months of therapy and are also observed in individuals without diabetes, suggesting that cardiorenal protection is mediated largely through hemodynamic and metabolic mechanisms rather than glycemic control alone [172]. Modest weight loss, blood pressure reduction, and improvements in uric acid, albuminuria, MASLD and gut microbiota further support their use in patients with insulin resistance and cardiorenal comorbidities [173,174].

SGLT2 inhibitors promote glycosuria by inhibiting glucose reabsorption in the proximal renal tubules, independent of insulin secretion, leading to osmotic diuresis and plasma volume reduction [175]. This glycosuric effect results in a daily caloric loss of 240 to 320 kcal, mimicking a fasting state and alleviating hyperinsulinemia [176]. Consequently, SGLT2 inhibition activates lipolysis, ketogenesis, and nutrient-sensing pathways such as sirtuin [177], AMPK [178], and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) [179], enhancing mitochondrial function and ATP efficiency [180]. These fasting-like changes are linked to autophagy [181], mitophagy [182], and suppression of mTOR and oxidative/ER stress [183,184]. Hemodynamically, SGLT2 inhibitors induce natriuresis and reduce interstitial volume, which lowers preload and intraglomerular pressure and enhances cardiac and renal function [185]. While transient eGFR dips are common, long-term renal preservation is maintained [186,187]. Furthermore, SGLT2 inhibitors promote a metabolic shift toward ketone utilization in myocardium and kidneys [188], increasing energy efficiency under conditions of metabolic stress [176].

Beyond glycemic and hemodynamic effects, SGLT2 inhibitors reduce myocardial glucotoxicity by suppressing insulin-independent glucose uptake and uncoupled glycolysis [189]. They also modulate iron metabolism by lowering hepcidin and ferritin and boosting erythropoietin and transferrin receptor levels [190], raising hematocrit [191]. Interorgan crosstalk is influenced by reductions in microbial-derived toxins such as p-cresol [192]. SGLT2 inhibitors exert anti-inflammatory actions by decreasing TNF-α, IL-6, CRP, and NLRP3 inflammasome activity [193,194]. Additionally, they reduce sympathetic tone via renal afferent modulation and sodium-hydrogen exchanger 1 (NHE1) inhibition [195], with no reflex tachycardia despite lowered blood pressure. Collectively, SGLT2 inhibition induces coordinated metabolic reprogramming—characterized by reduced hyperinsulinemia, enhanced lipid oxidation, improved mitochondrial efficiency, and dampened inflammatory signaling—thereby alleviating systemic insulin resistance while conferring durable cardiorenal protection.

EMERGENCE OF THE CARDIOVASCULAR–KIDNEY–METABOLIC CONCEPT AND THE PILLARED APPROACH FOR INSULIN RESISTANCE

Integrated pathophysiology and clinical implications

Metabolic disturbances drive parallel injury pathways in the heart, vasculature, and kidneys, leading to a markedly elevated risk of ASCVD, heart failure, and progressive CKD [196,197]. The American Heart Association formally unified this interconnected disease spectrum under the term cardiovascular–kidney–metabolic (CKM) syndrome in 2023 [198].

CKM syndrome is characterized by tightly linked hemodynamic, metabolic, inflammatory, and fibrotic pathways that propagate multi-organ dysfunction. Excess visceral adiposity and dysfunctional adipose tissue promote insulin resistance, trigger chronic low-grade inflammation, and generate oxidative stress that accelerate atherosclerosis, glomerulosclerosis, and myocardial remodeling (Fig. 5) [198]. Hyperglycemia and renin-angiotensin-aldosterone system activation further compound endothelial injury, glomerular hyperfiltration, and interstitial fibrosis, while CKD amplifies cardiovascular risk through albuminuria, accumulation of uremic toxins, vascular calcification, and worsening neurohormonal activation [198, 199]. This convergence of risk is synergistic rather than additive, creating a powerful rationale for a systems-based therapeutic strategy rather than isolated organ-specific care.

Paradigm shift toward multi-pillar therapy in diabetes

Given the systemic nature of T2DM, modern diabetes management has shifted from a glucose-centric approach to one emphasizing organ protection and multi-morbidity reduction. Therapeutically, the CKM concept provides a mechanistic rationale for the observed benefits of insulin resistance-targeting therapies. The American Diabetes Association Standards of Care 2026 recommend a structured pillared approach, advocating early use of medications with established cardiorenal benefits regardless of baseline HbA1c [200]. Within this framework, SGLT2 inhibitors and GLP-1RAs are essential pillars because they address multiple foundational risk factors—including hyperglycemia, hypertension, albuminuria, weight excess, and lipid abnormalities—and significantly reduce major cardiovascular and kidney outcomes in T2DM [201]. Similarly, the 2025 clinical practice guidelines for diabetes management in Korea issued by the Korean Diabetes Association advocate a balanced therapeutic approach that integrates glycemic management, correction of hypercatabolic states and β-cell dysfunction, and cardiovascular-renal risk reduction [202]. The guidelines also recommend the preferential use of SGLT2 inhibitors and GLP-1RAs in individuals with established or high risk of ASCVD, heart failure, CKD, or stroke, reflecting an emphasis on comprehensive organ protection and reduction of long-term complications beyond glycemic control. Overall, these recommendations are largely aligned with contemporary international guidelines, supporting the applicability of this organ-protective and mechanism-based treatment strategies in Asian populations. This paradigm embodies the transition from “glycemic control first” to “a holistic approach,” reflecting a major evolution in contemporary diabetes therapeutics. The shift toward pillared therapy aligns with this concept by: (1) targeting shared mechanisms across heart, kidney, and metabolic systems; (2) prioritizing cardiorenal protection as a therapeutic endpoint; and (3) supporting early, combined use of agents with complementary mechanisms [203]. This integrated approach is strongly supported by real-world data demonstrating improved CKM staging and 10-year CVD risk with multifactorial treatment intensification in T2DM [204]. More broadly, recognition of insulin resistance as a common upstream driver supports a systems biology approach that combines structured lifestyle intervention with early use of complementary pharmacologic therapies targeting shared metabolic pathways. Such a strategy may help overcome therapeutic inertia, reduce cumulative organ damage, and improve long-term cardiovascular, renal, and metabolic outcomes.

CONCLUSIONS

T2DM is fundamentally a disorder of systemic insulin resistance arising from coordinated metabolic, inflammatory, neuroendocrine, and immune disturbances across multiple organs. Insulin resistance in the liver, skeletal muscle, adipose tissue, kidney, pancreas, and central nervous system disrupts glucose and lipid homeostasis, driving hyperglycemia and a broad spectrum of cardiometabolic complications. The relative contribution of these tissue-specific defects varies across individuals, underscoring that T2DM represents a heterogeneous disease spectrum rather than a single entity.

From this perspective, β-cell dysfunction, although genetically and biologically central in many individuals, is often a context-dependent consequence of chronic insulin resistance and metabolic stress rather than the primary initiating defect in most cases. This conceptual shift challenges uniform, glucose-centered treatment paradigms and supports mechanism-based strategies that directly target insulin resistance across organs.

Contemporary therapies, including SGLT2 inhibitors and incretin-based agents, reflect this evolution by modifying systemic metabolic pathways and providing organ-protective benefits beyond glycemic control. Looking ahead, defining insulin resistance phenotypes through metabolic profiling, validated tissue-specific biomarkers, and integration of genetic, epigenetic, and environmental data will be essential for advancing personalized care. Coupled with multi-omics approaches, systems biology, and mechanistic clinical trials, these efforts may enable more durable, organ-protective interventions and ultimately alter the natural history of T2DM by targeting insulin resistance as a central driver of disease.

NOTES

CONFLICTS OF INTEREST

Seung-Hwan Lee has served as an associate editor of Diabetes & Metabolism Journal since 2022 but was not involved in the review process for this manuscript. The authors declare no competing interests related to this work.

FUNDING

This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2025-02214302 to Seung-Hwan Lee).

ACKNOWLEDGMENTS

During the course of preparing this work, the author used ChatGPT (Open AI) for the purpose of English language editing. Following the use of this tool/service, the author formally reviewed the content for its accuracy and edited it as necessary. The authors take full responsibility for all the content of this publication.

Fig. 1

Evolution of the concepts for the pathogenetic factors contributing to hyperglycemia. The pathophysiology of type 2 diabetes mellitus has evolved from the “triumvirate,” centered on insulin resistance in skeletal muscle and liver and β-cell dysfunction, to the “ominous octet,” encompassing additional organ systems. The “deleterious dozen” and subsequent extensions further incorporate inflammation, immune dysregulation, gut microbial dysbiosis, and other systemic drivers, reflecting type 2 diabetes mellitus as a complex, interconnected, and progressively maladaptive metabolic network.

Fig. 2

Hepatic insulin signaling and major points in development of insulin resistance: glycogen and protein synthesis. Protein kinase B (AKT) signaling is central to hepatocellular insulin action, leading to activation of glycogen and protein synthetic machinery. Black arrows represent activating events; red arrows represent inhibitory events. PIP₂, phosphatidylinositol 4,5-bisphosphate; PDK1, phosphoinositide-dependent protein kinase 1; PI3K, phosphoinositide-3-kinase; IRS, insulin receptor substrate; mTORC1, mechanistic target of rapamycin complex 1; SREBP1c, sterol regulatory element binding protein 1c; PP1, protein phosphatase 1; GL, glycogen-binding subunit of protein phosphatase 1; PTG, protein targeting to glycogen; FOXO1, forkhead box O1; pSer, phosphorylated serine; GSK3, glycogen synthase kinase 3; TSC2, tuberous sclerosis complex 2; PRAS40, proline-rich Akt substrate of 40 kDa; GLUT2, glucose transporter type 2; G6PC, glucose-6-phosphatase; PCK1, phosphoenolpyruvate carboxykinase 1; GCK, glucokinase; GPAT, glycerol-3-phosphate acyltransferase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase.

Fig. 3

Insulin signaling pathways regulating glucose uptake and glycogen synthesis and major points in development of insulin resistance in skeletal muscle. Activation of the insulin receptor substrate 1 (IRS1)–phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT) pathway by insulin promotes glucose transporter 4 (GLUT4) translocation via phosphorylation of TBC1 domain family member 4 (TBC1D4; AS160) and activation of Rab and Rac family small GTPase 1 (RAC1) GTPases, facilitating glucose uptake. In parallel, AKT-mediated inhibition of glycogen synthase kinase 3 (GSK3) α/β enhances glycogen synthase activity and glycogen synthesis. Defects at these distal signaling nodes (star) impair both glucose transport and storage in skeletal muscle, resulting in insulin resistance. FFA, free fatty acid; IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; IKKβ, inhibitor kappa-B kinase β; NF-κB, nuclear factor κB; DAG, diacylglycerol; GTP, guanosine triphosphate; GDP, guanosine diphosphate; pSer, phosphorylated serine; PP1, protein phosphatase 1.

Fig. 4

Insulin signaling pathways regulating glucose uptake and lipolysis and major points in development of insulin resistance in adipose tissue. Insulin activates the insulin receptor substrate (IRS)–phosphatidylinositol 3-kinase (PI3K)–protein kinase B2 (Akt2) pathway to promote glucose transporter 4 (GLUT4) storage vesicle (GSV) translocation and glucose uptake through phosphorylation of TBC1 domain family member 4 (TBC1D4; AS160) and regulation of Rab GTPases. Insulin also suppresses lipolysis via coordinated control of lipid droplet-associated proteins (perilipin, comparative gene identification-58 [CGI-58], adipose triglyceride lipase [ATGL], hormone-sensitive lipase [HSL]) and activation of phosphodiesterase-3B (PDE3B) and protein phosphatases (PP1, PP2A). Disruption of these pathways under conditions of nutrient excess and inflammation results in impaired glucose uptake, increased lipolysis, and excess free fatty acid flux, contributing to systemic insulin resistance. TUG protein is cleaved upon insulin stimulation to mobilize the GSVs. TC10 is an AKT-independent mediator in adipocytes. CDP138, C2 domain-containing phosphoprotein of 138 kDa; SYNIP, syntaxin 4–interacting protein; RGC2, regulator of cell cycle 2; SREBP1c, sterol regulatory element binding protein 1c; pSer, phosphorylated serine; GTP, guanosine triphosphate; GDP, guanosine diphosphate; PIST, PDZ protein interacting specifically with TC10.

Fig. 5

Insulin resistance as the central pathophysiological driver of cardiovascular–kidney–metabolic (CKM) syndrome. Systemic insulin resistance links adipose dysfunction to parallel injury pathways in the heart, vasculature, and kidneys, driving synergistic progression of cardiovascular–kidney–metabolic syndrome. Interconnected metabolic, inflammatory, hemodynamic, and fibrotic mechanisms amplify multi-organ dysfunction and support a systems-based therapeutic strategy. HF, heart failure; CKD, chronic kidney disease.

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Lim S, Lee SH, Eckel RH. Revisiting Insulin Resistance in the Pathophysiology of Type 2 Diabetes Mellitus: A Multi-Organ Perspective. Diabetes Metab J. 2026;50(4):641-665.

Received: May 04, 2026; Accepted: Jun 18, 2026

DOI: https://doi.org/10.4093/dmj.2026.0492.

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