Pathophysiological mechanisms and risk factors linking type 2 diabetes mellitus and sarcopenia: A narrative review

Abstract

Type 2 diabetes mellitus (T2DM) and sarcopenia often coexist in the elderly. This is a growing clinical challenge. T2DM accelerates the decline of skeletal muscle through metabolic disorders, and sarcopenia further aggravates insulin resistance and functional impairment. Yet the underlying mechanisms and optimal management strategies of T2DM-related sarcopenia are still not fully understood. This narrative review aims to systematically summarize the epidemiological characteristics, pathogenic mechanisms, risk factors, and current treatment strategies related to T2DM and sarcopenia. The words “T2DM“, “sarcopenia“, “skeletal muscle loss“, “insulin resistance“, “inflammatory“, “oxidative stress“ and “mitochondrial dysfunction“ and “therapeutic interventions“ were used as keywords to search the PubMed/MEDLINE and Web of Science databases for articles published from January 2000 to May 2026. Relevant clinical, experimental and review studies were screened and synthesized. The prevalence of sarcopenia varies according to diagnostic criteria and population characteristics. The prevalence in the elderly is about 10%-29%. In contrast, patients with T2DM are at significantly increased risk, and their prevalence is estimated to be about two to three times as high as those without diabetes. The prevalence of sarcopenia in Asian patients with T2DM is estimated to be 20%-37%. T2DM leads to muscle degeneration through impaired insulin signaling, chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, accumulation of advanced glycation end products, fatty infiltration, alteration of gut microbiota, and genetic regulation at the mechanism level. The advanced age, poor glycemic control (especially glycosylated hemoglobin ≥ 8.0%), malnutrition, physical inactivity, diabetic peripheral neuropathy, chronic kidney disease, and drug-related changes in body composition are the main risk factors. Comprehensive management requires early screening, individualized glycemic control goals, adequate protein intake, and resistance exercise. The hypoglycemic drugs should be selected reasonably according to the effect of hypoglycemic drugs on muscle health. T2DM related sarcopenia is a complex metabolic-musculoskeletal disorder that requires comprehensive management beyond conventional glycemic control. Early identification of high-risk individuals and implementation of multidisciplinary interventions targeting glucose metabolism, nutrition, physical activity, and optimal medication may improve muscle function and clinical outcomes. Further longitudinal studies and clinical trials are needed to elucidate the long-term effects of glucose lowering therapy on skeletal muscle protection.

Key Words: Type 2 diabetes mellitus; Muscle loss; Sarcopenia; Risk factors; Resistance training

Core Tip: Type 2 diabetes mellitus significantly accelerates skeletal muscle decline and is an independent risk factor for sarcopenia, particularly in older adults. This review highlights key interconnected mechanisms – including insulin resistance, chronic inflammation, mitochondrial dysfunction, and altered protein metabolism – that drive muscle loss in type 2 diabetes mellitus. Given the high and often underrecognized prevalence of sarcopenia in diabetic populations, early screening and integrated management are essential. Multimodal strategies combining glycaemic control, resistance exercise, adequate nutrition, and muscle-protective pharmacotherapy may effectively mitigate functional decline and improve patient outcomes.

INTRODUCTION

Diabetes represents a burgeoning global public health concern that affects more than 500 million people worldwide. The financial strain linked to this condition is substantial[1]. Diabetes comprises a group of metabolic disorders characterised by abnormalities in carbohydrate metabolism. Key pathophysiological changes include impaired glucose utilization, increased glycogenolysis and excessive glucose production[2]. It is also a chronic and progressive disease whose prevalence increases with age and frequently presents with a range of complications. These complications include neuropathy, microangiopathy and macroangiopathy[3].

Type 2 diabetes mellitus (T2DM) is the predominant form of diabetes and accounts for more than 90% of all cases. It is characterized by chronic hyperglycaemia which results from defects in insulin secretion and insulin resistance (IR)[4]. T2DM not only accelerates the age-related decline in muscle mass and strength but is also increasingly recognised as a major risk factor for sarcopenia which is a significant complication in older patients with T2DM[5].

Sarcopenia is an age-related skeletal muscle disorder characterized by the gradual loss of muscle mass and declines in muscle strength and physical function[6]. Several consensus groups have established diagnostic criteria for sarcopenia as shown in Table 1[7-11] while the reported prevalence rates vary significantly. Different definitions focus on different aspects of muscle dysfunction. The EWGSOP2 standard considers muscle strength as the primary indicator. Yet the AWGS2019 incorporates cutoff values for different populations and emphasizes the physical performance of Asian individuals. The FNIH standard mainly focuses on low muscle strength and limb lean mass related to functional decline[12]. The differences in prevalence estimates reflect the variations in diagnostic elements, assessment methods, and clinical perspectives rather than inconsistencies among studies. Standards based on muscle mass may identify individuals with reduced muscle mass but preserved function. Methods based on muscle strength are more capable of accurately capturing clinically significant functional impairments. A comprehensive assessment of muscle strength, muscle mass, and movement performance may be more clinically meaningful for T2DM patients who often have metabolic abnormalities and sarcopenic obesity.

Table 1 Methods for diagnostic criteria by different working groups.

Ref.	Muscle mass	Muscle strength	Physical performance
Cruz-Jentoft et al[7], EWGSOP2	DXA (ALM/height2): Male < 7.00 kg/m2, female < 6.00 kg/m2 or CT or BIA or MRI	Grip strength: Male < 27 kg, female < 16 kg	Gait speed: < 0.8 m/second or SPPB: ≤ 8 or TUG: ≥ 20 seconds
Bhasin et al[8], SDOC	Not specified	Grip strength: Male < 35.5 kg, female < 20 kg	Gait speed: < 0.8 m/second
Chen et al[9], AWGS	DXA (ASM): Male < 7.0 kg/m2, female < 5.4 kg/m2 or BIA (ASM): Male ≤ 7.0 kg/m2, female < 5.7 kg/m2	Grip strength: Male < 28 kg, female < 18 kg	Gait speed (6 m): < 1.0 m/second or 5 times stand-to-sit test: > 12 seconds or SPPB: ≤ 9
Fielding et al[10], IWGS	DXA (ALM/height2): Male < 7.23 kg/m2, female < 5.67 kg/m2	Not specified	Gait speed (4 m): < 1.0 m/second or standing up from a chair
Studenski et al[11], FNIH	DXA (ALM/BMI): Male < 0.789 kg/BMI, female < 0.512 kg/BMI	Grip strength: Male < 26 kg, female < 16 kg	Gait speed (4 m), gait speed (6 m): < 0.8 m/second

SDOC: Sarcopenia Definition and Outcomes Consortium; ALM: Appendicular lean mass; CT: Computed tomography; MRI: Magnetic resonance imaging; BMI: Body mass index; ASM: Appendicular skeletal mass; SPPB: Short physical performance battery; DXA: Dual-energy X-ray absorptiometry; BIA: Bioelectrical impedance.

Given the variable prevalence of sarcopenia in the general population, identifying populations at heightened risk is critical. T2DM is a well-established independent risk factor for sarcopenia and can significantly increase its incidence[13]. Meta-analyses have revealed that the prevalence of diabetes is estimated to be two to three times greater[14,15]. Systematic reviews indicate that the overall prevalence of sarcopenia among Asian patients with T2DM is approximately 23%. Its prevalence in Southeast Asia is 37.46%, whereas it is 21.95% in the Western Pacific region[16]. Sarcopenia affects an estimated 10%-16% of older adults on a global scale[17]. The incidence of sarcopenia is notably higher, reaching 18% in populations with diabetes[18].

The effective management of diabetes necessitates the normalization of blood glucose levels and the maintenance of metabolic homeostasis. These factors enable patients to achieve life expectancies and quality of life comparable to those of nondiabetic individuals. The elevated prevalence of sarcopenia among patients with T2DM underscores the importance of prompt identification and diagnosis. Previous reviews mainly focused on the epidemiological association or specific mechanisms between T2DM and sarcopenia. Yet no comprehensive framework integrating pathological mechanisms, risk stratification, diagnosis, and individualized management has been established yet. This review summarizes the research evidence published from January 2000 to May 2026. We mainly discuss the pathogenesis, risk factors, diagnostic methods, and treatment strategies of T2DM-related sarcopenia. Different from previous reviews, this study emphasizes clinical translation. We combine mechanistic understanding with practical management via integrating screening strategies, risk-based drug selection, and multidisciplinary intervention measures.

METHODOLOGY

A literature search was conducted for this narrative review using PubMed/MEDLINE and Web of Science databases. The search strategy included combinations of keywords related to T2DM mellitus and sarcopenia, including “T2DM mellitus“, “T2DM”, “diabetes mellitus”, “sarcopenia”, “skeletal muscle loss”, “muscle wasting”, “insulin resistance”, “inflammation”, “oxidative stress”, “mitochondrial dysfunction”, “advanced glycation end products”, “risk factors”, and “exercise”. The literature search included studies published from January 2000 to May 2026, with eligible articles limited to English-language publications. Retrieved articles were screened based on titles, abstracts, and full texts. Studies focusing on the mechanisms, risk factors, and therapeutic strategies linking T2DM and sarcopenia were included, whereas irrelevant studies, duplicate publications, and articles without sufficient information were excluded.

PATHOGENIC MECHANISMS OF T2DM-RELATED SARCOPENIA

IR

Muscle protein catabolism: IR is the core metabolic abnormality linking T2DM with skeletal muscle dysfunction (Figure 1A)[19]. Insulin promotes glucose uptake and maintains muscle protein homeostasis by activating the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway under physiological conditions. Yet the impaired insulin signaling leads to reduced AKT activity. It triggers downstream catabolic reactions by promoting the translocation of forkhead box O transcription factors (FOXO) 1/FOXO3 to the nucleus. Skeletal muscle serves as the principal site for insulin-mediated glucose uptake and plays a vital role in maintaining systemic glucose homeostasis. Insulin promotes glucose uptake and enhances protein synthesis which can support the preservation of muscle mass and overall metabolic health under normal physiological conditions. Impaired insulin signaling results in metabolic dysfunctions that compromise protein synthesis and increase protein degradation in the context of IR[20]. This mechanism promotes sarcopenia and creates a harmful feedback loop that accelerates disease progression.

Figure 1 Mechanisms of insulin resistance-induced skeletal muscle atrophy. A: Insulin resistance impairs insulin receptor-mediated phosphoinositide 3-kinase-protein kinase B (AKT) signaling, resulting in reduced AKT activity and subsequent nuclear translocation of forkhead box O transcription factors (FOXO) 1 and FOXO3; B: Activated FOXO1/FOXO3 promote the transcription of muscle-specific ubiquitin ligases, including Atrogin-1 and MuRF1, which induce ubiquitination and proteasomal degradation of myogenic regulatory proteins (MyoD, myogenin, and eIF3f) and contractile proteins (α-actin), thereby accelerating muscle protein degradation; C: FOXO3 activates autophagy-related genes, including Atg5 and Atg7, promoting autophagosome formation and autolysosomal degradation, which further contributes to skeletal muscle wasting; D: FOXO1 inhibits mechanistic target of rapamycin complex 1-mediated protein synthesis through both tuberous sclerosis complex 2 (TSC2)-dependent and TSC2-independent pathways. The Sestrin3-AMP-activated protein kinase-TSC2 pathway and rapamycin-insensitive companion of mechanistic target of rapamycin-mechanistic target of rapamycin complex 2-AKT pathway suppress mechanistic target of rapamycin complex 1 activity, leading to impaired muscle protein synthesis. AKT: Protein kinase B; FOXO: Forkhead box O transcription factors; mTORC1: Mechanistic target of rapamycin complex 1; mTORC2: Mechanistic target of rapamycin complex 2; TSC2: Tuberous sclerosis complex 2; Rictor: Rapamycin-insensitive companion of mechanistic target of rapamycin; AMPK: AMP-activated protein kinase.

Under normal conditions, insulin binding to its receptor initiates signalling through the activation of IRS-1. This activation subsequently stimulates PI3K, resulting in the production of PIP3 and AKT phosphorylation. Activated AKT then phosphorylates transcription factors, including FOXO1 and FOXO3, facilitating their movement from the nucleus to the cytoplasm and subsequently suppressing their transcriptional activity[21]. IR disrupts insulin signaling pathway by decreasing the activity of the PI3K-AKT pathway and inhibiting the phosphorylation of the transcription factors FOXO1 and FOXO3, thereby facilitating their translocation back into the nucleus. The activated FOXO1 and FOXO3 can directly regulate the muscle cell-specific ubiquitin ligases such as Atrogin-1 and MuRF1. These enzymes promote the ubiquitination and proteasomal degradation of myogenic regulatory proteins and contractile proteins (Figure 1B). This imbalance between protein synthesis and degradation leads to progressive muscle loss in patients with T2DM[22]. Target proteins are ubiquitinated and subsequently degraded via the UPS pathway. The proteasome facilitates the degradation of these ubiquitinated proteins following this activation. Furthermore, the upregulation of FOXO3 expression induces the gene expression events involving Atg5 and Atg7 in the autophagy pathway, thereby promoting the formation and maturation of autophagosomes (Figure 1C)[23,24].

Muscle protein synthesis: IR leads to the upregulation of FOXO expression, which subsequently suppresses mechanistic target of rapamycin complex 1 (mTORC1) activity via both tuberous sclerosis complex 2 (TSC2)-dependent and TSC2-independent mechanisms. In the TSC2-dependent pathway, FOXO1 interacts with the regulatory sequence of the Sestrin3 gene, enhancing its transcription. This upregulation of Sestrin3 activates AMP-activated protein kinase (AMPK) and subsequently results in the negative regulation of mTORC1[25]. FOXO1 enhances the expression of rapamycin-insensitive companion of mechanistic target of rapamycin (mTOR) and leads to increased mechanistic target of rapamycin complex 2 activity through a TSC2-independent pathway (Figure 1D). This activation subsequently stimulates AKT, which in turn suppresses mTORC1 activity. mTORC1 facilitates translation initiation and elongation primarily by phosphorylating 4E-BP1 and S6K1. IR contributes to skeletal muscle atrophy by simultaneously promoting FOXO-mediated protein degradation and impairing mTORC1-dependent protein synthesis[26]. Therefore, IR promotes skeletal muscle atrophy by simultaneously enhancing FOXO-dependent protein degradation and inhibiting mTORC1-mediated protein synthesis.

Impaired insulin signaling represents the core molecular bridge connecting T2DM and sarcopenia. Disruption of IRS-1/PI3K/AKT signaling reduces glucose uptake through defective GLUT4 trafficking. It also altered muscle protein turnover through FOXO activation and mTORC1 inhibition. This major signaling defect is mainly amplified by subsequent pathological stimuli, including inflammation, oxidative stress (OS), and lipid accumulation. They are not independently initiated IR pathways.

Chronic inflammation and OS

Chronic inflammation: In individuals with T2DM, sustained hyperglycaemia and increased circulating free fatty acid (FFA) concentrations create a proinflammatory microenvironment that markedly exacerbates chronic low-grade inflammation within skeletal muscle tissue (Figure 2). This pathological condition features the combined effects of elevated glucose and FFA levels on skeletal muscle fibres and resident immune cells, leading to increased secretion of chemokines, notably monocyte chemoattractant protein-1. This process can recruit Ly6Chi inflammatory monocytes from the peripheral bloodstream into the skeletal muscle interstitium[27]. These monocytes rapidly differentiate into classically activated M1 macrophages. Upon infiltrating muscle tissue, these macrophages increase the expression of proinflammatory cytokines. Notably, tumor necrosis factor-alpha (TNF-α) interacts with its receptor TNFR1, triggering the activation of the downstream kinase IKKβ. This kinase phosphorylates IκBα, resulting in its ubiquitiny and subsequent proteolysis, which facilitates the release of nuclear factor kappa-B (NF-κB) and its translocation into the nucleus. Following nuclear translocation, NF-κB substantially upregulates the transcription of suppressor of cytokine signaling 3 (SOCS3)[28]. Interleukin-6 (IL-6) initiates the JAK1-STAT3 signaling cascade through the formation of a complex with membrane-bound IL-6R and its coreceptor gp130. Upon phosphorylation, STAT3 forms dimers and enters the nucleus, where it interacts with NF-κB at the SOCS3 gene promoter, enhancing its transcription[29].

Figure 2 Inflammation induces insulin resistance in skeletal muscle. Elevated levels of glucose and free fatty acid stimulate the secretion of monocyte chemoattractant protein-1 from both muscle fibers and resident macrophages. This chemokine facilitates the recruitment of Ly6C^hi monocytes, which subsequently differentiate into pro-inflammatory M1 macrophages. These macrophages secrete pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1β. tumor necrosis factor-alpha activates the IKKβ-IκBα-nuclear factor kappa-B signaling cascade, whereas IL-6 induces phosphorylation of the JAK1-STAT3 pathway. The convergence of these signaling pathways leads to the upregulation of suppressor of cytokine signaling 3, which impairs insulin signaling by inhibiting insulin receptor autophosphorylation and promoting the ubiquitination and subsequent degradation of insulin receptor substrate-1. Collectively, these molecular events culminate in the development of insulin resistance within skeletal muscle tissue. MCP-1: Monocyte chemoattractant protein-1; TNF-α: Tumor necrosis factor-alpha; IL-6: Interleukin-6; SOCS3: Suppressor of cytokine signaling 3; FFA: Free fatty acid; IRS-1: Insulin receptor substrate-1.

The emerging biomarkers involved in inflammation remodeling may provide new insights into diabetic muscle atrophy. Chitinase-3-like protein 1 (CHI3 L1) is a multifunctional inflammatory mediator. It is associated with macrophage activation, fibrosis, and extracellular matrix remodeling. Recent studies have shown that elevated levels of CHI3 L1 are closely related to metabolic inflammation and IR[30]. CHI3 L1 may cause damage to tissue regeneration by promoting extracellular matrix remodeling and fibrotic changes in skeletal muscle. The direct role of CHI3 L1 in T2DM-related sarcopenia is currently unclear. Yet its involvement in chronic inflammation and tissue remodeling indicates that CHI3 L1 may become a potential biomarker for the relationship between metabolic inflammation and muscle degeneration.

Increased levels of the SOCS3 protein disrupt insulin signaling via two distinct mechanisms. Firstly, SOCS3 directly associates with the TK domain of the insulin receptor, inhibiting its autophosphorylation[31]. Conversely, it operates as an adapter that links targets to the E3 Ligase holoenzyme, which enables ubiquitin-dependent degradation through the 26S proteasome of IRS-1[32]. Chronic inflammation exacerbates IR primarily by reinforcing the previously described defects in insulin signaling. TNF-α and IL-6 activate IKKβ/JNK and JAK1/STAT3 pathways, respectively. This promotes SOCS3 induction and an inflammatory feedback loop. It further decreases insulin responsiveness. Inflammation is not an independent mechanism. It is an amplifying factor for IRS-1 dysfunction and metabolic deterioration in skeletal muscle[33,34]. Chronic inflammation downregulates GLUT4 expression through epigenetic and transcriptional mechanisms. The combined action of NF-κB and STAT3 suppresses the transcriptional activity of MEF2 and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), which are associated with PPARs. This suppression leads to chromatin condensation at the regulatory sequence of the GLUT4 gene. This repression persists and results in ineffective upregulation of GLUT4 expression even with transient restoration of insulin signaling[35].

OS: OS is not merely a concurrent manifestation of metabolic disturbances but constitutes a critical pathological mechanism that actively contributes to the progression towards insulin insensitivity and impairments in glucose metabolism within muscle biopsies obtained from individuals with T2DM (Figure 3). In combination with elevated circulating FFAs, hyperglycaemia stimulates two principal reactive oxygen species (ROS) production pathways, leakage from the mitochondrial respiratory chain and stimulation of the membrane-bound NADPH oxidase isoforms (NOX2 and NOX4). This leads to increased intracellular superoxide anion and hydrogen peroxide levels[36].

Figure 3 Reactive oxygen species contribute to insulin resistance and muscle atrophy in skeletal muscle through several molecular mechanisms. Specifically, hydrogen peroxide (H₂O₂) directly oxidizes cysteine residue 296 on insulin receptor substrate-1, thereby inhibiting the recruitment of phosphoinositide 3-kinase. Reactive oxygen species (ROS)-mediated activation of JNK and p38 MAPK leads to the inhibitory phosphorylation of insulin receptor substrate-1 at serine residues 307 and 636, which facilitates its ubiquitination and subsequent proteasomal degradation. Peroxynitrite (ONOO^-) nitrates cysteine 296 on protein kinase B, resulting in diminished kinase activity and impaired translocation of GLUT4. Furthermore, ROS induces oxidation of the transcriptional coactivators CBP/p300, causing epigenetic repression of GLUT4 gene expression. Concurrently, ROS activates the p38 MAPK- forkhead box O transcription factors signaling axis, which upregulates the expression of muscle-specific E3 ubiquitin ligases MAFbx and MuRF1, thereby promoting proteasomal protein degradation. Moreover, ROS triggers calcium release through oxidation of IP3R, which activates the Ca²⁺/CaMKKβ/AMP-AMP-activated protein kinase pathway. This activation inhibits mechanistic target of rapamycin complex 1 and stimulates ULK1-mediated autophagy, collectively contributing to a reduction in muscle fiber cross-sectional area. ROS: Reactive oxygen species; IRS-1: Insulin receptor substrate-1; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; FOXO: Forkhead box O transcription factors; mTORC1: Mechanistic target of rapamycin complex 1.

When the intrinsic antioxidant capacity is exceeded through the accumulation of excessive amounts of ROS, including those in the superoxide dismutase (SOD), catalase and glutathione systems, a cascade of events is triggered. These events involve various cellular processes, ranging from signal transduction to mitochondrial integrity and broadly disrupt glucose metabolic pathways[37,38]. Hyperglycaemia induces excess of NADH and FADH₂, causing electron leakage at mitochondrial complexes I and III, leading to increased mtROS production. The incomplete β-oxidation of FFAs further exacerbates this process. Hyperglycaemia, Ang II, or inflammatory mediators also activate NADPH oxidase by assembling p47phox and gp91phox, generating superoxide anions[39]. Studies using animal models have shown that inhibiting NOX2 expression significantly decreases ROS levels in skeletal muscle. Hyperglycaemia activates the polyol pathway, depleting NADPH activity and reducing γ-GCS activity. ROS can directly oxidize and impair key antioxidant enzymes, forming a harmful feedback loop[40].

In this context, ROS can affect insulin signaling through multiple mechanisms. The direct oxidation of Cys296 on IRS-1 by H₂O₂ prevents its tyrosine phosphorylation site from being recognized by PI3K p85. OS contributes to IR by modifying key signaling proteins and activating stress response kinases. Ros-mediated activation of JNK and p38 MAPK further enhances inflammatory signaling. It can promote muscle protein degradation through FOXO-dependent pathway. We considered OS as an upstream metabolic stressor. It converges with inflammatory pathways to accelerate impaired insulin signaling[41,42]. ROS have been shown to suppress GLUT4 gene expression over an extended period via epigenetic mechanisms and oxidative modification of the histone acetyltransferase CBP/p300. Additionally, ROS upregulate the E3 Ligase family members Atrogin-1 and MuRF1 through the p38 MAPK-FOXO signaling axis, thereby mediating ubiquitin conjugation and the subsequent proteolysis of sarcomeric proteins[43]. The oxidative modification of the endoplasmic reticulum IP3 receptor facilitates calcium release and activates the CaMKKβ/AMPK signaling pathway. This activation results in the inhibition of mTORC1 and the stimulation of ULK1, thereby promoting excessive autophagy and contributing to regression in the transverse sectional size of muscle fibres.

A robust positive feedback mechanism exists between ROS and inflammation. Mitochondrial ROS stimulate the priming of the NLRP3-containing inflammasome apparatus and then facilitate caspase-1-dependent maturation and the secretion of IL-1β[44].

Mitochondrial dysfunction

Muscle atrophy: Increased concentrations of glucose and FFAs impair electron transport chain function (Figure 4). The excessive reduction of complexes I and III results in substantial electron leakage which subsequently diminishes the efficiency of ATP synthesis and leads to an elevated AMP to ADP ratio. Consequently, conformational alterations in the AMPKγ subunit occur, promoting the activation of AMPK[45]. In the context of the persistent lipotoxic conditions characteristic of T2DM, the buildup of DAG triggers the stimulation of PKCθ. Such enzymatic activation subsequently induces the phosphorylation of AMPKα1 at serine residues 485 and 491, thereby impairing its ability to regulate the PGC-1α. Consequently, the initiation of mitochondrial biogenesis mediated by the PGC-1α-nuclear respiratory factors 1/2-mitochondrial mitochondrial transcription factor A pathway is inhibited[46].

Figure 4 Mechanisms underlying ceramide-induced and reactive oxygen species-induced insulin resistance in skeletal muscle involve multiple interconnected pathways. Ceramide impairs protein kinase B activity through inhibitory phosphorylation mediated by PKCζ and dephosphorylation facilitated by PP2A, thereby disrupting GLUT4 translocation. Concurrently, mitochondrial hydrogen peroxide (H₂O₂) activates IKKβ and JNK1, which promote inhibitory phosphorylation and subsequent degradation of insulin receptor substrate-1 (IRS-1). nuclear factor kappa-B suppresses IRS-1 gene transcription. Reactive oxygen species further stimulate the NLRP3 inflammasome, leading to interleukin-1β production that perpetuates inflammatory signaling. Nutrient excess activates the mechanistic target of rapamycin complex 1. PKCζ-mediated activation of p70S6K induces feedback phosphorylation of IRS-1. These coordinated molecular events convert skeletal muscle from an efficient glucose-utilizing tissue into one characterized by chronic insulin resistance and metabolic dysfunction. TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; AKT: Protein kinase B; FOXO: Forkhead box O transcription factors; SOD: Superoxide dismutase; IRS-1: Insulin receptor substrate-1; TSC: Tuberous sclerosis complex; mTORC1: Mechanistic target of rapamycin complex 1.

AMPK phosphorylates FOXO1 at serine 256 and FOXO3 at serines 253 and 315, leading to the dissociation of 14-3-3 proteins and facilitating their rapid translocation into the nucleus. This process positions FOXO proteins as key regulators of the protein degradation system. In the ubiquitin-proteasome pathway, FOXO transcription factors bind to the IRS of the MAF box/Atrogin-1 promoter and the GRE of the MuRF1 promoter, thereby increasing the transcriptional activity of both genes. MuRF1 subsequently recognizes lysine 48 on MYYHC via its RING domain and catalyzes the formation of K48-linked polyubiquitin chains in cooperation with the E2 ubiquitin-conjugating enzymes UbcH5 and UbcH13, targeting MYHC for proteasomal degradation[47]. The MAF box mediates the degradation of troponin I, the transcription factor MYOD, and the translation initiation factor eIF3-f, resulting in a triple disruption of structure, transcriptional regulation, and protein synthesis.

In addition, the direct oxidative activation of p38α MAPK (Thr180/Tyr182) by mtROS results in a 2-fold increase in DNA-binding activity by deblocking the FOXO NLS via MK2 phosphorylation, and increasing distal enhancer activity at the MAF box promoter, which increased transcription by an additional 40%[48]. Moreover, ROS oxidized AKT2-Cys296 and mTORC1-Cys1483, resulting in decreased kinase activity and the dephosphorylation of p70S6K and 4E-BP1. The global protein synthesis rate decreased by 40%, and the muscle fibres enter a severe state of degradation[49].

Glucose uptake dysfunction: Mitochondrial β-oxidation impairment initiates IR pathogenesis. Elevated NADH/NAD⁺ ratios and malonyl-CoA suppress CPT-1 activity, causing cytoplasmic accumulation of long-chain acyl-CoAs that undergo re-esterification into DAG and ceramides. Mitochondrial dysfunction leads to IR primarily through lipid overload and impaired metabolic flexibility. Excessive accumulation of DAG and ceramide is capable of activating PKC isoforms. It enhances skeletal muscle metabolic dysfunction by promoting the inhibitory regulation of insulin signaling components. Mitochondrial ROS further interacts with inflammatory pathways. Each other establishes a vicious cycle of impaired energy metabolism and muscle wasting[50,51].

Ceramide inactivates AKT through a bilayer mechanism. It interacts with the C1 domain of PKCζ, facilitating the phosphorylation of the inhibitory site AKT Thr34. Secondly, it recruits the PP2A-B56α holoenzyme, which specifically dephosphorylates the activating residue AKT Thr308. These combined actions lead to a reduction in AKT kinase activity[52]. The inactivation of AKT fails to phosphorylate AS160 (TBC1D4) Thr642, and GLUT4 vesicles were retained in the tubulo-vesicular domain. Moreover, FOXO1 is dephosphorylated into the nucleus and upregulates the expression of gluconeogenic genes such as PEPCK and G6Pase[53]. Although skeletal muscle is not the major gluconeogenic organ, this reaction may slightly increase glucose output and indirectly aggravate hyperglycaemia, resulting in the formation of a metabolic closed loop.

The O₂•^- generated by complex III is enzymatically converted into H₂O₂ by SOD2. H₂O₂ is subsequently translocated to the cytoplasm via VDAC, where it facilitates the activation of IKKβ through phosphorylation at serine residues 177 and 181, as well as JNK1 via phosphorylation at threonine 183 and tyrosine 185. Activated IKKβ phosphorylates IRS-1 at serine 307, whereas JNK1 concurrently targets IRS-1 at serine residues 307 and 636. The simultaneous inhibition of these phosphorylation events results in a dual blockade of their functional activity[54]. Mitochondrial H₂O₂ which is derived from SOD2-mediated dismutation of complex III-derived O₂•^- and exported via VDAC channels activates IKKβ and JNK1. The former selectively targets IRS-1 Ser307. The latter strikes simultaneously at Ser307 and Ser636. Dual phosphorylation cripples the function of IRS-1. Nuclear NF-κB p65 upregulates TNF-α and IL-6 levels. It occupies κB motifs on the IRS-1 promoter, silencing transcription and depleting IRS-1 protein. The mtROS trigger NLRP3 inflammasome assembly. Caspase-1 cleaves pro-IL-1β, forming mature IL-1β, which activates IL-1R-MyD88-IRAK4 signaling, reactivating IKKβ. This creates a self-sustaining loop. ROS cause inflammation, which further suppresses IRS-1. The JAK1-STAT3 axis adds another layer of suppression. It dampens IRS-1 tyrosine phosphorylation and suppresses PGC-1α, further eroding mitochondrial biogenic capacity[29].

Although high nutritional status should activate Ragulator-Rheb-mTORC1 to promote synthesis, PKCθ/ζ also activates p70S6K (Thr389), which then reverses the phosphorylation of IRS-1 at Ser629/636 (in humans/murine), triggering its ubiquitination and degradation[55]. The paradox of short-term active mTORC1 alongside long-term inhibition of insulin signaling leads to the evolution of IR from an acute reversible state to a chronic solidified phenotype. Finally, the glucose uptake capacity of skeletal muscle decreases, and typical cell-autonomous IR occurs. Lipid deposition, OS and chronic inflammation work together to transform the originally efficient glucose disposal organ into a complex lesion of metabolic failure.

Advanced glycation end products

Myosclerosis caused by advanced glycation end cross-linking: Persistent hyperglycaemia is a critical determinant of the complications of diabetes mellitus and is closely related to the biogenesis of advanced glycation ends (AGEs). AGEs are heterogeneous substances produced when glucose binds to proteins, lipids, and nucleic acids during nonenzymatic processes and their sources include exogenous intake and endogenous synthesis.

AGEs nonenzymatically accumulate on collagen in aging muscle mainly through the Maillard reaction, which involves the chemical binding of glucose and its derivatives to amino acid residues in proteins to form irreversible cross-linked structures. These cross-links not only increase tissue stiffness, but also alter the physical properties of the extracellular matrix, resulting in a stiffer microenvironment that further impairs muscle health and function. AGEs-induced collagen deposition and cross-linking make the connections between muscle fibres tighter and stiffer, affecting muscle elasticity and contraction ability and leading to impaired skeletal muscle power and motor function. In addition, AGEs can hinder the biogenesis of novel vasculature, limit the supply of nutrients and oxygen, and further exacerbate muscle atrophy.

The AGEs-ROS-mitochondria-inflammation axis: AGEs induce ROS production by activating specific receptors. This process can cause OS. The excessive production of ROS can induce substantial injury to mitochondrial function and interfere with normal energy metabolic pathways.

Specifically, ROS attack the respiratory chain complexes situated at the inner membrane of the mitochondria, resulting in reduced efficiency of ATP production and the generation of highly active hydroxyl radicals (•OH) via the Fenton reaction, causing extensive lipid peroxidation, protein oxidation, and DNA damage. AGEs also upregulate the expression of proinflammatory mediators via induction of the NF-κB signal transduction cascade, which further aggravates the inflammatory response and tissue damage. Upon binding to RAGE, AGEs activate multiple downstream signaling pathways, including p38 MAPK and JNK, which lead to endothelial cell apoptosis and barrier dysfunction, reduce blood flow, and decrease the provision of O₂ along with nutritional substrates, ultimately leading to muscle atrophy and loss of function. AGEs stimulate macrophages and monocytes to secrete proinflammatory factors such as TNF-α and IL-6, which recruit more immune cells into the damaged area in autocrine and paracrine ways, resulting in the formation of a local inflammatory environment. Long-term immune response not only intensifies structural damage, but also inhibits the regeneration process and further aggravates muscle atrophy.

Fatty infiltration

Fatty infiltration, or myosteatosis, refers to the age-related redistribution and accumulation of adipose tissue within skeletal muscle[56]. This process is characterized by three main types of intramuscular fat, of which intermuscular adipose tissue (IMAT) is most strongly associated with diminished muscular strength, impaired insulin sensitivity, and an elevated risk of T2DM[57,58]. IMAT contributes to metabolic dysfunction by fostering a local inflammatory milieu and lipotoxicity. It secretes proinflammatory cytokines, including TNF-α, monocyte chemoattractant protein-1, and IL-6, which disrupt insulin signaling through mechanisms such as the phosphorylation of IRS at serine residues coupled with the upregulation of SOCS family members, thereby inducing skeletal muscle IR[59-61].

In addition to its metabolic effects, fat infiltration disrupts muscle mechanics. IMAT and intramyocellular lipids accumulate, pushing aside contractile fibres. This alters muscle structure. It also weakens the contraction efficiency[62]. Adipose tissue infiltration hardens the tissue and reduces strength, as it is stiffer than muscle which heightened stiffness compromises muscle performance and increases the risk of falls[63]. The IR induced by myosteatosis can lead to widespread metabolic dysregulation given that skeletal muscle is responsible for approximately 80% of insulin-stimulated glucose uptake. This process underscores its critical role in the interplay among ageing, obesity and diabetes[64].

Gut microbiota

In the pathogenesis of both T2DM and sarcopenia, gut bacteria are increasingly seen as critical regulators of systemic metabolism[65,66]. A key mechanism involves short-chain fatty acid (SCFA) synthesis by the intestinal microbiota. These SCFAs can increase insulin sensitivity and promote muscle hypertrophy through the activation of AMPK, PGC-1α, and insulin-like growth factor 1 (IGF-1) signaling pathways[67-69]. Reduced SCFA levels are associated with intramuscular lipid accumulation and IR and then contribute to muscle loss[70]. Elevated levels of faecal butyrate are correlated with the preservation of muscle mass in older adults[71]. Supplementation with SCFAs has been shown to reverse muscle wasting in animal models induced by high-fat diets[72]. The metabolic effects of SCFAs are complex. Propionate has been shown to worsen IR by triggering glucagon and FABP4 release, resulting in increased glycogen breakdown and high blood sugar levels[73,74].

Experimental studies offer compelling evidence for the interaction between the gut microbiome and muscle health. Transplanting the faecal microbiota from high-functioning older adults into germ-free mice led to a significant improvement in grip strength. This positive effect was associated with an increase in the abundance of Prevotella and Barnesiella in the gut[75]. The use of antibiotics to deplete the gut microbiota has been shown to impair muscle endurance. This negative effect is partly due to a reduction in glycogen stores[67]. Acetate supplements can restore endurance and preserve muscle function in mice lacking SCFAs[76,77]. Additional microbial metabolites which include bile acids and branched-chain amino acids also significantly influence IR[68].

Genetic and molecular interactions

T2DM and sarcopenia share significant genetic and molecular mechanisms. Chien et al[78] reported that 15 shared genes, including UPF3A, CSTB, and PEA15s, are key to the interaction between these diseases. Li et al[79] revealed that the overexpression of PGK1 can reduce metabolic stress and enhance muscle performance. Davegårdh et al[80] reported that deficiencies in vacuolar protein sorting 39 (VPS39) can disrupt autophagy and epigenetic regulation. This disruption leads to impaired glucose uptake and compromised muscle stem cell differentiation. Bin et al[81] reported that the gene encoding adiponectin (ADIPOQ) expression is increased in sarcopenia and is associated with AMPK activation. Wu et al[82] reported that the CEBPA-FGF21 regulatory network promotes skeletal muscle atrophy in T2DM via activating the autophagy-lysosome pathway.

These findings underscore the importance of genes involved in the pathophysiology of T2DM and sarcopenia which include UPF3A, CSTB, PEA15, PGK1, VPS39, ADIPOQ and FGF2. The precise mechanisms underlying their interactions remain to be elucidated. Further experimental investigations and clinical trials are warranted to elucidate the role of PGK1 in muscle atrophy, the function of VPS39 in autophagic processes and the involvement of ADIPOQ in AMPK-mediated fatty acid oxidation.

RISK FACTORS FOR T2DM-RELATED SARCOPENIA

Poor glycaemic control

Inadequate glycaemic control is closely linked to a higher incidence of sarcopenia among patients with T2DM[83]. Increased blood glucose and glycosylated hemoglobin (HbA1c) levels have been linked to diminished muscle mass and impaired muscular strength[84-86]. Zhang et al[87] reported that fasting plasma glucose (odds ratio = 1.52, 95%CI: 1.17-1.96) and HbA1c (odds ratio = 1.35, 95%CI: 1.05-1.73) both increased the likelihood of sarcopenia risk. Lin et al[88] demonstrated that elevated HbA1c levels and blood glucose variability increased the risk of sarcopenia among 482 hospitalised patients with T2DM. The correlation between blood glucose concentrations and skeletal muscle risk underscores the need for stringent glycaemic surveillance in patients with T2DM.

Vitamin D deficiency

Vitamin D plays a crucial role in regulating muscle function, calcium homeostasis, and metabolic processes. It is essential for the maintenance of skeletal muscles. Vitamin D deficiency is common among patients with T2DM. This condition is associated with decreased muscle strength and an increased risk of sarcopenia[89].

Vitamin D deficiency is widespread in the T2DM population. Both IR and impaired insulin secretion can be exacerbated by this nutritional deficit[90,91]. Multiple observational studies have shown that lower serum 25-hydroxyvitamin D levels in patients with T2DM are associated with reduced muscle mass and decreased physical function. A survey of patients with T2DM also indicated that insufficient vitamin D levels are independently associated with an increased risk of leptin syndrome. Insufficient vitamin D intake has a tendency to accelerate muscle deterioration in elderly patients with diabetes[92]. Whether vitamin D deficiency directly causes muscle wasting is currently unclear. Assessment and supplementation of vitamin D may be a potential adjunctive strategy. This strategy is particularly applicable to elderly and nutritionally vulnerable patients with T2DM.

Insufficient protein intake

Sufficient protein intake is crucial for maintaining skeletal muscle mass and preventing functional decline[93]. In patients with T2DM, insufficient protein intake may increase the risk of muscle atrophy. IR and chronic inflammation can impair the anabolic response of skeletal muscle[94]. This leads to a decrease in the efficiency of muscle protein synthesis.

Metabolic resistance related to aging requires a higher protein intake to maintain muscle homeostasis[95]. This indicates that elderly patients with T2DM are particularly vulnerable. Epidemiological studies have shown that low protein intake is associated with decreased muscle strength, reduced physical function, and increased risk of disability in the diabetic population.

Current recommendations generally suggest that elderly individuals should consume approximately 1.0-1.2 g of protein per kilogram of body weight per day. Yet the individualized adjustments are necessary for patients with chronic kidney disease (CKD) or other metabolic complications. Nutritional assessment and adequate protein supplementation should be regarded as an important component in preventing muscle atrophy for patients with T2DM.

Hormonal dysregulation

The hormonal regulation of muscle mass is mediated through its effects on anabolic processes, satellite cell dynamics, and energy utilization. Testosterone, oestrogen, growth hormone (GH), IGF-1 and other anabolic hormones promote muscle growth while catabolic hormones such as cortisol have the opposite effect. The balance between these hormones is essential for skeletal muscle health.

Sex hormones are critical for maintaining muscle health. Testosterone not only stimulates the synthesis of muscle proteins but also triggers the activation of satellite cells which can enhance muscle repair and regeneration[96]. Men’s testosterone levels steadily decrease with age which causes skeletal muscle to deteriorate in distal muscle groups[97]. Du and colleagues reported a significantly elevated risk of sarcopenia in men with T2DM compared with women[98]. Testosterone replacement therapy (TRT) has been shown to have multiple metabolic benefits in men with T2DM and concomitant hypogonadism which can reduce fat mass, increase muscle mass, and improve blood sugar control and insulin sensitivity[99-101]. But the long-term safety of TRT remains uncertain. Current expert guidelines advise initiating TRT only in men with T2DM and functional hypogonadism who display typical symptoms and have low total testosterone concentrations (less than 2.3 ng/mL)[102]. It is crucial to acknowledge that TRT can present a potential risk of cardiovascular complications and prostate health issues[103]. Oestrogen aids in muscle regeneration and can improve overall muscle health[104]. The Baltimore Longitudinal Study of Ageing revealed that serum oestradiol (E2) levels and the free oestrogen index are positively linked to appendicular lean mass and thigh muscle composition[105].

GH stimulates IGF-1 production and supports soft tissue growth. GH/IGF-1 activity decreases with aging and subsequently results in muscle atrophy and greater fat accumulation which underscores the significance of the GH/IGF-1 system in preserving muscle health[106]. Muscle strength and muscle mass are positively correlated with serum IGF-1 levels in individuals with T2DM which further supports the role of the GH/IGF-1 system in maintaining muscle health[107]. It may also exacerbate IR by antagonizing the antilipolytic effects of insulin though studies have shown that GH supplementation enhances muscle strength and mass in animal models[108,109].

Neuroendocrine dysfunction, which includes abnormal cortisol rhythms, is frequently observed in patients with T2DM[110]. Research by Liu et al[111] revealed that midnight cortisol hypersecretion was substantially more prevalent in those with sarcopenia. Hypercortisolemia accelerates myofibrillar protein catabolism, attenuates protein biosynthesis, and disrupts growth-related signal transduction[112,113].

Ageing

Advancing age is an indisputable risk factor for sarcopenia onset given the inexorable decline in both muscle mass and quality that accompanies senescence. Research conducted by Ai et al[114] revealed a robust link between older age and increased susceptibility to sarcopenia among patients with T2DM. These findings align with observations by Murata et al[115] who reported that prevalence of sarcopenia among octogenarian patients with T2DM exceeded 40%. An age-dependent stepwise increase in the prevalence of sarcopenia was further demonstrated by Ji et al[116] in their cross-sectional assessment of 408 patients with T2DM. The rates reach 12.6% in the sixth decade, 32.1% in the seventh to eighth decades and 51.9% in octogenarians.

Gender

The influence of gender on the risk of sarcopenia in patients with T2DM remains controversial. Multiple studies suggest that male patients may be more prone to sarcopenia. There are reports indicating that the prevalence of sarcopenia in male patients with T2DM is significantly higher than that in female patients (41.3% vs 20.1%)[98]. Similar results were also observed in the analysis stratified by age. The prevalence of sarcopenia in male patients increases more significantly with age[117]. Other studies have shown that women with T2DM may also be at high risk. The prevalence is higher during the postmenopausal stage[115,118,119]. Possible explanations include differences in diagnostic criteria, racial and regional variations, basic body composition, hormonal status, and lifestyle-related factors. For example, postmenopausal estrogen deficiency may accelerate muscle loss and promote fat accumulation. This increases the risk of muscle loss in elderly women[120].

The influence of gender on diabetic muscle atrophy remains an unresolved issue. The use of standardized diagnostic criteria needs to be implemented in the future. Studies on menopausal status, hormonal changes, and body composition parameters need to be integrated to clarify these gender-specific associations.

Body mass index

The relationship between body mass index (BMI) and sarcopenia in patients with T2DM is rather complex. BMI cannot accurately distinguish between fat mass and skeletal muscle mass. A low BMI is regarded as an indicator of malnutrition and reduced muscle reserve[98,121,122]. Yet it may not fully reflect the risk of muscle dysfunction in the diabetic population. Multiple studies have shown that a low BMI is associated with a high incidence of sarcopenia in elderly patients with type 2 diabetes. This association may reflect factors such as insufficient nutrient intake, chronic inflammation, and accelerated muscle catabolism[123].

Relying solely on BMI may underestimate the risk of sarcopenia in overweight or obese patients. The sarcopenic obesity is increasingly being recognized in patients with T2DM. It is characterized by a reduction in skeletal muscle mass while accompanied by excessive fat accumulation. Even with a normal or elevated BMI but excessive fat tissue, inflammation, IR, and muscle catabolism can still occur[124]. It is recommended to conduct a comprehensive assessment using body composition testing techniques such as dual-energy X-ray absorptiometry (DXA), bioelectrical impedance (BIA), computed tomography, or ultrasound, rather than relying solely on BMI for identifying diabetic patients at risk of sarcopenia[125]. These methods not only offer more extensive data but make sarcopenia diagnosis more accurate and improve the management of T2DM-related complications.

Smoking

Smoking markedly increases the risk of sarcopenia by disrupting insulin production and intensifying IR[126]. Tobacco use can lead to transcriptional upregulation of MSTN alongside the induction of MAFbx expression. These effects damage the biological energy metabolism of muscles and inhibit protein synthesis while stimulating protein breakdown mediated by proteasomes[127]. OS and chronic inflammation from smoking activate NF-κB and MAPK pathways to disrupt muscle protein balance. This process would lead to muscle fibre loss and atrophy. Smoking also increases arterial stiffness and reduces muscle blood flow, and impedes nutrient and waste exchange which can further accelerate muscle damage[128].

A meta-analysis of 68 studies revealed that smoking was a major independent risk factor for sarcopenia. Other factors, such as poor nutritional status, poor sleep duration, and a lack of exercise[129], significantly contribute to the detrimental association between smoking and sarcopenia in diverse populations. This finding was confirmed by Liu et al’s meta-analysis[130] which reported consistent findings in community-dwelling adults and nursing home residents. It is strongly recommended that patients with T2DM quit smoking as early as possible with nicotine replacement therapy as an option to support cessation.

Insufficient physical activity

Multiple studies have consistently identified insufficient exercise as a significant risk factor for sarcopenia[131,132]. Prolonged sedentary behavior is a significant risk factor for sarcopenia, a link potentially mediated by chronic low-grade inflammation, which promotes protein degradation and inhibits muscle protein synthesis[133]. Therefore, increasing physical activity and decreasing sedentary behavior are essential strategies for preventing sarcopenia.

A retrospective study using multivariate analysis and the extreme gradient boosting (XGBoost) algorithm revealed that physical activity was the strongest protective predictor of sarcopenia. Other factors such as diabetes, advanced age, and depression were also identified as significant risk factors[134]. In support of these findings, Lee’s study[135] showed significantly higher rates of sarcopenia in individuals who did not have resistance training experience than in those who had engaged in high-intensity resistance exercises. A longitudinal study in Malaysia found that both low-intensity and moderate-intensity physical activities were significantly linked to sarcopenia which suggests that even lower intensity exercises may play an important role in preventing sarcopenia[136]. Physical inactivity is strongly linked to sarcopenia in patients with T2DM which highlights the importance of regular exercise in reducing muscle loss[137].

T2DM-related complications

T2DM frequently coexists with macrovascular and microvascular complications which significantly increase the risk of sarcopenia. Approximately half of those with T2DM experience diabetic peripheral neuropathy (DPN) which is a prevalent microvascular condition[138]. DPN is closely linked to sarcopenia, which manifests as reduced muscle mass and function[139]. Male patients with DPN show significantly reduced handgrip strength. Enhanced muscle mass could aid in restoring nerve conduction velocity which could be a promising approach to improve neural function[140].

Diabetic retinopathy and nephropathy also play roles in the development of sarcopenia. Diabetic retinopathy is linked to an increased risk of reduced muscle mass, and the incidence of sarcopenia increases as retinopathy becomes more severe. Therefore, managing these complications is crucial for preventing or delaying sarcopenia[141]. CKD accelerates muscle wasting with low muscle strength observed in 43.4% of patients with CKD[142]. The main cause of this muscular atrophy is a sustained increase in muscle protein catabolism driven by inflammation, OS and mitochondrial dysfunction[143].

Peripheral arterial disease (PAD) is a frequent macrovascular issue that restricts blood flow to the extremities and leads to a direct decrease in muscle strength and functionality. These findings underscore the importance of addressing muscle health in PAD management[144]. PAD further accelerates muscle loss through reduced physical activity and intermittent claudication and exacerbates sarcopenia[83,145]. These microvascular and macrovascular complications worsen sarcopenia, highlighting the need for proactive measures to maintain muscle mass and function in patients with T2DM. Therefore, comprehensive treatment plans for T2DM should focus on muscle health.

COMPREHENSIVE MANAGEMENT STRATEGIES FOR T2DM-RELATED SARCOPENIA

Risk-based screening and diagnostic assessment

The clinical management of patients at high risk of sarcopenia should start with structured screening. The enhanced assessment is required for elderly patients with T2DM and HbA1c ≥ 8.0%, DPN, CKD, non-autonomous weight loss, reduced food intake, insufficient physical activity, recurrent falls, or rapid weight loss due to treatment[83]. These factors should be regarded as triggers for further evaluation.

Practical stepwise assessment methods include risk identification, SARC-F screening, muscle strength assessment, body composition measurement, and physical performance evaluation. The patients with positive SARC-F results or those whose clinical suspicion remains should undergo grip strength testing or the five-stand-up sit-down test[146]. The bioelectrical impedance analysis or dual-energy X-ray absorptiometry should be used to measure the mass of skeletal muscles in the limbs if muscle strength is found to be decreased. Subsequently, gait speed, brief physical performance assessment scales, or the standing-up walking test can be used to evaluate the severity of the disease[147]. The result may be negative in high-risk patients due to the limited sensitivity of SARC-F. Yet the further evaluation should not be excluded.

Individualized glycemic targets

The target for blood glucose control should be determined based on the patient's functional status, comorbidities, cognitive function, risk of hypoglycemia, treatment burden, and life expectancy. It cannot be set solely based on age. A HbA1c target of approximately 7.0%-7.5% might be more reasonable for elderly individuals with good cognitive function, fewer comorbidities, and independent living skills[148]. For those with multiple chronic diseases or diagnosed sarcopenia, a target of approximately 7.5%-8.0% would be more appropriate[84,85]. Yet the treatment should prioritize avoiding symptomatic hyperglycemia and hypoglycemia for severely frail, severely cognitively impaired or those with a short life expectancy. Such cases should not have a fixed HbA1c value set.

These targets should be flexible. The treatment intensity should be considered for reduction when there are repeated hypoglycemic events, falls, continuous weight loss, reduced food intake, cognitive decline, or overly complex treatment regimens[149]. The attention should also be paid to blood glucose fluctuations and the time below the normal range for patients using insulin or sulfonylurea drugs. HbA1c levels ≥ 8.0% may indicate an increased risk of muscle problems[150]. Yet adjustments to the treatment intensity should be based on assessments of compliance, nutritional status, renal function, hypoglycemia, complications, and muscle status.

Integrated nutrition and exercise intervention

Management should follow a comprehensive five-step approach. This includes individualized blood sugar control, nutritional support, exercise prescriptions, risk-adapted drug therapy, and long-term follow-up monitoring. The relationship between nutritional interventions and sarcopenia in T2DM is summarized in Table 2[92,151-158]. Physical exercise is a cornerstone non-pharmacological strategy for managing T2DM and concurrent sarcopenia. The multifaceted benefits of exercise for these patients are summarized in Table 3[78,159-162].

Table 2 Studies on the effect of nutritional intervention on sarcopenia in type 2 diabetes mellitus.

Nutrition intervention	Study design	Target population	Age (years old)	Research objectives	Results	Ref.
Vitamin intake	Prospective cohort study	T2DM patients	≥ 65	Loss of muscle mass	Vitamin D intake is associated	Takahashi et al[92]
Protein intake	Cross-sectional	T2DM patients	≥ 31	Muscle loss	Negative impact	Fanelli et al[151]
Protein supplementation	Randomized controlled study	T2DM patients	> 55	Physical performance and body composition	Positively improved	Argyropoulou et al[152]
BCAAs	Longitudinal study	T2DM patients	56.6 ± 10.6	Skeletal muscle loss	Negatively associated	Low et al[153]
Medical nutrition therapy	prospective study	T2DM patients	74 ± 6.0	Handgrip strength	Effective	Gaglio et al[154]
Omega-3 fatty acids intake	Cross-sectional	T2DM patients	74.2 ± 5.7	Sarcopenia	Negatively associated	Okamura et al[155]
BCAAs	Randomized controlled study	T2DM patients	65-80	Skeletal muscle mass	No significant correlation	Matsuda et al[156]
Exercise and protein intake	Cohort study	T2DM patients	≥ 65	Decreasing skeletal muscle mass index	Negatively associated	Hashimoto et al[157]
Resistance training and nutritional interventions	Prospective cohort study	Frail T2DM patients	79 ± 5.6	SPPB, maximal strength and power output	Positively improved	Izquierdo et al[158]

SPPB: Short physical performance battery; T2DM: Type 2 diabetes mellitus; BCAAs: Branched-chain amino acids.

Table 3 Studies on the effect of physical exercise on sarcopenia with T2DM.

Physical exercise intervention	Study design	Duration	Target population	Research objectives	Results	Ref.
Low-volume walking high-intensity interval training	Randomized controlled trial	12 weeks	Older women with T2DM	Cardiovascular risk profile and physical capacity	Significantly improved	Marcotte-Chénard et al[159]
ST, aerobic training	Randomized, controlled trial	9 months	Normal-weight T2DM	HbA1c level and body composition	ST – significantly improved outcomes and increased lean body mass	Kobayashi et al[160]
Progressive sandbag exercise training	Randomized, controlled trial	12 weeks	Patients with T2DM and possible sarcopenia	HbA1c levels, muscle strength, and physical performance	Significantly improved	Chien et al[78]
Resistance exercise	Own-controlled before-and-after cohort study	24 hours	Older patients with T2DM and sarcopenia	Blood glucose	Lower blood glucose	Zhao et al[161]
In-Hospital exercise rehabilitation	Randomized, controlled trial	12 weeks	Middle-aged and elderly patients with T2DM and sarcopenia	Blood glucose, lipids, and muscle strength	Effectively improve	Shi et al[162]

T2DM: Type 2 diabetes mellitus; HbA1c: Glycosylated hemoglobin; ST: Strength training.

Targeted nutritional interventions positively impact muscle health within elderly cohorts and patients suffering from persistent pathological conditions[153,163,164]. Nutritional intervention should ensure adequate energy intake. Approximately 1.0-1.2 g per kilogram of protein per day should be provided for general patients. At least 1.2 g per kilogram of protein per day can be considered to provide for patients whose renal function and clinical condition permit. Protein should be consumed in multiple meals. Focus on choosing high-quality foods rich in leucine. The deficiency of vitamin D in patients should be identified and corrected[165]. The protein intake should be adjusted individually for patients with advanced CKD or unstable metabolism.

Exercise should be structured according to frequency, intensity, duration and type. Two to three progressive resistance training sessions involving major muscle groups should be conducted weekly[166]. The moderate-intensity aerobic exercise should gradually reach approximately 150 minutes per week if conditions permit. The balance, gait and functional training should be increased for patients with neuropathy, slow walking speed, decreased ability to stand against a wall, or a history of falls. Patients who cannot achieve the full exercise goals should start with supervised low-intensity exercises[167]. Such exercises include using resistance bands, sitting up exercises or short intervals of walking. The treatment effect should be evaluated through indicators such as HbA1c, weight, appetite, protein intake, muscle strength, gait function, fall situations and functional independence.

Risk-adapted selection of antidiabetic medications

The effects of hypoglycemic drugs on muscle mass, strength and physical function should be considered separately. Changes in lean body mass do not necessarily correspond to changes in functional skeletal muscle[168]. There is a lack of direct evidence indicating that a single hypoglycemic drug can prevent or reverse sarcopenia.

Metformin is a reasonable basic treatment option when patients tolerate well and have no contraindications. It may indirectly promote muscle metabolism by improving insulin sensitivity[169]. Yet its direct muscle-protective effect has not been confirmed. Long-term use may lead to vitamin B12 deficiency. Their vitamin B12 levels should be evaluated for patients with anemia, neuropathy, or unexplained functional decline[170]. The effect of DPP-4 inhibitors on body weight is neutral. The risk of hypoglycemia during use is low[171]. They usually do not significantly reduce appetite or body weight. These characteristics make them a suitable choice for patients who are weak or prone to muscle atrophy. Yet it should be described as a relatively neutral muscle protector rather than a proven muscle-strengthening drug.

Insulin can reduce catabolism when there is severe hyperglycemia or insulin deficiency. Yet hypoglycemia, weight gain, and treatment complexity may increase the risk of falls[172]. Sulfonylurea and glinide drugs should be used with caution in elderly patients at high risk. Thiazolidinedione drugs may improve insulin sensitivity. Yet there are issues such as edema, weight gain, risk of heart failure, and fracture risk during medication use. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have significant cardiovascular and renal benefits. They should not be discontinued merely because of the risk of muscle loss[173]. Some patients may experience a decrease in lean muscle or skeletal muscle mass after using them. For individuals with low body weight, inadequate intake, active weight loss, or diagnosed with muscle loss, monitoring of fluid status, nutritional intake, body weight, muscle strength, and body composition should be conducted.

Glucagon-like peptide-1 (GLP-1) receptor agonists can significantly reduce body weight and fat mass. Yet they may also cause measurable loss of lean muscle. There is insufficient evidence to confirm that sitagliptin or other GLP-1 receptor agonists can directly protect the muscles[174]. The dosage of these drugs should be adjusted with caution for patients who are frail or prone to muscle atrophy. The adequate protein intake and resistance training should be combined during medication. Metformin and/or DPP-4 inhibitors have relatively neutral effects on body weight and a lower risk of hypoglycemia[175]. They are more suitable for high-risk patients without clear indications related to heart and kidney in other drug categories. The muscle strength, physical function, nutritional intake, weight change trend and body composition should be re-evaluated approximately three to six months later and during periods of rapid weight loss when SGLT2 inhibitors or GLP-1 receptor agonists have clinical indications.

Adverse-event surveillance and longitudinal monitoring

Clinical monitoring should include hypoglycemia, weight loss, dehydration, muscle function decline, and falls. Baseline assessment should record body weight and recent changes, appetite, protein intake, grip strength, standing ability, gait speed, fall history, postural symptoms, renal function, and current risk of hypoglycemia[176]. Additional BIA or DXA examinations can be conducted if conditions permit[150]. These examinations are particularly important before treatments that are expected to cause significant weight loss. The low blood sugar monitoring for patients using insulin, sulfonylurea drugs, or glinide drugs should also be strengthened. The treatment intensity should be adjusted when patients have recurrent episodes, unexplained falls, or severe hypoglycemia.

The grip strength and gait speed should be re-evaluated approximately every three months during active intervention or rapid weight changes. High-risk patients receiving SGLT2 inhibitors or GLP-1 receptor agonists should be re-evaluated for body composition every three to six months[177]. The causes of muscle atrophy should consider factors such as malnutrition, lack of exercise, or weight loss[178]. Fall risk assessment should include previous fall history, gait and balance ability, orthostatic blood pressure, vision, footwear, home environment risk factors, peripheral neuropathy, medication burden, and exposure to hypoglycemia. A comprehensive medical or geriatric re-evaluation should be conducted immediately if patients experience rapid involuntary weight loss, recurrent falls, or severe hypoglycemia.

Multidisciplinary implementation and individualized care

Muscle loss associated with T2DM requires a multidisciplinary collaborative approach for comprehensive treatment. A diabetes specialist or geriatrician can serve as the main coordinator to set individualized blood sugar and functional goals. A nutritionist should assess total energy intake, leucine-rich foods, vitamin deficiencies, and renal dietary restrictions. A physical therapist or exercise specialist should evaluate strength, gait, and balance abilities. A pharmacist should assess the risk of hypoglycemia, multiple medications, renal function dose adjustment, vitamin B12 deficiency, etc.[179]. A diabetes nurse can assist with blood sugar monitoring, treatment education, and foot care.

Heart failure, neuropathy, repeated falls, cognitive impairment, or severe weakness, additional professional opinions should be obtained as per clinical needs for patients with CKD. The shared treatment plan should clearly define blood sugar targets, nutritional prescriptions, exercise programs, medication basis, monitoring frequency, and trigger conditions for re-evaluation. Clinical implementation may be limited by the lack of BIA or DXA, restricted use of dynamometers, etc. A stratified approach may increase feasibility[180]. A basic assessment can be conducted through SARC-F screening, weight changes, fall history, grip strength, and gait speed in routine diabetes clinics. Targeted physical composition, nutrition, and exercise assessments should be carried out for high-risk patients[181]. A comprehensive multidisciplinary assessment should be conducted for patients diagnosed with sarcopenia, repeated falls, or significant functional decline.

FUTURE DIRECTIONS

Future research should focus on the in-depth exploration of the pathophysiological mechanisms linking T2DM and sarcopenia which include IR, muscle metabolic pathways and the regulation of muscle protein synthesis or degradation. Detailed molecular studies will identify potential biomarkers and therapeutic targets. Drug development should focus on novel antidiabetic agents that specifically preserve muscle mass.

The effects of GLP-1RAs and SGLT2is on muscle mass require further investigation, but they have shown potential in improving IR. Exploring new drug targets of the mTOR pathway and AMPK regulation in muscle growth offers new avenues for treatment. Future strategies should include gene therapy, stem cell-based approaches and personalized exercise interventions as part of a multidisciplinary approach beyond pharmacotherapy. These methods still face challenges in terms of technology and clinical translation though they have shown promise in early clinical studies. Future research should bridge basic science with clinical practice, emphasizing the clinical validation and translational application of novel therapeutic strategies to improve patient quality of life and reduce diabetes-related complications.

CONCLUSION

T2DM-related sarcopenia is a complex metabolic-musculoskeletal disorder. It is not merely a simple consequence of aging or the course of diabetes. The occurrence of sarcopenia in patients with T2DM is caused by the interaction of factors such as insulin signaling disorder, chronic inflammation, OS, mitochondrial dysfunction, nutritional imbalance, and reduced physical activity. These mechanisms indicate that protecting skeletal muscle should become an important part of comprehensive diabetes management.

The early identification of high-risk individuals is crucial from a clinical perspective. Their muscle strength, physical function and body composition should be evaluated promptly for elderly patients with poor glycemic control, unexplained weight loss, insufficient protein intake, lack of physical activity, presence of diabetic complications or functional decline. Diabetes management should not only focus on lowering blood sugar. The potential impact of treatment strategies on muscle mass, physical function and nutritional status should also be considered.

Future research should prioritize strategies with clinical application value. Prospective longitudinal studies are needed to establish standardized screening and risk prediction models for diabetic sarcopenia. The long-term effects of different hypoglycemic treatment methods on muscle mass and functional outcomes still need further research. Reliable biomarkers that can reflect early muscle deterioration and metabolic dysfunction are also extremely important for achieving personalized intervention. Well-designed clinical trials should determine the best combination of strategies for different subgroups of T2DM. This includes resistance training, nutritional support and medication management.

Multidisciplinary approaches such as metabolic control, nutritional optimization, physical activity and individualized monitoring need to be integrated. This may provide more effective strategies for preventing and managing sarcopenia related to T2DM and improving long-term functional outcomes.