Diabetes and Sarcopenia: Unraveling the Metabolic Crossroads of Muscle Loss and Glycemic Dysregulation

Abstract

The intersection of type 2 diabetes mellitus (T2DM) and sarcopenia, often termed diabetic sarcopenia, represents a critical yet underrecognized comorbidity that significantly impacts the quality of life and functional capacity of older adults. This paper explores the complex interplay between T2DM and sarcopenia, focusing on the prevalence, risk factors, and underlying mechanisms driving muscle mass and strength decline in this population. Drawing from recent clinical studies, we highlight a prevalence of sarcopenia ranging from 15.36% to 30.2% among elderly T2DM patients, with notable gender disparities (41.3% in men versus 20.1% in women) and regional variations. Key risk factors identified include poor glycemic control (HbA1c ≥8%), longer diabetes duration (>5 years), low body mass index (BMI), and reduced levels of 25-hydroxyvitamin D and insulin-like growth factor-1 (IGF-1). We also recommend a practical screening algorithm for diabetic sarcopenia, integrating tools like the SARC-F questionnaire, dynamometry, and BMI-adjusted calf circumference to facilitate early diagnosis and staging in clinical settings. The review underscores the need for a multidisciplinary approach—encompassing pharmacological optimization, nutritional interventions with high-protein diets, and tailored physical exercise—to mitigate muscle loss and improve metabolic outcomes. Future research directions should focus on validating diagnostic protocols and diagnosis techniques and further exploring specific therapies to effectively address this dual burden.

1. Introduction

Type 2 diabetes mellitus (T2DM) stands as a formidable global health challenge, currently affecting over 537 million adults worldwide—a figure projected to reach 783 million by 2045. Beyond its primary metabolic disturbances, T2DM initiates a cascade of complications that fundamentally alter the clinical landscape of affected individuals. Among these complications, sarcopenia—the progressive loss of skeletal muscle mass, strength, and function—has emerged as a critical yet frequently overlooked comorbidity that significantly impacts patient outcomes and quality of life [1,2].

The intersection between T2DM and sarcopenia represents a complex bidirectional relationship where each condition perpetuates and exacerbates the other. This relationship has been termed “diabetic sarcopenia,” referring specifically to the muscle mass atrophy characteristic of people with diabetes mellitus, contrasting with the histological and physiological normality of muscle mass in healthy individuals [1]. Current evidence demonstrates that T2DM patients face a substantially elevated risk of developing sarcopenia, with prevalence rates ranging from 15.36% to 30.2%—nearly three times higher than age-matched controls without diabetes [2,3].

Multiple pathophysiological mechanisms underlie this elevated risk. Insulin resistance, a hallmark of T2DM, disrupts the PI3K/Akt/mTOR pathway, which normally drives protein synthesis and muscle growth. Chronic hyperglycemia promotes the accumulation of advanced glycation end-products (AGEs) in skeletal muscle, while persistent low-grade inflammation creates a catabolic environment that accelerates protein degradation [4]. Additionally, microvascular complications such as diabetic neuropathy and peripheral arterial disease reduce oxygen delivery to muscles by approximately 30%, contributing to muscle ischemia and discouraging physical activity. [2]

The clinical significance of diabetic sarcopenia extends beyond simple muscle loss. The SeDREno study revealed alarming statistics: 54.7% of T2DM patients over 70 are at risk for sarcopenia, with 40.7% meeting GLIM criteria for moderate-to-severe sarcopenia-related malnutrition [3]. Key risk factors include male gender (OR: 4.997; 95% CI: 2.611–9.564), low BMI (OR: 1.525; 95% CI: 1.353–1.718), poor glycemic control (HbA1c ≥8%), diabetes duration >5 years, and reduced levels of 25-hydroxyvitamin D and insulin-like growth factor-1 (IGF-1) [2,5].

The reciprocal nature of this relationship creates a vicious cycle that compounds both metabolic dysfunction and physical decline. Muscle loss reduces glucose disposal capacity, as skeletal muscle accounts for approximately 80% of insulin-mediated glucose uptake. This reduction in muscle mass consequently worsens insulin sensitivity, driving further hyperglycemia and perpetuating the cycle of metabolic deterioration. Simultaneously, decreased physical activity resulting from muscle weakness further impairs glucose metabolism and accelerates the progression of both conditions [6].

Despite growing recognition of diabetic sarcopenia’s clinical importance, several critical knowledge gaps persist. Current diabetes management guidelines provide limited guidance on muscle health assessment and intervention strategies. Diagnostic approaches lack standardization for diabetic populations, and evidence-based therapeutic protocols that simultaneously address both muscle preservation and glycemic control remain underdeveloped. Furthermore, the optimal timing for sarcopenia screening in diabetes care pathways and the long-term consequences of untreated diabetic sarcopenia on cardiovascular and metabolic outcomes require urgent investigation.

This comprehensive review addresses these knowledge gaps by examining the current understanding of diabetic sarcopenia across multiple dimensions. We synthesize evidence on prevalence patterns, underlying molecular mechanisms, and diagnostic advances while exploring the systemic impacts that extend to cardiovascular and hepatic complications. Additionally, we evaluate current management approaches and identify emerging therapeutic strategies that hold promise for improving outcomes in this challenging comorbidity.

The review is structured to provide clinicians and researchers with practical insights for managing diabetic sarcopenia. We begin with an exploration of molecular mechanisms driving muscle–glucose interactions, followed by comprehensive coverage of diagnostic tools and their clinical applications. Subsequent sections examine systemic health consequences, current therapeutic approaches, and future research directions. Throughout, we emphasize implementation strategies that can be readily incorporated into existing diabetes care frameworks while highlighting areas where continued investigation is most critically needed to advance patient care and improve long-term outcomes.

2. Epidemiology and Clinical Overlap

Type 2 diabetes mellitus (T2DM) and sarcopenia demonstrate a concerning epidemiological overlap that extends far beyond mere coincidence. The prevalence of sarcopenia among older adults with T2DM ranges from 15.36% to 30.2%, representing nearly three times the rate observed in age-matched non-diabetic peers [4,6]. In a community-based study involving 500 older adults with type 2 diabetes mellitus, a notable gender disparity in sarcopenia prevalence was observed: 35.8% of men and 18.2% of women were affected, highlighting a significantly higher burden of muscle loss among males in this population (p < 0.01) [7]. These figures translate into a profound clinical burden: millions of older T2DM patients face substantially elevated risks of falls, fractures, functional decline, and increased healthcare utilization, perpetuating a self-reinforcing cycle where metabolic dysfunction accelerates physical deterioration and vice versa.

The SeDREno study (Screening for Disease-Related Malnutrition), a multicenter Spanish investigation that assessed hospital malnutrition prevalence according to GLIM (Global Leadership Initiative on Malnutrition) criteria, provides particularly sobering insights into this intersection. This comprehensive study revealed that 54.7% of T2DM patients over 70 years were at risk for sarcopenia, while 40.7% met GLIM criteria for moderate-to-severe sarcopenia-related malnutrition. Key independent predictors were age ≥ 75 years (OR 4.3; 95% CI 3.2–5.8), male sex (OR 3.9; 95% CI 2.3–6.6), and BMI < 24 kg/m² (OR 1.6; 95% CI 1.2–2.1) [8].

Diagnostic criteria for sarcopenia in this population require careful contextual understanding, as their performance characteristics and clinical applications differ significantly. The SARC-F questionnaire, a widely utilized five-item self-report tool assessing strength, walking assistance, chair rise capability, stair climbing, and falls history, offers practical bedside screening, when validated in T2DM cohorts, SARC-F sensitivity was 42% and specificity 85% against DXA-defined low lean mass [9]. This substantial diagnostic gap means that over half of early sarcopenia cases may be missed when relying solely on this instrument. Calf circumference measurement, adjusted for BMI with cutoffs of <33 cm in men and <32 cm in women, provides a simple anthropometric proxy for low muscle mass [4], while appendicular lean mass index (ALMI) via dual-energy X-ray absorptiometry offers quantitative confirmation with established thresholds (<7.0 kg/m² in men, <5.5–5.7 kg/m² in women) [5]. However, ALMI may overestimate lean mass in obese individuals—a common scenario in T2DM populations—highlighting the limitations of any single diagnostic approach [7].

The clinical reality reveals profound screening gaps and systematic underdiagnosis of sarcopenia in T2DM patients. Despite the established high prevalence, opportunistic computed tomography analyses detect sarcopenia in 28.5% of hospitalized T2DM cohorts, whereas electronic health records document this condition in merely 0.05% of similar populations. This 570-fold discrepancy between radiological detection and clinical documentation represents massive missed opportunities for early intervention and appropriate management. Contributing factors to this underrecognition include clinical practice patterns that prioritize glycemic control metrics over functional assessment, limited clinician awareness of sarcopenia diagnostic pathways, inadequate integration of muscle health evaluation into diabetes care guidelines, and the absence of systematic screening protocols [4].

The implications of this diagnostic neglect extend beyond individual patients to broader healthcare systems, as untreated sarcopenia compounds diabetes complications, increases hospitalization rates, and accelerates functional decline. Addressing these screening gaps requires implementing systematic assessment protocols that combine self-report questionnaires, anthropometric measurements, and imaging modalities within routine diabetes care pathways, creating opportunities for timely interventions including resistance training, nutritional optimization, and targeted pharmacological approaches to preserve muscle mass and function [5].

3. Pathophysiology and Molecular Dynamics

The development of sarcopenia in patients with type 2 diabetes mellitus (T2DM) stems from the disease’s fundamental metabolic disruptions, which create a destructive cycle where muscle breakdown accelerates while metabolic control deteriorates. At the heart of this process lies insulin resistance, T2DM’s defining characteristic, which simultaneously blocks glucose uptake in skeletal muscle and disrupts the cellular machinery responsible for maintaining muscle mass.

Under normal circumstances, insulin activates the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway—essentially the body’s master switch for building and preserving muscle protein. When insulin resistance develops, this crucial pathway becomes severely impaired. The activity of Akt (also called protein kinase B) drops by approximately 34% in T2DM patients, which in turn slashes mTOR activation and reduces protein synthesis by 30–40%. This occurs because the cellular processes that initiate protein production—translation initiation and ribosome assembly—cannot function properly without adequate mTOR signaling [10].

In T2DM, insulin resistance impairs the PI3K/Akt/mTOR pathway, reducing protein synthesis by approximately 30%. Hyperglycemia-induced oxidative stress further suppresses myofibrillar repair, and low-grade inflammation—driven by elevated IL-6—enhances proteasomal degradation. Together, these mechanisms form a self-reinforcing cycle of muscle atrophy and metabolic dysregulation [10].

At the molecular level, the balance between protein synthesis and breakdown becomes severely disrupted. When insulin resistance prevents normal Akt activation, protein synthesis machinery malfunctions dramatically. Key downstream proteins like 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1) cannot be properly phosphorylated, reducing ribosome recruitment to messenger RNA by 60–70% and severely limiting protein production in diabetic muscle [10,11].

Simultaneously, protein breakdown pathways become overactive. Forkhead box O (FoxO) transcription factors, normally suppressed by insulin, enter cell nuclei where they increase expression of genes responsible for protein degradation. This includes activation of E3 ubiquitin ligases like MuRF1 and Atrogin-1, as well as autophagy-related genes such as LC3 and Beclin-1. These pathways promote muscle loss through both the ubiquitin–proteasome system and lysosomal degradation processes [10,11].

A particularly important discovery involves the WWP1-KLF15 pathway. Chronic hyperglycemia reduces WWP1 activity, leading to accumulation of KLF15, a transcription factor that triggers genes responsible for muscle atrophy. This pathway alone accounts for up to 25% of muscle mass reduction in experimental models. Importantly, research has shown that pharmacologically boosting WWP1 can reverse this process, reducing KLF15-driven muscle wasting by approximately 30%—highlighting a promising therapeutic target [10].

Additional factors compound the muscle-destructive environment in T2DM. Lipotoxicity occurs when excess lipids accumulate in muscle cells, impairing mitochondrial function and reducing ATP production by up to 40%. Concurrently, diabetic microvascular complications such as neuropathy and peripheral arterial disease reduce oxygen delivery to muscles by about 30%, creating ischemia and discouraging physical activity [11]. Structural changes in the muscle’s extracellular matrix, particularly excessive collagen buildup, increase the distance insulin must travel to reach its receptors, further weakening the PI3K/Akt signaling pathway [10,11].

Hormonal disruptions worsen the situation, with elevated myostatin levels (acting as a muscle growth inhibitor), reduced IGF-1, and decreased testosterone contributing to muscle decline. Mitochondrial dysfunction, marked by reduced mitofusin-2 (MFN2), leads to increased reactive oxygen species production and activation of the NLRP3 inflammasome, amplifying muscle damage [11].

These interconnected molecular disruptions—affecting protein synthesis, breakdown pathways, inflammatory responses, and cellular structure—create a self-perpetuating cycle of muscle degeneration that characterizes diabetic sarcopenia [10,12].

4. Diagnostic Advances: Tools for Early Detection

Early diagnosis of diabetic sarcopenia is vital to prevent disability, falls, hospitalizations, and diminished quality of life in patients with type 2 diabetes mellitus (T2DM). Recent advances in screening strategies and imaging techniques offer practical, clinically accessible methods for earlier detection. Diabetic sarcopenia—defined by progressive loss of muscle mass and strength driven by diabetes-related metabolic disturbances—differs from typical age-related decline [2,4]. Identifying high-risk groups, such as patients with poor glycemic control (HbA1c ≥ 8%), diabetes duration > 5 years, or use of muscle-impacting therapies (e.g., sulfonylureas, glinides, SGLT2 inhibitors), enables timely intervention [4].

Clinical “red flags”—including unexplained fatigue, recurrent falls, difficulty rising from a chair, dizziness, and vascular complications—should prompt further evaluation. Although the SARC-F questionnaire is quick and widely used, its sensitivity for detecting early sarcopenia is only about 45%, necessitating complementary approaches [4,13].

Current consensus recommends initial assessment of muscle strength to define probable sarcopenia. Handgrip dynamometry (cutoffs: <27 kg in men, <16 kg in women) and the five-time chair-stand test (>15 s) are practical, useful and validated measures [3,5].

When muscle weakness is detected, assessing muscle quantity becomes crucial to confirm the diagnosis. While this step may appear straightforward, it is paradoxically complex due to the variety of available methods for measuring muscle mass. However, only a limited number of these techniques are well validated and possess established reference ranges and cut-off points. Among the simplest and most practical methods is the measurement of calf circumference, adjusted for body mass index (BMI), with thresholds set at less than 33 cm for men and less than 32 cm for women, providing a reliable bedside assessment of muscle mass in clinical practice [4,14].

Imaging techniques offer superior diagnostic precision and are increasingly adopted in select clinical settings. Dual-energy X-ray absorptiometry (DXA) quantifies appendicular lean mass index (ALMI; 7.0 kg/m² in men, <5.5–5.7 kg/m² in women), although it may overestimate lean mass in obesity. Computed tomography (CT) at the third lumbar vertebra (L3) remains the research gold standard for measuring muscle mass and calculating the skeletal muscle index (SMI; 39–41 cm²/m² in women, 52–55 cm²/m² in men); however, specific cut-offs for T2DM patients are not yet defined and require urgent standardization. Magnetic resonance imaging (MRI) and ultrasound (US) also assess muscle quantity, but validated reference thresholds for diabetic sarcopenia are lacking. While most modalities can evaluate muscle quality in research settings, only DXA currently offers routine clinical measures [11].

Recent studies highlight ultrasound as an affordable, practical option—particularly when assessing the gastrocnemius—using cross-sectional area (CSA), muscle thickness, and shear-wave elastography (SWE). These metrics correlate closely with DXA-derived ALMI and grip strength, achieving diagnostic accuracy comparable to DXA (AUC up to 0.80; sensitivity >80% in T2DM cohorts). Other muscle groups, such as the rectus femoris, vastus lateralis, and biceps brachii, also demonstrate echo-intensity correlations with both low strength and reduced mass. However, patient positioning and scan exposure may limit outpatient feasibility [5,15].

Bioelectrical impedance analysis (BIA) is widely accessible for estimating skeletal muscle mass. Using EWGSOP2 thresholds (<7.0 kg/m² in men, <5.5–5.7 kg/m² in women), BIA aligns with DXA definitions. However, hydration status, food intake, electrode placement, and manufacturer-specific algorithms introduce variability, leading to potential overestimation in overhydrated or obese individuals and underestimation in dehydration. When combined with functional tests and clinical judgment, BIA remains a practical tool for monitoring body composition changes [15].

Biochemical markers can enhance the diagnosis and risk assessment of sarcopenia development. Among the key risk factors, the combination of low BMI, reduced 25-hydroxyvitamin D, low insulin-like growth factor-1 (IGF-1), and diminished testosterone levels in men has been shown to predict sarcopenia with a combined area under the curve (AUC) of 0.848 (77.7% sensitivity, 80.2% specificity) [4].

Furthermore, in some studies, circulating irisin levels below 4.1 μg/L have been proposed as a cut-off point for requesting body composition assessment by DXA in obese T2DM patients with suspected sarcopenia [16].

One of the greatest challenges in routine clinical practice is the lack of functional assessment tools to guide diagnosis and management of diabetic sarcopenia. To address this, an integrated screening algorithm has been proposed that clinical risk factors, objective performance measures, and imaging or biochemical indicators. A key innovation of this algorithm is its staged classification of sarcopenic diabetes—stratifying patients by functional capacity, performance metrics, comorbidities, and complications—to tailor treatment intensity and schedule appropriate follow-up intervals [4].

These advancements equip clinicians with a clear framework for early intervention, enabling targeted strategies to preserve muscle mass, delay frailty onset, and ultimately improve long-term outcomes in T2DM.

The comprehensive

Table 1. Diagnostic Cutoffs for Sarcopenia in Type 2 Diabetes Mellitus.

Parameter	Men	Women	Method
Muscle Strength
Handgrip Strength	<27 kg	<16 kg	Dynamometry
Five-Time Chair Stand	>15 s	>15 s	Functional test
30-Second Chair Stand	<17 stands	<15 stands	Functional test
Anthropometric Measures
Calf Circumference [BMI-adjusted] *	<33 cm	<32 cm	Tape measure
Imaging-Based Assessment
DXA ALMI	<7.0 kg/m2	<5.5–5.7 kg/m2	Appendicular lean mass index
CT SMI [L3]	<52–55 cm2/m2	<39–41 cm2/m2	L3 skeletal muscle index
Body Composition Analysis
BIA SMI **	<7.0 kg/m2	<5.5–5.7 kg/m2	Skeletal muscle mass index

* Calf circumference cutoffs require BMI adjustment; specific BMI ranges may further modify thresholds [14,17,18]. ** BIA cutoffs align with EWGSOP2 values; T2DM-specific validation remains limited [5,14,19]. Abbreviations: DXA: Dual-Energy X-ray Absorptiometry; CT: Computed Tomography; BIA: Bioelectrical Impedance Analysis; ALMI: Appendicular Lean Mass Index; SMI: Skeletal Muscle Index; L3: Third lumbar vertebra.

, below summarizes evidence-based cut-off values for each assessment tool, harmonizing major international consensus criteria with diabetes-specific adjustments to support standardized clinical evaluation and research.

5. Systemic Impacts: Cardiovascular and Hepatic Links

Diabetic sarcopenia exerts effects well beyond muscle loss and impaired glycemic control, substantially contributing to systemic morbidity. Cardiovascular disease (CVD) remains a leading cause of death globally, sarcopenia in T2DM patients markedly amplifies this risk. Sarcopenia nearly doubles the overall CVD incidence (HR 1.89; 95% CI 1.61–2.21), increases heart failure risk by over 2.5-fold (HR 2.59; 95% CI 2.12–3.18), and almost doubles stroke risk (HR 1.90; 95% CI 1.38–2.63). Progression to sarcopenia further elevates cardiovascular event risk (HR 1.37; 95% CI 1.08–1.73), whereas restoration of muscle mass reduces CVD risk by 60% (HR 0.40; 95% CI 0.20–0.82) [20].

Physiologically, diminished muscle mass reduces insulin-sensitive tissue, exacerbating insulin resistance and systemic inflammation. This pro-inflammatory state impairs endothelial function and accelerates atherogenesis, thereby heightening CVD susceptibility [20].

Liver disease represents another critical comorbidity. Sarcopenia increases the odds of metabolic dysfunction-associated steatotic liver disease (MASLD) by over fivefold and doubles the likelihood of liver fibrosis (OR 2.05 for MASLD; OR 1.25; 95% CI 1.08–1.44 for fibrosis). In advanced stages, progression to metabolic dysfunction-associated steatohepatitis (MASH) reflects overlapping inflammatory and fibrogenic pathways. Elevated interleukin-6 (IL-6) in sarcopenia promotes hepatic lipogenesis and steatosis via mediators such as TNF-α, TGF-β, and IL-1. Patients with both MASLD and sarcopenia face higher odds of advanced fibrosis (OR 1.49; 95% CI 1.03–2.14), underscoring the systemic metabolic derangements linking these conditions [21].

These cross-organ sequelae position diabetic sarcopenia as a central driver of cardiometabolic complications in T2DM, mandating multidisciplinary management strategies that integrate endocrinology, hepatology, cardiology, nutrition, and physical therapy.

6. Therapeutic Strategies and Clinical Management

The management of diabetic sarcopenia demands a structured, multidisciplinary team approach that simultaneously addresses metabolic control and muscle preservation.

Lifestyle modification remains foundational. Although aerobic exercise has historically been emphasized, current evidence supports a combination of resistance and aerobic training to optimize both glycemic regulation and muscle anabolism. However, adherence challenges—reported at up to 50% dropout among older T2DM patients with sarcopenia due to comorbidities, physical limitations, and insufficient support—underscore the need for adaptable, patient-centered programs. Home-based resistance routines, chair-based strength exercises, and community-based group sessions can improve long-term engagement. Recently, the American Diabetes Association has incorporated muscle-strengthening recommendations into its physical activity guidelines, endorsing resistance training to mitigate sarcopenia risk and reduce cardiovascular events [22,23].

Nutrition is equally critical. Malnutrition affects over 30% of hospitalized T2DM patients, making dietary optimization imperative. A high-protein intake (1.2–1.5 g/kg/day) supports muscle protein synthesis, while correction of micronutrient deficiencies—particularly vitamin D (>30 ng/mL)—improves muscle function and reduces fall incidence. Among supplements, β-hydroxy-β-methylbutyrate (HMB) shows the strongest evidence for attenuating proteolysis and preserving lean mass in older adults [13,23].

While lifestyle interventions remain foundational, pharmacological therapies have increasingly been explored for their effects on muscle mass in obesity and diabetes. Among these, metformin may confer muscle-preserving benefits via enhanced mitochondrial function and insulin sensitivity, whereas sodium–glucose cotransporter-2 inhibitors (SGLT2i) exhibit mixed results: some data link SGLT2i to increased proteolysis, while other studies report neutral or beneficial lean-mass effects. On the other hand, GLP-1 receptor agonists (GLP-1RAs) and dual GLP-1/GIP agonists have attracted particular interest.

Liraglutide, a GLP-1RA, induces meaningful weight loss but its effects on muscle are mixed. In a randomized trial, 16 weeks of liraglutide 3 mg/day plus a hypocaloric, normoproteic diet and structured exercise achieved greater weight loss (−9.8% vs. −8.1%) and greater absolute fat-free mass (FFM) reduction compared with control [24]. However, when FFM loss was adjusted for total weight lost, no significant difference emerged between groups, and resistance training did not attenuate FFM loss. Thus, FFM reduction appeared proportional to overall weight loss, highlighting that neither GLP-1RA nor exercise alone reliably spares lean tissue without targeted nutritional support [24].

Semaglutide, a long-acting GLP-1RA, similarly induces meaningful weight loss while appearing to spare muscle mass relative to fat. In Chinese adults with obesity treated for 24 weeks, semaglutide achieved an 11.2% mean weight reduction (9.9 kg) with fat-mass loss of 5.6 kg compared to skeletal muscle loss of only 1.4 kg, preserving muscle strength and calf circumference. Once-weekly semaglutide in the STEP trials confirmed sustained weight loss of up to 15% over 68 weeks alongside minimal declines in lean mass, resulting in improved fat-to-lean ratios and functional measures [25].

Tirzepatide, a dual GLP-1/GIP agonist, has demonstrated robust body-weight reductions of up to 22–25% over 72 weeks in populations with obesity and type 2 diabetes, with corresponding decreases in fat mass and waist circumference. In pooled analyses from the SURPASS trials, tirzepatide led to a 33.9% mean reduction in total fat mass versus 8.2% with placebo, and a 10.9% reduction in fat-free mass versus 2.6% with placebo; however, the fat-to-lean mass ratio declined favorably, reflecting a predominant loss of adipose tissue relative to lean tissue. However, tirzepatide-associated lean-mass loss raises questions about sarcopenia risk. In a real-world case report, up to 15.5% skeletal muscle mass loss occurred over nine months of tirzepatide therapy, suggesting that as much as one-third of total weight lost can be lean tissue [26,27].

These findings underscore the need for serial body-composition monitoring and adjunctive strategies to preserve muscle, such as optimized protein intake and resistance exercise [27].

Finally, emerging myostatin inhibitors—most notably bimagrumab—have produced meaningful anabolic responses (around 15% muscle-mass gain in pre-clinical and early human trials), although confirmatory clinical trials are still pending [13].

An integrated and multidisciplinary care model that includes endocrinologists, geriatricians, physical therapists, and dietitians is essential to carry out a personalized approach, focused on patient care. Furthermore, validated staging systems—such as the proposed sarcopenia–diabetes algorithm that stratifies patients by functional capacity, comorbidity burden, and complication severity—offer practical guidance for tailoring intervention intensity and monitoring progress [2,4].

The following

Table 2. Staging system for diabetic sarcopenia [4].

Stage	Defining Features	Validated Assessment Tools
Stage I—Isolated Sarcopenia	Low strength and low muscle mass without additional diabetes complications.	Handgrip dynamometry; Five-time chair-stand; Calf circumference
Stage IIA—Metabolic Impact	Sarcopenia plus poor glycemic control (HbA1c ≥ 8%) or >5 years’ diabetes duration.	SARC-F; DXA-derived ALMI, CT, BIA.
Stage IIB—Functional Decline	Sarcopenia with measurable functional impairment without T2DM complications.	Short Physical Performance Battery; Timed-Up-and-Go, gait speed test.
Stage IIC—Complication Burden	Sarcopenia plus T2DM complications and functional impairment.	All of the above.

, synthesizes the proposed staging system and lists validated assessment tools to facilitate its practical implementation.

The staging matrix clarifies priorities: Stage I patients benefit from lifestyle counseling, Stage IIA emphasizes metabolic optimization (e.g., selecting muscle-sparing antihyperglycemics), Stage IIB adds structured resistance training and nutritional supplementation, and Stage IIC requires intensive rehabilitation plus close monitoring of comorbid complications.

By integrating targeted exercise, optimized nutrition, and strategic pharmacotherapy within a staged, multidisciplinary protocol, clinicians can break the vicious cycle of muscle loss and metabolic decline, thereby preserving independence and improving long-term outcomes in T2DM patients.

7. Discussion, Conclusions and Future Directions

Diabetic sarcopenia has emerged as a significant complication of type 2 diabetes mellitus (T2DM), deserving acknowledgment on par with established microvascular and macrovascular complications. Despite the marked impact on functional capacity, quality of life, and glycemic control, current guidelines for diabetes and sarcopenia omit this dual pathology from assessment and management frameworks.

This review advocates integrating muscle evaluation into routine T2DM care by adopting tools such as the SARC-F questionnaire and advanced imaging modalities to enable comprehensive morphofunctional assessment and early detection.

Given the progressive nature of diabetes-associated muscle loss, the American Diabetes Association should recommend annual sarcopenia screening—using SARC-F or equivalent instruments—for all patients over 60 years. Moreover, muscle health metrics must inform interpretation of glycemic targets (e.g., HbA1c, time in range), particularly in older adults where diminished muscle mass exacerbates insulin resistance and glycemic variability.

Routine inclusion of body composition analysis and muscle function testing represents a pivotal advance in patient-centered evaluation. Beyond quantifying lean mass, these assessments—by DXA, CT, or ultrasound—will permit future precision adjustments based on active body cell mass (BCM) or lean mass, optimizing therapeutic efficacy and minimizing adverse effects.

While DXA, CT, and ultrasound provide high diagnostic accuracy, bioelectrical impedance analysis (BIA) remains the most accessible, low-cost option for serial monitoring of at-risk individuals. Despite limitations such as inter-device variability and hydration sensitivity, BIA’s growing use of raw phase angle, Bioelectrical Impedance Vector Analysis (BIVA), and BCM metrics enhances its clinical utility.

The 2019 EWGSOP2 consensus marked a paradigm shift by formally incorporating muscle function—measured through handgrip dynamometry, the five-repetition chair-rise test, and gait speed—into sarcopenia diagnosis alongside traditional mass criteria. This novel emphasis unified definitions and provided validated bedside tools, enabling more accurate identification of functional impairment, guiding individualized rehabilitation strategies, and laying the groundwork for the multidisciplinary management essential to patients with coexisting T2DM and sarcopenia.

Embracing the term morphofunctional assessment—which integrates muscle function and body composition—creates a unified framework. To prioritize muscle preservation alongside optimal metabolic and glycemic control as core goals, clinical guidelines should evolve to include formal recommendations on sarcopenia screening, staging, and personalized interventions thereby enabling the multidisciplinary management vital for safeguarding muscle health in type 2 diabetes.

Future research should prioritize validating and harmonizing diagnostic protocols—establishing universal imaging cut-offs for ultrasound, BIA, MRI, and CT—and deepening our exploration of targeted therapies (e.g., WWP1 E3 ligase modulation, myostatin inhibition) to preserve muscle health [2,28]. Precision medicine approaches—leveraging emerging biomarkers (e.g., circulating myostatin, systemic inflammation index) and genetic markers such as PAM variants (Peptidylglycine-alpha-amidating Monooxygenase)—promise to refine risk stratification and tailor treatment selection, though we still have much to learn about their optimal integration into clinical practice [29].

Technological innovations, notably AI-driven predictive algorithms integrated with electronic health records, have demonstrated up to 85% accuracy in identifying high-risk sarcopenia cases [29]. Telemedicine platforms further extend multidisciplinary care to underserved and rural populations, enabling remote monitoring of muscle function and metabolic parameters for over 80% of T2DM patients, thus reducing health disparities and improving global outcomes [2].

Pharmacological treatment with incretin-based therapies—GLP-1/GIP agonist and GLP-1RAs—achieves substantial adipose-tissue reduction in obesity and type 2 diabetes, yet it is invariably accompanied by some lean-tissue loss. The balance between fat and muscle loss favors adiposity reduction, but the absolute decline in muscle mass warrants vigilance. Clinicians should incorporate regular body-composition assessments, prioritize high-protein diets, and prescribe resistance-training regimens to mitigate sarcopenia risk. Current evidence remains insufficient to determine whether these agents worsen or improve sarcopenic obesity in the long term. Well-designed trials comparing GLP-1/GIPa-GLP-1RAs, as well as combination lifestyle protocols, are urgently needed to establish evidence-based recommendations for preserving muscle mass and function during pharmacological weight-loss therapy.

In conclusion, shifting from isolated glycemic management to personalized, integrated metabolic-musculoskeletal care acknowledges T2DM’s complexity. Embedding diabetic sarcopenia assessment into routine practice is essential to preserve independence and enhance quality of life for millions worldwide.