Type 2 diabetes mellitus (T2DM) represents one of the most significant global health burdens, with prevalence rising disproportionately in South Asian populations. While clinical diagnosis relies upon hyperglycaemia, pathophysiological disruption begins years before glucose thresholds are exceeded. Visceral adipose tissue (VAT) dysfunction, manifesting as adipokine dysregulation, increased free fatty acid flux, and systemic inflammation, is increasingly recognised as a primary upstream driver of insulin resistance and cardiometabolic deterioration.

Cardiopulmonary fitness (CPF), most precisely quantified as maximal oxygen uptake (VO₂max), is an established biomarker of integrative physiological reserve. Low CPF predicts incident T2DM, cardiovascular disease, and all-cause mortality independently of conventional risk factors. Despite this, the mechanistic relationship between visceral adiposity and CPF in normoglycaemic adults at hereditary risk remains incompletely characterised.

Individuals with first-degree relatives diagnosed with T2DM exhibit altered adipocyte biology, impaired mitochondrial oxidative capacity, and heightened inflammatory tone even before glycaemic dysregulation becomes detectable. The Visceral Adiposity Index (VAI)—a surrogate marker incorporating waist circumference, BMI, triglycerides, and HDL—has demonstrated superior sensitivity in capturing metabolically active visceral fat compared with anthropometric measures alone.

The present study was designed to evaluate visceral adiposity, CPF, and their interrelationship in normoglycaemic adults stratified by family history of T2DM, with the aim of identifying structural determinants of reduced aerobic capacity preceding overt metabolic disease.

2.1 Study Design and Setting A cross-sectional comparative analytical study was conducted in the Department of Physiology in collaboration with Biochemistry and Community Medicine. Participants were recruited from outpatient departments, institutional health screening camps, and community health programs. All biochemical analyses were performed in a NABL-accredited central laboratory. 2.2 Participants Two hundred and forty normoglycaemic adults aged 18–60 years were enrolled: Group I (FH+, n = 120): at least one first-degree relative with diagnosed T2DM; Group II (FH–, n = 120): no family history. Normoglycaemia was defined per ADA criteria (fasting plasma glucose < 100 mg/dL). Inclusion required BMI 18.5–29.9 kg/m² and willingness to provide written informed consent. Exclusion criteria included known diabetes or impaired fasting glucose, cardiovascular or pulmonary disease, autoimmune or inflammatory conditions, renal or hepatic disease, current smoking, alcohol dependence, pregnancy, and regular competitive athletic training. 2.3 Visceral Adiposity Assessment Waist circumference was measured at the midpoint between the lower costal margin and iliac crest. Hip circumference was measured at the greatest gluteal prominence. WHR was calculated as waist/hip. BMI was computed as weight (kg)/height² (m²). VAI was calculated using validated sex-specific formulae incorporating waist circumference, BMI, triglycerides, and HDL cholesterol, providing a composite index of visceral fat dysfunction. 2.4 Cardiopulmonary Fitness Assessment CPF was assessed using the standardised Bruce graded treadmill protocol. Pre-test preparation included abstention from vigorous exercise (24 h), caffeine (12 h), and heavy meals (3 h). Resting ECG and blood pressure were obtained before testing. VO₂max was estimated from exercise duration using validated Bruce protocol prediction equations. METs achieved and total exercise duration were recorded as secondary fitness indices. 2.5 Statistical Analysis Data are presented as mean ± SD. Between-group comparisons were performed using independent t-tests following Shapiro–Wilk normality assessment. Pearson correlation quantified the VAI–VO₂max relationship. Multiple linear regression identified independent predictors of VO₂max. Statistical significance was defined as p < 0.05 (SPSS version XX).

3.1 Demographic and Anthropometric Characteristics

Groups were comparable in age (38.4 ± 9.2 vs 37.8 ± 8.7 years; p = 0.62) and sex distribution (p = 0.71), ensuring valid between-group comparisons. Despite similar BMI ranges, the FH+ group demonstrated markedly higher central adiposity, as shown in Table 1.

Table 1. Anthropometric and Visceral Adiposity Parameters

* Statistically significant (p < 0.05). FH+ = positive family history; FH– = no family history; VAI = Visceral Adiposity Index.

3.2 Cardiopulmonary Fitness Parameters

Cardiopulmonary fitness was significantly impaired in FH+ individuals across all exercise performance metrics. Table 2 presents comparative fitness data.

Table 2. Cardiopulmonary Fitness Parameters

* Statistically significant (p < 0.05). METs = metabolic equivalents.

3.3 VAI–VO₂max Correlation and Regression Analysis

A strong negative correlation was observed between VAI and VO₂max (r = −0.61; p < 0.001), indicating that higher visceral adiposity was associated with markedly reduced aerobic capacity. Multiple linear regression (Table 3) identified VAI as the strongest independent predictor of VO₂max, with inflammatory and oxidative markers contributing additional independent variance.

Table 3. Multiple Linear Regression – Independent Predictors of VO₂max

Model R² = 0.52. * Statistically significant (p < 0.05). hs-CRP = high-sensitivity C-reactive protein; MDA = malondialdehyde.

The principal finding of this study is that normoglycaemic adults with familial T2DM risk exhibit significantly higher visceral adiposity and substantially reduced cardiopulmonary fitness compared with individuals without hereditary risk, despite comparable fasting glucose levels. The VAI–VO₂max correlation of r = −0.61 represents one of the stronger adiposity–fitness associations reported in normoglycaemic cohorts, underscoring the functional consequences of central fat accumulation preceding metabolic disease.

The higher VAI observed in FH+ individuals despite similar total BMI reflects the tendency for preferential visceral fat deposition in genetically susceptible individuals—a pattern consistent with evidence demonstrating altered adipocyte biology in offspring of T2DM patients. Genetic variants influencing adipocyte differentiation, lipid partitioning, and insulin signaling may predispose to visceral rather than subcutaneous fat accumulation. This distribution is metabolically critical, as visceral adipocytes exhibit heightened lipolytic activity, releasing excess free fatty acids into the portal circulation to promote hepatic insulin resistance.

Reduced VO₂max in FH+ individuals likely reflects multiple overlapping mechanisms. Elevated intramyocellular lipid deposition, facilitated by increased fatty acid flux, activates protein kinase C and impairs insulin-mediated glucose uptake in skeletal muscle. Mitochondrial oxidative phosphorylation efficiency is reduced—evidenced by diminished PGC-1α expression in

familial risk populations—compromising aerobic ATP production. Concurrently, endothelial dysfunction driven by inflammatory cytokines and reduced nitric oxide bioavailability impairs exercise-induced vasodilation, limiting oxygen delivery to working muscle.

The regression model accounted for 52% of VO₂max variance, with VAI contributing the largest independent effect (β = −0.48). The additional independent contributions of hs-CRP (β = −0.29) and MDA (β = −0.21) confirm that inflammation and oxidative stress are not merely epiphenomena of adiposity but are mechanistically implicated in reducing aerobic capacity. This points toward an adiposity–inflammation–fitness axis in which structural fat distribution initiates inflammatory and oxidative cascades that converge on mitochondrial and vascular dysfunction to impair exercise capacity.

From a clinical perspective, these findings challenge glucose-centric screening paradigms. Fasting plasma glucose was not significantly different between groups, yet CPF was substantially impaired in FH+ individuals. This dissociation highlights the diagnostic blind spot created by sole reliance on glycaemic indices. VAI and waist circumference—low-cost, reproducible, and feasible in primary care settings—may serve as first-line screening tools to identify normoglycaemic individuals at high cardiometabolic risk, warranting earlier preventive intervention.

Visceral adiposity, quantified by the Visceral Adiposity Index, is the strongest independent predictor of reduced cardiopulmonary fitness in normoglycaemic adults with familial T2DM risk. Significant reductions in VO₂max, exercise duration, and METs—alongside elevated central adiposity indices—occur despite normoglycaemia, demonstrating that cardiometabolic dysfunction precedes detectable hyperglycaemia. These findings support incorporating anthropometric indices of visceral adiposity and functional fitness assessment into early cardiometabolic risk stratification protocols, particularly for individuals with hereditary diabetes risk. Exercise-based preventive interventions targeting visceral fat reduction may improve both CPF and downstream metabolic outcomes in this high-risk normoglycaemic population. CONFLICTS OF INTEREST The authors declare no conflicts of interest. FUNDING This research received no specific external funding.

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