EndocrinologyReview
Beyond glycemic thresholds: Redefining prediabetes screening for the south Asian phenotype
The global epicenter of Type 2 diabetes mellitus (T2DM) has shifted decisively to South Asia, where countries such as Nepal are witnessing an unprecedented surge in metabolic disorders. Evidence demonstrates that timely intervention during the prediabetic phase remains the most effective strategy for reversing insulin resistance. Yet, prevailing screening and diagnostic frameworks are fundamentally inadequate. International guidelines – most notably those of the American Diabetes Association (ADA) – continue to rely on rigid, universal biochemical thresholds, namely fasting plasma glucose (FPG) levels of 100–125 mg/dL and glycated hemoglobin (HbA1c) values of 5.7–6.4%; 2h Plasma Glucose Oral Glucose Tolerance Test (OGTT): 140–199 mg/dL These standardized cutoffs, however, fail to capture the unique metabolic phenotype of South Asian populations, thereby perpetuating underdiagnosis and delayed intervention. Unfortunately, this uniform methodology overlooks the intricate pathophysiology inherent to the South Asian phenotype. In our region, advanced metabolic failure occurs long before blood glucose levels surpass traditional screening markers. To curb this looming crisis, South Asian clinicians and policymakers must dismantle Western-centric screening thresholds and deploy risk-stratified, population-specific frameworks. THE SOUTH ASIAN PARADOX: “THIN-FAT” AND ECTOPIC ADIPOSITY The principal systemic failure of current prediabetes screening in South Asia is its rigid dependence on conventional body mass index (BMI) thresholds as the trigger for diagnostic evaluation. Western frameworks typically recommend screening asymptomatic individuals only when BMI exceeds 25 kg/m2. This approach, however, overlooks a defining paradox of the South Asian metabolic profile – the so called “thin fat” phenotype. Individuals in this population often present with relatively low skeletal muscle mass yet disproportionately high visceral, abdominal, and ectopic adiposity, even at BMI levels conventionally considered normal. Such discordance 1between BMI and true metabolic risk undermines early detection and perpetuates delayed intervention in a region already burdened by escalating rates of T2DM. This phenotype triggers an aggressive, rapid pathogenetic cascade: • Nutrient overflow: Visceral fat stores saturate superficial subcutaneous tissues prematurely, causing excess lipids to overflow as ectopic fat directly into the liver and pancreas. • Hepatic insulin resistance: The accumulation of fat in the liver compromises hepatic insulin clearance, generating profound systemic hyperinsulinemia long before peripheral glucose rises. • Accelerated β-cell burnout: Unlike Western cohorts, who often tolerate decades of insulin resistance, South Asian pancreatic β-cells experience an early, rapid decline in secretory capacity and insulin reserve. Consequently, a patient with a “normal” BMI of 21 or 22 kg/m2 may already suffer from advanced tissue-level insulin resistance and silent metabolic dysfunction. Waiting for an FPG of 100 mg/dL to signify prediabetes means entering the therapeutic window far too late, when significant functional pancreatic β-cell mass has already been permanently exhausted. [Standard Western Protocol] ──► Waits for BMI ≥25 kg/m2 ──► Misses Ectopic Fat ──► Late Diagnosis [Proposed Regional Protocol] ──► Triggers at BMI ≥23 kg/m2 ──► Tracks Visceral Fat ──► Early Interception GROUNDING THE CRISIS: THE EPIDEMIOLOGICAL REALITY IN NEPAL The urgency of revising current screening guidelines is underscored by recent epidemiological evidence from Nepal. Meta analyses indicate that the national prevalence of prediabetes has risen to 9.2%, closely paralleling a T2DM prevalence of 8.5%. Importantly, this metabolic burden is not evenly distributed. Disaggregated provincial data reveal striking disparities, with diabetes prevalence in Bagmati Province (Province 3) and Gandaki Province (Province 4) reported to be nearly fivefold higher than in less urbanized regions such as Karnali. These regional gradients highlight the interplay between urbanization, lifestyle transitions, and genetic susceptibility, and they expose the inadequacy of uniform, population agnostic screening thresholds in capturing the true risk landscape of South Asia. LIMITATIONS OF STANDALONE HBA1C AND FPG SCREENING Relying entirely on HbA1c or FPG as standalone screening tools further compromises diagnostic sensitivity in South Asian primary care settings. Hemoglobinopathies and anemia The high regional prevalence of nutritional iron-deficiency anemias and inherited hemoglobin variants across Nepal frequently distorts glycation rates, rendering standard HbA1c readings artificially skewed and highly unreliable for subtle prediabetes detection. Impaired fasting glucose (IFG) versus impaired glucose tolerance (IGT) South Asians exhibit a distinct metabolic pattern where IGT and postprandial glucose spikes occur far more frequently and aggressively than isolated IFG. Because standard primary care testing rarely includes the cumbersome OGTT, a vast subpopulation of patients with normal fasting glucose but dangerous postprandial glucose excursions goes entirely undetected. Furthermore, emerging clinical insights show that prediabetes is not a uniform status but rather a constellation of distinct metabolic subtypes – ranging from isolated muscle insulin resistance to progressive fatty liver-induced dysmetabolism. Standard glycemic metrics fail to differentiate these high-risk subtypes from benign, slow progressing hyperglycemia. A call for action: Calibrating regional guidelines To address these diagnostic shortfalls, healthcare systems across Nepal and South Asia must pioneer adapted, multitiered prediabetes screening guidelines: • Lowering physical screening thresholds: Regional guidelines must mandate a lower screening BMI trigger of ≥23 kg/m2 for South Asians, coupled with mandatory waist-to-height ratio evaluations to track visceral fat deposition. • Integrating secondary biomarkers: Screening protocols should incorporate affordable, non-glycemic biomarkers. Elevated triglyceride-to-high-density lipoprotein cholesterol ratios and low-cost noninvasive liver scores, such as the Fibrosis-4 index, can flag early metabolic dysfunction and hepatic steatosis well before blood glucose rises. • Culturally adapted preventive nutrition: Interventions must shift toward region-specific dietary restructuring. Data from South Asian cohorts suggest that preventing prediabetes progression requires reducing refined carbohydrate intake (such as polished white rice and maida) to 50–56% of daily energy and elevating high quality protein intake to 18–20%. This represents a crucial departure from standard Western low-fat models. CONCLUSION Continuing to screen for prediabetes through a Western lens places a massive, preventable burden on South Asian clinical infrastructure. By the time a patient crosses standard glycemic thresholds, substantial and often irreversible pancreatic damage has occurred. It is time for regional bodies to reform these guidelines by integrating lower BMI triggers, visceral fat tracking, and lipid biomarkers into routine primary care. Only by catching metabolic failure at its physiological roots can we stop the progression of diabetes across South Asia.
Asian Journal of Medical Sciences5 min1 Sept 2026
