Heterogeneity of Insulin Resistance Surrogates in Thousands of Non-Diabetic Adults: Multi-Modal Data Reveals Discordant Metabolic Phenotypes

The transition from metabolic health to type 2 diabetes unfolds through progressive insulin resistance (IR), yet the gold-standard hyperinsulinemic-euglycemic clamp is inapplicable at population scale and fasting insulin is not uniformly available. Several surrogate measures have been described in the literature, but whether these surrogates identify the same individuals, and whether continuous glucose monitoring (CGM) or NMR metabolomics carry information beyond conventional markers, remains unresolved. Here, we analyzed IR surrogates in 10,114 non-diabetic adults (35-75 y) from the Human Phenotype Project (HPP), integrated with 14-day CGM, dual x-ray absorptiometry (DEXA) body composition, liver and carotid ultrasound, sleep monitoring, and NMR metabolomics and established sex-specific, age-resolved reference ranges. IR surrogates were moderately inter-correlated but captured distinct metabolic facets. We next focused on DEXA-derived visceral adipose tissue (VAT), one of the strongest correlates of clamp-measured insulin resistance. Our analysis showed that VAT can be reliably predicted from anthropometric measurements alone (R{superscript 2} = 0.659). However, it is only modestly predicted by CGM features alone (R2 = 0.078). Among CGM-derived features, markers of glycemic variability were stronger predictors of VAT than conventional mean-glucose metrics. Residual-based analyses identified individuals whose visceral adiposity was substantially higher than expected given their BMI or HbA1c levels. Notably, 1.2% of adults in the HPP cohort exhibited elevated visceral adiposity despite having both a normal BMI (< 25 kg/m{superscript 2}) and normoglycemic HbA1c (< 5.7%). These discordant subpopulations harbored adverse profiles across lipid, hepatic, vascular, sleep, and metabolomic domains. NMR lipoprotein subfractions (VLDL, HDL) discriminated discordant phenotypes. A CGM variability-only model separated discordant individuals at AUC = 0.63, with negligible gain from adding mean glucose. Findings were validated in an independent cohort with available fasting insulin data. Together, these results establish normative IR surrogate reference ranges, quantify the fraction of metabolically at-risk individuals missed by conventional BMI and HbA1c screening, and highlight CGM variability metrics and NMR lipoprotein profiling as complementary tools for early metabolic risk stratification. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/26352290v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1f491a6org.highwire.dtl.DTLVardef@18660a9org.highwire.dtl.DTLVardef@133fa14org.highwire.dtl.DTLVardef@1675463_HPS_FORMAT_FIGEXP M_FIG C_FIG