ORF42-04 - Sex-Specific Immune-Metabolic Subtypes of Type 2 Diabetes

Background: Existing data-driven subtyping frameworks for type 2 diabetes (T2D) emphasize glycemic indices, insulin resistance (IR), beta-cell function, and BMI, yielding largely phenotypic classifications. We evaluated whether using waist circumference (WC) and mechanistic inflammatory & oxidative stress markers yielded similar or new T2D clusters.

Methods: Adults with T2D not on insulin and without overt liver disease (AST & ALT < 500 IU/L, bilirubin < 1.2mg/dl) were identified from the 2015-2023 National Health and Nutrition Examination Surveys. Clustering variables included age at diagnosis, HbA1c%, WC, homoeostatic model assessment (HOMA)-2 estimates of beta-cell function (HOMA2B) and IR per fasting insulin, triglyceride-to-HDL ratio (THR; proxy for hepatic IR), C-reactive protein (CRP, inflammation), neutrophil-to-lymphocyte ratio (NLR, inflammation), & total bilirubin (endogenous antioxidant). Sex-stratified Gaussian mixture models with 5 clusters (optimal per silhouette width) were fit across 1,000 iterations, accounting for survey design, to obtain robust, national estimates.

Results: Among 709 men (mean age 59.7y, 61% non-Hispanic White [NHW], mean HOMA2B 67%, mean HOMA2-IR 2.5, mean A1c 7.1%), five T2D subtypes were identified. A later-onset subtype (25%) demonstrated low IR (HOMA2-IR mean [SD]: 1.16 [0.49]) and low inflammation (CRP: 1.1 [0.7] mg/L). A metabolically moderate, mild-inflammation subtype with preserved B-cell function and low IR comprised 15%. Two IR phenotypes emerged: 1) a traditional IR subtype (28%) with high WC (117 [14] cm), elevated THR, low inflammation; and 2) a distinct immune-activated, hyperinsulinemic (HOMA2-B: 128% [78]) IR subtype (13%) characterized by the highest IR (HOMA2-IR: 5.9 [3]), marked inflammation (CRP: 11.2 [10]), and high WC (125 [19] cm). An insulin-deficient subtype (20%) showed the highest HbA1c (9.2 [1.8] %) and lowest HOMA2B (24 [13]%). Among 631 women (mean age 59.4y, 53% NHW, mean HOMA2B 73%, mean HOMA2-IR 2.4, mean A1c 6.9%), there was no immune-dominant decoupling. Clusters included 1) an inflammatory, adiposity-related IR subtype (11%) with elevations in IR (HOMA2-IR: 4.6 [3.5], THR: 5.4 [5.0]) and inflammation (CRP: 21 [14] mg/L, NLR: 2.8 [1.4]); 2) a milder inflammatory, adiposity-related IR subtype (31%); 3) a metabolically moderate subtype without inflammation (20%); 4) an insulin-deficient subtype (5%) with reduced HOMA2-B (15 [10]%) and poor glycemic control; and 5) a mixed metabolic-inflammatory cluster reflected overlapping phenotypes. Bilirubin played no role in differentiating clusters.

Conclusion: Adding inflammatory markers revealed a new inflammation-dominant IR phenotype in men, while in women inflammation tracked with adiposity-related IR. Longitudinal studies are needed to improve classification schema and assess long-term outcomes of distinct IR phenotypes.