Specific Aim 2

Specific Aim 2

Investigate molecular mechanisms of T2D in normal-weight Asian individuals, focusing on genetic, metabolic, and molecular pathways.

Specific Aim 2 – Year 2 Highlights

  • Expanded normal-weight diabetes research through iPSC models, beta-cell biology, metabolic phenotyping, and integrated multi-omic analyses.
  • Advanced pathway analysis by integrating genetic, proteomic, metabolomic, RNA, miRNA, and clinical data to better define biological mechanisms underlying diabetes risk in Asian populations.
  • Generated and prioritized testable hypotheses for normal-weight diabetes through AI-assisted literature synthesis, multi-omic integration, and cross-cohort collaboration.

Investigating microvascular function in normal-weight Asian T2D utilizing patient iPSCs

Lead Postdoctoral Researcher: Debarun Patra, PhD

Year 2 Highlights: This project advanced patient-derived iPSC models to investigate molecular mechanisms of T2D in normal-weight Asian individuals. The experimental plan includes differentiating iPSCs into microvascular cell types (endothelial cell, pericyte) and exposing them to metabolic stress conditions to assess basal and stress-induced responses. Proteo-transcriptomic analyses identified FABP4 as a candidate biomarker associated with endothelial dysfunction in lean East Asian T2D, and collaboration efforts were initiated to validate FABP4 and additional candidate biomarkers in STRONG-D plasma samples and Tirzepatide-treated participants. A related JCI review manuscript is also in revision.

Looking Ahead: Next steps include continuing metabolic stress experiments, impedance assay, genetic manipulation of target gene(s), scRNA-seq, Tirzepatide multi-omic analyses, biomarker validation, and revision of the JCI review manuscript.

Metabolic Profile of Normal Weight Diabetes (NWD) in Asians

Principal Investigator: Tracey McLaughlin, MD, MS

Year 2 Highlights: This project continued deep metabolic phenotyping and regional fat imaging to better understand the underlying causes of normal-weight diabetes. The team continued enriching the cohort with Asian participants and identifying opportunities for collaboration across ADVANCE, including studies of antibodies, metabolomics, transcriptomics, beta-cell function, and glucose responses. The project is designed to compare Asian and non-Asian individuals, as well as East and South Asian subgroups, to better understand metabolic subphenotypes and potential treatment responses.

Looking Ahead: The team will continue recruitment and analysis, further evaluate mechanisms of beta-cell decline, and identify molecular collaborations that can connect deep phenotyping with ADVANCE multi-omics and pathway studies.

Beta-cell dysfunction disproportionately affects Asian populations and drives susceptibility to T2D

Principal Investigator and Collaborators: Joshua Knowles, MD, PhD; Themistocles (Tim) Assimes, MD, PhD, MS; Justin Annes, MD, PhD

Year 2 Highlights: Advancement of work focused on beta-cell dysfunction as a key mechanism contributing to T2D susceptibility in Asian populations. The ADVANCE Specialized Seed Grant on proteomic signatures of beta-cell dysfunction in East and South Asians was highlighted, and related scientific outputs are being tracked through abstracts and publications. This project contributes to the broader Aim 2 strategy by linking beta-cell biology, proteomics, insulin secretion, and ancestry-informed diabetes risk.

Looking Ahead: Next steps include expanding the efforts to improve statistical power, tracking seed grant outputs, connecting findings with Aim 2 pathway and proteomics analyses, and supporting future manuscripts and presentations on beta-cell dysfunction in Asian populations.

Morphological measures of beta-cell function in individuals of Asian descent – demographic characterization of targeted samples

Principal Investigator: Justin Annes, MD, PhD

Year 2 Highlights: This project continued work examining beta-cell morphology and function to better understand mechanisms that may contribute to diabetes risk in Asian populations. Activities focused on characterizing targeted samples and studying morphological measures that may reveal differences in beta-cell architecture, function, adaptive hyperplasia, and diabetes susceptibility. These studies complement other Aim 2 efforts by adding an anatomic and cellular perspective to the molecular and metabolic research portfolio

Looking Ahead: The team will continue beta-cell analyses and evaluate relationships between beta-cell morphology, function, adaptive hyperplasia, and diabetes risk in individuals of Asian descent.

Pathway Analysis Subgroup

Principal Investigator and Collaborators: Latha Palaniappan, MD, MS; Daniel Panyard, PhD; Ruoqi Liu, PhD; Tania Chen, MPH, M.B.B.S; Aayan Patel, MS; Saif Ali, MD; Debarun Patra, PhD

Year 2 Highlights: The Pathway Analysis Subgroup became a major Year 2 driver of ADVANCE’s scientific strategy. Starting with recent genetic evidence from partitioned polygenic risk scores (pPRS) studies across different populations, the group integrated T2D genetic clusters with genetic, proteomic, and miRNA associations. These cross-study and cross-omic connections were analyzed using a combination of AI-powered literature synthesis with expert validation and interpretation. This work also expanded integration of clinical, RNA, protein, and metabolite data to better define the molecular profile of normal-weight diabetes in Asian populations. The subgroup also focused on several specific hypotheses for normal-weight diabetes in Asians, prioritizing lipodystrophy, fat distribution, brown versus white adipose biology, visceral adiposity, and liver fat/MASLD. Finally, as the subgroup developed testable hypotheses for biobank-based analyses, the subgroup began building collaborations with leading multiomic population studies of diabetes in Asian populations to partner with for later replication studies.

Looking Ahead: While the subgroup continues the above efforts to synthesize existing evidence across populations and omic data types, the subgroup is now starting to pivot to conduct novel analyses to answer the hypotheses developed from the literature synthesis. Early efforts are now underway to identify the mechanism and location of action of implicated miRNA in normal-weight diabetes; to conduct genetic analyses to explore diabetes risk loci in Asian populations; to identify genetic cross-talk between diabetes and Asian-population-relevant phenotypes (e.g., lipodystrophy, beta cell dysfunction); and to identify a molecular signature of normal-weight diabetes. Future studies will also evaluate metabolite and protein associations in Asians compared with non-Asians and assess whether multi-omic approaches can improve diabetes diagnosis and phenotyping. The subgroup will prioritize Stanford/KPRB/public repository discovery analyses with targeted replication in UCLA ATLAS, UK Biobank, Singapore’s SG100K, and other cohorts as feasible.