Human Models of Selective Insulin Resistance - PROJECT SUMMARY/ABSTRACT The twin metabolic pandemics of type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver dis- ease (MASLD) both appear to be rooted in hepatic insulin resistance (IR) and are characterized, respectively, by unchecked hepatic glucose production (HGP) and de novo lipogenesis (DNL) of triglycerides (TG). However, the pathophysiology of this high glucose + high TG phenotype remains unclear, as pure loss of function of the insu- lin receptor decreases, rather than increases, DNL. Thus, the common (multifactorial) IR associated with MASLD appears to be selective. We hypothesize that the insulin-signaling threshold for stimulating DNL is lower than for inhibiting HGP, and so the compensatory hyperinsulinemia needed to maintain euglycemia also, counter- productively, promotes excessive DNL. This concept remains controversial, but understanding insulin’s role in the dual pathology of T2D and MASLD is essential to treating – or potentially even preventing – them both. In this proposal, the PI (Dr. Joshua Cook) plans to prove the existence of selective IR in humans by taking two independent approaches (Specific Aims 1 and 2) to demonstrate that high levels of insulin continue to drive DNL even when the liver is resistant to insulin’s glucose-lowering effects. Both Specific Aims will be carried out in patients with MASLD and IR (prediabetic state + fasting hyperinsulinemia) in a randomized, placebo-con- trolled, crossover design. In Specific Aim 1, subjects will receive a two-week course of the insulin anti-secreta- gogue diazoxide (2 mg/kg per dose) versus placebo to directly lower insulin levels. In Specific Aim 2, hyperinsu- linemic signaling will be blockaded by a single dose of the phosphoinositide-3-kinase inhibitor alpelisib (300 mg) versus placebo. In both cases, the PI will use stable isotope tracers to measure several aspects of hepatic TG metabolism, including the primary endpoint of overnight (fasting) DNL, measured as incorporation of 13C-la- beled sodium acetate into very low-density lipoprotein (VLDL) TG. The lipid-kinetic findings will be contextu- alized by quantifying the degree of systemic IR resulting from the study treatments via the insulin suppression test. Proving that hyperinsulinemia continues to drive DNL during IR would support future clinical trials of “hyperinsulinemia reduction” as a novel therapeutic strategy for MASLD. The proposed Specific Aims will be achieved under the guidance of an Advisory Commi^ee led by Drs. Henry Ginsberg (Primary Mentor) and Blandine Laferrère (Co-Mentor), along with three Advisors possessing expertise to germane to each of three Career Development Aims: Drs. Julia Wa^acheril (patient-oriented re- search), Rebecca Haeusler (lipid kinetics), and Jaime Rubin (academic career skills). Columbia University is the ideal institution for the PI’s research training, boasting world-class resources such as the Irving Institute for Clinical and Translational Research, the Naomi Berrie Diabetes Center, and the Mailman School of Public Health. This structured career development plan will enable Dr. Cook to become a R01-funded clinical investigator.
