Human Models of Selective Insulin Resistance: Alpelisib, Part I

Description

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an under-appreciated complication of lipid dysmetabolism in type 2 diabetes (T2DM). Although it appears that insulin resistance (IR) is a mechanism common to both, the mechanisms linking IR to unhealthy fat accumulation in liver remains unclear. “Pure” IR would be expected to disinhibit hepatic glucose production while dampening hepatic triglyceride (TG) biosynthesis, but the excessive hepatic de novo lipogenesis (DNL) of IR-associated MASLD suggests that hepatic IR is “selective.” However, the concept of IR selectivity is controversial, and because of clinical heterogeneity, lead-time discrepancies, co-morbidities, and medication effects, parsing out this pathophysiologic conundrum in humans is challenging. The investigators plan to test whether the multifactorial IR in patients at risk of T2DM/MASLD is selective by determining if inducing a discrete, “pure” form of IR, via pharmacologic inhibition of phosphoinositide-3-kinase (PI3K) with alpelisib, versus placebo, attenuates excessive DNL. Investigators will also study this question in healthy, insulin-sensitive (IS) volunteers.

Participants in this randomized crossover trial will be admitted twice to the inpatient clinical research unit. During each admission, they will take a dose of either alpelisib or placebo (in randomized order) in the evening and receive infusions of [13C] sodium acetate and [2H] D-glucose to measure DNL and endogenous glucose production (EGP), respectively, during an overnight fast. DNL measurement will then continue during the following day during 8 hours of standardized mixed-meal feedings. Blood will be drawn at defined intervals for determining levels of glucose, insulin, lipids including triglycerides and free fatty acids, and tracer/tracee enrichments for the stable-isotope tracers. There will be a 2-8-week hiatus for drug washout between the two inpatient study admissions.