NCT06354088

Human Models of Selective Insulin Resistance: Alpelisib, Part I

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 32 (estimated)
• Sponsor: Columbia University · Academic / Other
• Sex: All
• Age: 18 Years – 70 Years
• Healthy volunteers: Accepted

Summary

The goal of this clinical trial is to understand how the blood sugar-lowering hormone insulin works in healthy adults versus those who are at risk for type 2 diabetes. The study will use a drug called alpelisib, which interferes with insulin's actions in the body, to answer the study's main question: does the liver continue to respond to insulin's stimulation of fat production even when it loses the ability to stop making glucose (sugar) in response to insulin. Researchers will compare the impact of single doses of both alpelisib and placebo (inert non-drug) in random order (like flipping a coin) in study participants. Participants will be asked to stay twice overnight in the hospital, take single doses of alpelisib and placebo (one or the other on each of the two hospital stays), and receive intravenous (into the vein) infusions of non-radioactive "tracer" molecules that allow researchers to measure the production of glucose (sugar) and fats by the liver. Measurements will be done both overnight, while participants are asleep and fasting (not eating or drinking other than water) and while consuming a standardized diet of nutritional beverages during the following day. The objective is to evaluate the effect of lowering insulin levels, while maintaining constant mild hyperglycemia, on plasma glucose and lipid levels.

Detailed 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.

Conditions

• Insulin Resistance
• Prediabetic State
• Overweight and Obesity
• Non-Alcoholic Fatty Liver Disease

Interventions

Type	Name	Description
DRUG	Alpelisib 300 mg	All participants will ingest one dose of alpelisib 300 mg (2 x 150-mg overencapsulated tablets) on one of two study admissions.
DRUG	Placebo	All participants will ingest one dose of placebo (2 overencapuslated doses of microcrystalline cellulose) on one of two study admissions.
DRUG	[1-13C] sodium acetate	All participants will receive continuous infusions of \[1-13C\] sodium acetate for up to 23 hours on both study visits in order to quantify de novo lipogenesis (DNL). (non-experimental)
DRUG	[6,6-2H2] D-glucose	All participants will receive continuous infusions of \[6,6-2H2\] D-glucose for up to 15 hours on both study visits in order to quantify de novo lipogenesis (DNL). (non-experimental)
DIETARY_SUPPLEMENT	Nestlé BOOST Plus	All participants will ingest standardized mixed meals of Nestlé BOOST Plus on Study Day 1 and then smaller portions hourly x 8 hours on Study Day 2 of each study visit. (non-experimental)

Timeline

• Start date: 2024-04-24
• Primary completion: 2026-12-31
• Completion: 2026-12-31
• First posted: 2024-04-09
• Last updated: 2026-04-09

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study