Bile Acids in Acute Insulin Resistance

Sponsor

Columbia University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05571670

Collaborator

(none)

Enrollment

Location

42.3

Anticipated Duration (Months)

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective observational study with a primary goal of monitoring changes in circulating bile acid profiles and parameters of glucose and lipid metabolism prior, during, and after cancer treatment with agents that directly impair insulin action: PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. Patients will not receive any cancer treatment specifically for the purposes of this study. Rather, this study will be based on treatment decisions made independently by participants' oncologists according to standard of care or other clinical trial protocol. This study seeks to enroll at least 25 participants each for PI3K inhibitors, mTOR inhibitors and, once available for open-label treatment, AKT inhibitors.

Condition or Disease	Intervention/Treatment	Phase
PI3K Gene Mutation AKT Gene Mutation MTOR Gene Mutation Cancer Insulin Resistance	Drug: Drug-induced acute insulin resistance due to PI3K inhibitor, AKT inhibitor, or mTOR inhibitor

Detailed Description

The primary objective of this study is to determine the effect of drug-induced acute insulin resistance (diaIR) on the ratio of 12α-hydroxylated bile acids (12-HBA) to 12α-hydroxylated bile acids (non-12-HBA) in cancer patients treated with phosphatidylinositol-4,5-bisphosphate kinase (PI3K) inhibitors (PI3Ki), mammalian target of rapamycin (mTOR) inhibitors (mTORi), and AKT inhibitors (AKTi) once possible. Specifically, this study will: (1) verify the induction of diaIR by monitoring changes in fasting ± postprandial blood glucose, insulin/c-peptide, and fructosamine; and (2) assess qualitative and quantitative changes in the circulating bile acid (BA) pool (including bile acid intermediary metabolites) by mass spectrometry in the fasting ± postprandial states prior to and then at 2 and 4 weeks after starting treatment. This study focuses in particular on determining changes in the 12α-hydroxylated bile acids to 12α-hydroxylated bile acids, as well as each of these subclasses and their individual substituents as a proportion of the overall BA pool.

Study Design

Study Type:

Observational

Anticipated Enrollment :

75 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Official Title:

Bile Acid and Lipid Metabolism in Patients With Drug-induced Acute Insulin Resistance

Anticipated Study Start Date :

Dec 1, 2022

Anticipated Primary Completion Date :

Jun 10, 2026

Anticipated Study Completion Date :

Jun 10, 2026

Arms and Interventions

Arm	Intervention/Treatment
Patients treated with PI3K/AKT/mTOR inhibitors for cancer Patients with cancer being treated with PI3K/AKT/mTOR inhibitors will be studied prospectively for the impact of treatment on bile acid metabolism as a function of drug-induced acute insulin resistance. Treatments will be selected by patients' treating oncologist based on standard of care.	Drug: Drug-induced acute insulin resistance due to PI3K inhibitor, AKT inhibitor, or mTOR inhibitor Participants will be treated with PI3K/AKT/mTOR inhibitors by their treating oncologist based on standard of care. This study will prospectively monitor bile acids and parameters of insulin resistance before and during treatment with these drugs.

Arm

Intervention/Treatment

Patients treated with PI3K/AKT/mTOR inhibitors for cancer

Patients with cancer being treated with PI3K/AKT/mTOR inhibitors will be studied prospectively for the impact of treatment on bile acid metabolism as a function of drug-induced acute insulin resistance. Treatments will be selected by patients' treating oncologist based on standard of care.

Drug: Drug-induced acute insulin resistance due to PI3K inhibitor, AKT inhibitor, or mTOR inhibitor

Participants will be treated with PI3K/AKT/mTOR inhibitors by their treating oncologist based on standard of care. This study will prospectively monitor bile acids and parameters of insulin resistance before and during treatment with these drugs.

Outcome Measures

Primary Outcome Measures

Ratio of 12-HBA to non-12-HBA [1-2 Months]
Insulin resistance is expected to cause a rise in total bile acids, but with 12-alpha-hydroxylated bile acid (12-HBA) species outpacing non-12-alpha-hydroxylated bile acid (non-12-HBA) species, leading to a rise in the 12-HBA:non-12-HBA ratio. This would indicate that insulin resistance per se is sufficient to alter 12-HBA balance, and thus 12-HBA may be a useful therapeutic target for management of the macrovascular complications of insulin resistance. BA profile and levels of BA intermediates 7-HCO and 7,12-diHCO will be measured by LC-MS/MS when fasting +/- after 2-hour mixed meal tolerance test.
Insulin resistance [1-2 months]
Determine the timing and extent of PI3K/AKT/mTOR inhibitor treatment on parameters of insulin resistance: glucose, insulin, c-peptide, and adiponectin when fasting +/- following 2-hour mixed meal tolerance test

Secondary Outcome Measures

Lipid profile [1-2 months]
The primary endpoint is the outcome of the secondary objective: namely, evaluation of the effect of PI3Ki/AKTi/mTORi-induced insulin resistance on the lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, free fatty acids) when fasting +/- after 2-hour mixed meal tolerance test
Surrogate markers of BA signaling [1-2 months]
Determine the timing and extent of PI3K/AKT/mTOR inhibitor treatment on parameters of bile acid signaling: fibroblast growth factor 19 (FGF-19) and glucagon-like peptide-1 (GLP-1). We expect that a shift in BA pool composition (especially as regards 12-HBA vs non-12-HBA) will impact differentially on FGF-19 and GLP-1 levels.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years
Speaks English and/ or Spanish
Any cancer diagnosis
Planned for treatment with:
PI3K inhibitors
Alpelisib
Inavolisib
Any experimental PI3K inhibitor
AKT inhibitors (if these become available for open-label use during the study course)
Afuresertib
Capivasertib
Ipatasertib
Miransertib
Uposertib
mTOR inhibitors
Everolimus
Sirolimus
Temsirolimus
Signed informed consent

Exclusion Criteria:

Known dysglycemia
Known diagnosis of diabetes mellitus
Treatment with glucose-lowering medications at baseline
Insulin
Sulfonylureas or meglitinides
Metformin >1000mg total daily dose
Thiazolidinediones
SGLT2 inhibitors
GLP-1 receptor agonists
DPP4 inhibitors
Amylin mimetics
Acarbose
Significant biochemical evidence of liver dysfunction on lab tests within 30 days before starting drug that have not fallen to below the following thresholds prior to starting drug
Significant functional or anatomical abnormalities of the small intestine
Use of certain medications at baseline, within 7 days of starting cancer drug
Allergy to cow dairy or soy (only excludes from MMTT, does not exclude from fasting blood draws)
Inability to provide informed consent