Pancreatic Clamp in NAFLD

Summary

This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the specific dose-response impact of insulin infusion rate (IIR) on blood glucose levels during a pancreatic clamp study. The investigators will recruit participants with a history of overweight/obesity and evidence of insulin resistance (i.e., fasting hyperinsulinemia plus prediabetes and/or impaired fasting glucose and/or Homeostasis Model Assessment of Insulin Resistance \[HOMA-IR\] score \>=2.73), and with evidence of, or clinically judged to be at high risk for, uncomplicated non-alcoholic fatty liver disease (NAFLD). Participants will undergo two pancreatic clamp procedures in which individualized basal IIR are identified, followed in one by maintenance of basal IIR (maintenance hyperinsulinemia, MH) and in the other by a stepped decline in IIR (reduction toward euinsulinemia, RE). In both clamps the investigators will closely monitor plasma glucose and various metabolic parameters. The primary outcome will be the absolute and relative changes in steady-state plasma glucose levels at each stepped decline in IIR.

Conditions

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

Interventions

DRUG

Insulin human

Insulin infusion rate (IIR) will be determined empirically first to maintain mean basal fasting plasma glucose, and then either maintained at the basal rate (MH protocol) or be reduced stepwise toward euinsulinemia (RE protocol).

DRUG

Octreotide Acetate

Octreotide will be infused at 30 ng/kg/min to suppress endogenous insulin, glucagon, and growth hormone secretion. Co-administered with glucagon and rhGH.

DRUG

Glucagon

Glucagon will be replaced at a constant rate of up to 0.65 ng/kg/min to maintain baseline counterregulatory response. Co-administered with octreotide and rhGH.

DRUG

Growth Hormone, Human

Recombinant human growth hormone (rhGH) will be replaced at a constant rate of up to 3 ng/kg/min to maintain baseline counterregulatory response. Co-administered with octreotide and glucagon.

OTHER

[6,6-2H2] D-glucose

Stable isotope tracer administered to calculate glucose kinetics during pancreatic clamp.

DRUG

20% D-glucose (aq)

20% D-glucose (aq) (D20W) will be administered to counteract hypoglycemia or strongly downward blood glucose trends, as needed.

DIETARY_SUPPLEMENT

BOOST Plus

Nutritional supplement will be administered to provide three standardized "mixed meals" on the day before the pancreatic clamp.

DIETARY_SUPPLEMENT

CORE Bar

Energy bar used as a standardized snack on the day before the pancreatic clamp.

DEVICE

Harvard Apparatus PHD ULTRA CP syringe pump

Syringe pump used for highly precise administration of insulin, octreotide/glucagon/rhGH, and D20W (as needed) even at low infusion rates.

DEVICE

Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer

Glucose oxidase analyzer used to detect plasma glucose levels at the point of care. YSI have been the gold standard in clamp studies for many years. Two machines will run in parallel to ensure accuracy of results.

Sponsors & Collaborators

• Albert Einstein College of Medicine

  collaborator OTHER

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  collaborator NIH

• Columbia University

  lead OTHER

Principal Investigators

• Joshua R. Cook, MD, PhD · Columbia University

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2023-08-29

Primary Completion

2025-09-24

Completion

2025-09-24

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations