Human Models of Selective Insulin Resistance: Pancreatic Clamp

Summary

This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the impact of lowering insulin levels on hepatic glucose production (HGP) vs de novo lipogenesis (DNL) in people with insulin resistance. 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 metabolic dysfunction-associated steatotic liver disease (MASLD). Participants will undergo two pancreatic clamp procedures -- one in which serum insulin levels are maintained near hyperinsulinemic baseline (Maintenance Hyperinsulinemia or "MH" Protocol) and the other in which serum insulin levels are lowered by 50% (Reduction toward Euinsulinemia or "RE" Protocol). In both clamps the investigators will use stable-isotope tracers to monitor hepatic glucose and triglyceride metabolism. The primary outcome will be the impact of steady-state clamp insulinemia on HGP vs DNL.

Conditions

• Insulin Resistance
• Hyperinsulinemia
• Metabolic Dysfunction Associated Steatotic Liver Disease
• Non-Alcoholic Fatty Liver Disease
• Prediabetic State
• Obesity

Interventions

DRUG

Insulin human

Insulin infusion rate (IIR) will be determined either to maintain fasting serum insulin levels (MH protocol) or to reduce fasting serum insulin levels by approximately 50% 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.

DRUG

20% D-glucose (aq)

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

DIAGNOSTIC_TEST

[6,6-2H2] D-glucose

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

DIAGNOSTIC_TEST

[1-13C1] sodium acetate

Stable isotope tracer administered to calculate de novo lipogenesis during pancreatic clamp.

DIETARY_SUPPLEMENT

Nestle BOOST Plus

Nutritional supplement will be administered to provide standardized "mixed meals" prior to the pancreatic clamp.

DIETARY_SUPPLEMENT

KIND Bar

Energy bar snack will be administered the evening 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

• University of California, Berkeley

  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

2027-01-01

Primary Completion

2028-12-31

Completion

2029-02-28

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations