Human Models of Selective Insulin Resistance: Pancreatic Clamp

Official 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.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: CROSSOVER
• Masking: SINGLE
• Enrollment: 36 participants

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.

Primary Outcomes

• Hepatic de novo lipogenesis (DNL) (absolute value) (Up to 6.5 hours of pancreatic clamp protocol)
• Hepatic de novo lipogenesis (DNL) (relative value) (Up to 6.5 hours of pancreatic clamp protocol)
• Endogenous glucose production (EGP) (absolute value) (Up to 6.5 hours of pancreatic clamp protocol)
• Endogenous glucose production (EGP) (relative value) (Up to 6.5 hours of pancreatic clamp protocol)
• Plasma glucose level (Up to 6.5 hours of pancreatic clamp protocol)

Secondary Outcomes

• Serum or plasma triglyceride level (Up to 6.5 hours of pancreatic clamp protocol)
• Plasma free fatty acids level (Up to 6.5 hours of pancreatic clamp protocol)
• Glucose kinetics: rate of appearance (absolute value) (Up to 6.5 hours of pancreatic clamp protocol)
• Glucose kinetics: rate of appearance (relative value) (Up to 6.5 hours of pancreatic clamp protocol)
• Glucose kinetics: rate of disappearance (absolute value) (Up to 6.5 hours of pancreatic clamp protocol)

Trial Locations

• Columbia University Irving Medical Center, New York, New York, United States

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