NCT06558422

Human Models of Selective Insulin Resistance: Pancreatic Clamp

• Status: Not Yet Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 36 (estimated)
• Sponsor: Columbia University · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

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.

Detailed description

Although high blood sugar and risk of heart disease are the most well-known health effects of type 2 diabetes (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), in which too much fat accumulates in the liver, has come to be recognized as another important complication. Unchecked, MASLD can progress to severe liver inflammation, liver failure, and even liver cancer. The investigators suspect that high levels of the blood sugar-lowering hormone insulin leads to excessive fat production by the liver, and so lowering insulin levels might help to improve MASLD. In order to answer this question, the investigators will recruit people with MASLD at risk for T2DM to perform a "pancreatic clamp" - a procedure in which the body's production of insulin is temporarily shut off and then replaced at the same or lower levels. Again, the investigators expect that lowering insulin levels will lower fat production ("de novo lipogenesis" or DNL). Research participants in this prospective, randomized, controlled (crossover) study will therefore undergo two pancreatic clamps in random order: one roughly maintaining their own internal ("basal") insulin level ("MH Protocol") and one in which the investigators lower that basal insulin level by 50% ("RE Protocol"). In each case, the investigators will observe the absolute and relative changes in the liver's production of glucose (hepatic glucose production, HGP) and of triglycerides (de novo lipogenesis, DNL) using stable-isotope tracers.

Conditions

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

Interventions

Type	Name	Description
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.

Timeline

• Start date: 2027-01-01
• Primary completion: 2028-12-31
• Completion: 2029-02-28
• First posted: 2024-08-16
• Last updated: 2026-02-06

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study
• FDA-regulated device study