Human Models of Selective Insulin Resistance: Pancreatic Clamp

Conditions

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

Eligibility Criteria

Sex

ALL

Age

18 Years - 65 Years

Healthy Volunteers

Not accepted

Interventions

• Insulin human — DRUG
  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).
• Octreotide Acetate — DRUG
  Octreotide will be infused at 30 ng/kg/min to suppress endogenous insulin, glucagon, and growth hormone secretion. Co-administered with glucagon and rhGH.
• Glucagon — DRUG
  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.
• Growth Hormone, Human — DRUG
  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.
• 20% D-glucose (aq) — DRUG
  20% D-glucose (aq) (D20W) will be administered to counteract hypoglycemia or strongly downward blood glucose trends, as needed.
• [6,6-2H2] D-glucose — DIAGNOSTIC_TEST
  Stable isotope tracer administered to calculate glucose kinetics during pancreatic clamp.
• [1-13C1] sodium acetate — DIAGNOSTIC_TEST
  Stable isotope tracer administered to calculate de novo lipogenesis during pancreatic clamp.
• Nestle BOOST Plus — DIETARY_SUPPLEMENT
  Nutritional supplement will be administered to provide standardized "mixed meals" prior to the pancreatic clamp.
• KIND Bar — DIETARY_SUPPLEMENT
  Energy bar snack will be administered the evening before the pancreatic clamp.
• Harvard Apparatus PHD ULTRA CP syringe pump — DEVICE
  Syringe pump used for highly precise administration of insulin, octreotide/glucagon/rhGH, and D20W (as needed) even at low infusion rates.
• Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer — DEVICE
  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.

Study Details

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.

Key Dates

Start date

Jan 1, 2027

Status verified

Feb 2026

Primary completion

Dec 31, 2028

Completion

Feb 28, 2029

Study Design

Enrollment

36 participants (estimated)

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Arms

• Experimental: Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) Protocol
  On Pancreatic Clamp Visit 1 (MH Protocol), the insulin infusion rate (IIR) will be set to approximately replicate participants' endogenous fasting serum insulin levels based on screening visit data for the duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (RE Protocol), the IIR will be set to reduce serum insulin levels to roughly 50% of the screening fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.
• Experimental: Reduction toward euinsulinemia (RE) protocol
  On Pancreatic Clamp Visit 1 (RE Protocol), the insulin infusion rate (IIR) will be set to produce serum insulin levels of approximately 50% that of the screening fasting serum insulin level for the full duration of the pancreatic clamp. On Pancreatic Clamp Visit 2 (MH Protocol), the IIR will be set to approximately replicate the full fasting serum insulin for the duration of the pancreatic clamp. In both cases, plasma glucose will be clamped to approximately 140 mg/dL +/- 10%.

Primary Outcome Measure

Hepatic de novo lipogenesis (DNL) (absolute value) [ Time Frame: Up to 6.5 hours of pancreatic clamp protocol ]

Central Contacts

• Joshua R Cook, MD, PhD
  2123056289
  [email protected]
• Ishwari Nagnur
  2123059336
  [email protected]

Locations (1)

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