NCT06126354

Dexamethasone/Pancreatic Clamp P&F

Role of Hyperinsulinemia in NAFLD: Dexamethasone-Pancreatic Clamp Pilot & Feasibility Study

• Status: Withdrawn
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 0 (actual)
• 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 specific dose-response impact of insulin infusion rate (IIR) on blood glucose levels during a pancreatic clamp study in the setting of dexamethasone-induced insulin resistance. The investigators will recruit participants with a history of overweight/obesity but no history of prediabetes or diabetes. Participants will be rendered temporarily insulin resistant by taking seven doses of dexamethasone. They will then 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.

Detailed description

Although high blood sugar and risk of heart disease are the most well-known health effects of type 2 diabetes (T2DM), nonalcoholic fatty liver disease (NAFLD), in which too much fat accumulates in the liver, has come to be recognized as another important complication. Unchecked, NAFLD 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 NAFLD. In order to answer this question, the investigators will temporarily render volunteers insulin resistant -- that is, simulating the risk of T2DM and NAFLD -- using seven doses of dexamethasone. They will then 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. Because this is a new research approach, the investigators first need to understand how lowering insulin levels affects blood sugar. Research participants in this pilot study will therefore undergo two pancreatic clamps, each following seven doses of dexamethasone, in random order: one roughly maintaining their own internal ("basal") insulin level and one in which the investigators lower that basal insulin level by 10%, 20%, and 40%. In each case, the investigators will observe the absolute and relative changes in blood sugar and the levels of certain fats as the investigators change the insulin level. Once the investigators have found a lower insulin level that they can safely maintain, the investigators will go on to study its effect on fat production in a later study.

Conditions

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

Interventions

Type	Name	Description
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	Human Growth Hormone	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	Dexamethasone Oral	Synthetic pure glucocorticoid used to induce temporary insulin resistance, administered orally as seven 1-mg doses over 72 hours.
OTHER	[6,6-2H2] D-glucose	Stable isotope tracer administered to calculate glucose kinetics during pancreatic clamp. (Non-investigational)
DRUG	20% D-glucose (aq)	20% D-glucose (aq) (D20W) will be administered to counteract hypoglycemia or strongly downward blood glucose trends, as needed. (Non-investigational)
DIETARY_SUPPLEMENT	BOOST Plus	Nutritional supplement will be administered to provide three standardized "mixed meals" on the day before the pancreatic clamp. (Non-investigational)
DEVICE	Harvard Apparatus PHD ULTRA CP syringe pump	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. (Non-investigational)
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. (Non-investigational)
OTHER	Normal saline	Normal saline (0.9% NaCl, aq), variable rate (as needed)
OTHER	Human albumin	Human albumin (5%, aq), 0.4 g per 100 mL of infusion (0.4% (w/v) in insulin and OCT/GCG/GH bags)

Timeline

• Start date: 2024-07-01
• Primary completion: 2025-11-30
• Completion: 2026-03-31
• First posted: 2023-11-13
• Last updated: 2024-07-10

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study