Human Models of Selective Insulin Resistance: Pancreatic Clamp
NCT Number: NCT06558422
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE1
Conditions: Insulin Resistance|Hyperinsulinemia|Metabolic Dysfunction Associated Steatotic Liver Disease|Non-Alcoholic Fatty Liver Disease|Prediabetic State|Obesity
Interventions: DRUG: Insulin human|DRUG: Octreotide Acetate|DRUG: Glucagon|DRUG: Growth Hormone, Human|DRUG: 20% D-glucose (aq)|DIAGNOSTIC_TEST: [6,6-2H2] D-glucose|DIAGNOSTIC_TEST: [1-13C1] sodium acetate|DIETARY_SUPPLEMENT: Nestle BOOST Plus|DIETARY_SUPPLEMENT: KIND Bar|DEVICE: Harvard Apparatus PHD ULTRA CP syringe pump|DEVICE: Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer
Sponsor: Columbia University
Collaborators: University of California, Berkeley|National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 36
Study Design: Allocation: RANDOMIZED|Intervention Model: CROSSOVER|Masking: SINGLE (PARTICIPANT)|Primary Purpose: BASIC_SCIENCE
Start Date: 2024-09-01
Completion Date: 2026-12-31
Locations: Columbia University Irving Medical Center, New York, New York, 10032, United States

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, or clinically judged to be at high risk for, uncomplicated non-alcoholic fatty liver disease (NAFLD). 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.

Primary Outcome Measures: Hepatic de novo lipogenesis (DNL) (absolute value), Percent incorporation of newly synthesized fatty acids into plasma or very low-density lipoprotein (VLDL) triglyceride (TG) during pancreatic clamp procedures. (Unit: %), Up to 6.5 hours of pancreatic clamp protocol|Hepatic de novo lipogenesis (DNL) (relative value), Percent incorporation of newly synthesized fatty acids into plasma or VLDL TG during pancreatic clamp procedures. (Unit: fold difference and/or ∆% versus other group), Up to 6.5 hours of pancreatic clamp protocol|Endogenous glucose production (EGP) (absolute value), Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: mg/kg/min), Up to 6.5 hours of pancreatic clamp protocol|Endogenous glucose production (EGP) (relative value), Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: fold difference and/or ∆% versus other group), Up to 6.5 hours of pancreatic clamp protocol|Plasma glucose level, Plasma glucose level during pancreatic clamp procedures. (Units: mg/dL), Up to 6.5 hours of pancreatic clamp protocol|Serum insulin level, Serum insulin level during pancreatic clamp procedures (Units: µU/mL), Up to 6.5 hours of pancreatic clamp protocol
Secondary Outcome Measures: Serum or plasma triglyceride level, Serum or plasma triglyceride level in response to pancreatic clamp procedures (Units: mg/dL), Up to 6.5 hours of pancreatic clamp protocol|Plasma free fatty acids level, Plasma free fatty acids level in response to pancreatic clamp procedures. (Units: mmol/L), Up to 6.5 hours of pancreatic clamp protocol|Glucose kinetics: rate of appearance (absolute value), Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: mg/kg/min), Up to 6.5 hours of pancreatic clamp protocol|Glucose kinetics: rate of appearance (relative value), Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: fold difference and/or ∆% versus other group), Up to 6.5 hours of pancreatic clamp protocol|Glucose kinetics: rate of disappearance (absolute value), Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: mg/kg/min), Up to 6.5 hours of pancreatic clamp protocol|Glucose kinetics: rate of disappearance (relative value), Calculated from D2G tracer enrichment by the Steele equations during pancreatic clamp procedures. (Units: fold difference and/or ∆% versus other group), Up to 6.5 hours of pancreatic clamp protocol
Other Outcome Measures: Serum C-peptide level, Serum C-peptide level in response to octreotide infusion during pancreatic clamps. (Units: ng/mL), Up to 6.5 hours of pancreatic clamp protocol|Plasma glucagon level, Plasma glucagon level in response to octreotide infusion during pancreatic clamps. (Units: ng/L), Up to 6.5 hours of pancreatic clamp protocol|Serum growth hormone level, Serum growth hormone level in response to octreotide infusion during pancreatic clamps. (Units: ng/mL), Up to 6.5 hours of pancreatic clamp protocol