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.
Who can participate
Age range18 Years – 65 Years
SexALL
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Inclusion criteria
✓. Men and women (using highly effective contraception if of childbearing potential) aged 18-65 years
✓. Body mass index of 25.0-39.9 kg/m2
✓. Able to understand written and spoken English and/or Spanish
✓. Evidence of normal glucose metabolism (euglycemia), represented by not meeting the American Diabetes Association's definitions for prediabetes, impaired fasting glucose (IFG), or diabetes on screening labs. Thus, participants must meet both of the following conditions on screening labs:
✓. Normal fasting serum insulin (fasting insulin level \< 12 μIU/mL) on screening labs
✓. Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.
Exclusion criteria
✕. Unable to provide informed consent in English or Spanish
✕. Concerns arising at screening visit (any of the following):
What they're measuring
1
Absolute values of plasma glucose
Timeframe: Up to 425 minutes from the start of the procedure
2
Relative change in plasma glucose
Timeframe: Up to 425 minutes from the start of the procedure
3
Absolute values of serum insulin
Timeframe: Up to 425 minutes from the start of the procedure
4
Relative change in serum insulin
Timeframe: Up to 425 minutes from the start of the procedure
5
Absolute values of serum C-peptide
Timeframe: Up to 425 minutes from the start of the procedure
6
Relative change in serum C-peptide
Timeframe: Up to 425 minutes from the start of the procedure
✕. Unwillingness to comply with masking and COVID-19 testing requirements per hospital policy
✕. Reproductive concerns i. Women of childbearing potential not using highly effective contraception, defined as:
✕. Concerns related to glucose metabolism i. Known, documented history of having met any of the American Diabetes Association's definitions of prediabetic state or of diabetes mellitus (i.e., overt diabetes):
✕. Concerns related to lipid metabolism i. Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia in the participant or a first-degree relative ii. Use of certain lipid-lowering drugs within 90 d prior to screening visit:
✕. Known, documented history, at the time of screening, of any of the following medical conditions:
✕. Clinical concern for increased risk of volume overload, including due to medications and/or heart/liver/kidney problems, as listed above