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.
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Hepatic de novo lipogenesis (DNL) (absolute value)
Timeframe: Up to 6.5 hours of pancreatic clamp protocol
Hepatic de novo lipogenesis (DNL) (relative value)
Timeframe: Up to 6.5 hours of pancreatic clamp protocol
Endogenous glucose production (EGP) (absolute value)
Timeframe: Up to 6.5 hours of pancreatic clamp protocol
Endogenous glucose production (EGP) (relative value)
Timeframe: Up to 6.5 hours of pancreatic clamp protocol
Plasma glucose level
Timeframe: Up to 6.5 hours of pancreatic clamp protocol
Serum insulin level
Timeframe: Up to 6.5 hours of pancreatic clamp protocol