Effect of Insulin Lowering on Lipogenesis

Inclusion Criteria: * Adults aged 18-65 years * Body mass index of 30-45 kg/m2 * Able to understand written and spoken English and/or Spanish * Able to have pre-randomization screening labs drawn and study protocol initiated within 60 days of eligibility determination * Presence of uncomplicated metabolic dysfunction-associated steatotic liver disease (MASLD) by vibration-controlled transient elastography (VCTE) * Steatosis score of S1-S3 * Fibrosis score of F0-F2 (Note that if VCTE result is available from within past 6 months, then do not have to repeat VCTE for study purposes) * Evidence of insulin resistance, represented by any or all of the following criteria: * Meeting either of the American Diabetes Association's definitions for prediabetes or impaired fasting glucose (IFG) on screening labs: * Prediabetes: Hemoglobin A1c 5.7-6.4% * IFG: plasma glucose of 100-125 mg dL-1 after ≥ 8-h fast * Homeostasis Model of Insulin Resistance (HOMA-IR) score ≥ 2.73 * Fasting hyperinsulinemia (fasting insulin level ≥ 13 μU/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): * Documented weight loss of ≥ 5.0% of baseline within the previous 3 months * Abnormal blood pressure (including on treatment, if prescribed) * Systolic blood pressure (SBP) \< 90 mm Hg or \> 160 mm Hg, and/or * Diastolic blood pressure (DBP) \< 60 mm Hg or \> 100 mm Hg * Resting heart rate \< 55 bpm or ≥ 110 bpm * Abnormal screening electrocardiogram (or if on file, performed within previous 90 days) * Laboratory evidence of diabetes mellitus: * Hemoglobin A1c ≥ 6.5%, and/or * Fasting plasma glucose ≥ 126 mg/dL * Positive qualitative serum β-human chorionic gonadotropin (β-hCG, i.e., pregnancy test) in women of childbearing potential * Liver function abnormalities: transaminases (aspartate aminotransferase or alanine aminotransferase) \> 3.0 x the upper limit of normal, and/or total bilirubin \> 1.25 x the upper limit of normal * Abnormal screening fasting triglycerides \> 500 mg/dL * Abnormal screening serum electrolytes that are considered clinically significant according to the clinical judgment of the PI * Creatinine equating to estimated glomerular filtration rate \< 60 mL/min/1.73 m2 * Abnormal screening blood counts (any of the following): * Hemoglobin \< 10 g/dL * White blood cell count below the lower limit of normal for sex * Platelet count below the lower limit of normal for sex * Uric acid level above the upper limit of normal * Reproductive concerns * Women currently pregnant (tested by serum and/or urine β-hCG) * Women currently breastfeeding * Concerns related to glucose metabolism * History of having met any of the American Diabetes Association's definitions of diabetes mellitus (i.e., overt diabetes): * Hemoglobin A1c ≥ 6.5% * Plasma glucose ≥ 126 mg/dL after 8-h fast * Plasma glucose of ≥ 200 mg/dL at 2 h after ingestion of a 75-g glucose load * Random plasma glucose ≥ 200 mg/dL associated with typical hyperglycemic symptoms, diabetic ketoacidosis, or hyperglycemic-hyperosmolar state * History of gestational diabetes mellitus within the previous 5 years * Use of antidiabetic medications except metformin within the 90 days prior to screening * Clinical concern for absolute insulin deficiency (e.g., type 1 diabetes, pancreatic disease) * Concerns related to lipid metabolism * Known diagnoses of familial hypercholesterolemia, familial combined hyperlipidemia, or familial hyperchylomicronemia * Use of fibrates, prescription-strength omega-3 fatty acids, or high-dose niacin within the 90 days prior to screening: * Known, documented history (i.e., not to be newly screened/tested for study purposes), at the time of screening, of any of the following medical conditions: * Pancreatic pathology, including but not limited to neoplasia, pancreatitis, pancreatectomy * Cardiovascular disease (N.B. uncomplicated hypertension is not exclusionary) * Atherosclerotic cardiovascular disease: stable or unstable angina, myocardial infarction, ischaemic or hemorrhagic stroke, or transient ischaemic attack, peripheral arterial disease (claudication), use of dual antiplatelet therapy (aspirin + P2Y12 inhibitor), history of percutaneous coronary intervention * Heart rhythm abnormalities * Congestive heart failure of any New York Heart Association class * Symptomatic valvular heart disease (e.g., aortic stenosis) * Pulmonary hypertension * Chronic kidney disease, Stage 3 or higher (estimated glomerular filtration rate \< 60 mL/min/ 1.73 m2), of any cause * Chronic liver disease other than uncomplicated MASLD, including but not limited to: * Advanced liver fibrosis, as determined by non-invasive testing, including fibrosis scores of F3-F4 on VCTE * Cirrhosis of any etiology * Autoimmune hepatitis or other rheumatologic disorder affecting the liver * Biliopathy (e.g., progressive sclerosing cholangitis, primary biliary cholangitis) * Chronic liver infection (e.g., viral hepatitis, parasitic infestation) * Hepatocellular carcinoma * Infiltrative disorders (e.g., sarcoidosis, hemochromatosis, Wilson disease) * Gout * Chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) * Malabsorptive conditions * Active seizure disorder (including controlled with antiepileptic drugs) * Psychiatric diseases that are or have been decompensated within 1 year of screening, and/or require use of antipsychotic drugs associated with significant weight gain/metabolic dysfunction (e.g., clozapine, olanzapine), monoamine oxidase inhibitors, tricyclic antidepressants, or lithium * Known glucose-6-phosphate dehydrogenase (G6PD) deficiency * Other clinically significant endocrinopathies * Venous thromboembolic disease (deep vein thrombosis or pulmonary embolism) or any required use of therapeutic anticoagulation * Active malignancy, or hormonally active benign neoplasm, except allowances for non-melanoma skin cancer and differentiated thyroid cancer (Stage I only) * Clinical concern for increased risk of volume overload or hypotension (SBP \<90 and/or DBP \<60 mm Hg), including due to medications and/or heart/liver/kidney problems, as listed above * Clinical concern for increased risk of volume overload or hypotension (SBP \<90 and/or DBP \<60 mm Hg), including due to medications and/or heart/liver/kidney problems, as listed above * Use of certain medications currently or within 90 d prior to screening: * Prescribed medications used for any of the indications in the preceding list of excluded conditions, or their use within 90 d prior to screening, except allowances for: * Statins for primary prevention of cardiovascular disease * Use of drugs prescribed for indications other than the exclusionary diagnoses/purposes listed above (e.g., non-hydantoin antiepileptic drugs used for non-seizure indications, angiotensin converting enzyme inhibitor/angiotensin receptor blocker used for uncomplicated hypertension rather than for congestive heart failure, etc.) * Vasodilating drugs for any indication: hydralazine, nitrates, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), minoxidil (oral) * Phenytoin or fosphenytoin for any indication * Oral or parenteral corticosteroids (at greater than prednisone 5 mg daily, or equivalent) for more than 3 days within the previous 90 days; topical and inhaled formulations are permitted * History of certain weight-loss (bariatric) surgeries, including: * Roux-en-Y gastric bypass * Biliopancreatic diversion * Restrictive procedures (lap band, sleeve gastrectomy) performed within past year * Clinical concern for alcohol overuse, including based on chart review and/or by participant's report of consuming more than 14 standard drinks per week for males or more than 7 standard drinks per week for females * Regular use of tobacco, either daily or an average of at least 1 cigarette per day, and/or nicotine vaping more than 1 day per week * Positive urine drug screen, except for lawfully prescribed medications or marijuana/tetrahydrocannabinol positivity, provided that the participant agrees not to use it during the same period that they will abstain from alcohol) * Atypical circadian rhythm, such as due to night shift work, within 30 days of screening or expected within 30 days of each treatment period * History of severe infection or ongoing febrile illness within 14 days of screening * Any other disease or condition or laboratory value that, in the opinion of the investigator, would place the participant at an unacceptable risk and/or interfere with the analysis of study data. * Known allergy/hypersensitivity to any component of the medicinal product formulations (including sulfa drugs), other biologics, intravenous (IV) infusion equipment, plastics, adhesive or silicone, history of infusion site reactions with IV administration of other medicines, or ongoing clinically important allergy/hypersensitivity as judged by the investigator. * Concurrent enrollment in another clinical study of any investigational drug therapy or use of any biologicals within 5 half-lives of an investigational agent or biologic