The purpose of this study is to help us better understand how plasma ketones respond to a low-carb diet when combined with an SGLT2 inhibitor.

We will combine an SGLT2i with an adaptive study diet that gradually reduces dietary carbohydrates to safely achieve moderate ketosis in healthy adult volunteers.

Inclusion criteria:

• M/F
• Age 18-60 years
• Weight stable (+/- 3 kg over past 6 months)
• Body mass index (BMI): 21-35 kg/m2
• Otherwise healthy, as determined by medical history and laboratory tests
• Understands the procedures and agrees to participate by giving written informed consent
• Willing and able to comply with scheduled visits, laboratory tests, and other study procedures

Exclusion criteria:

Acute or chronic medical conditions or medication that would contraindicate the participation in the research testing or could potentially affect metabolic function including, but not limited to:

1. History or presence of cardiovascular disease (unstable angina, myocardial infarction or coronary revascularization within 6 months, presence of cardiac pacemaker, implanted cardiac defibrillator)
2. Diagnosis of type 1 or type 2 diabetes mellitus, or prior diabetic ketoacidosis
3. Blood pressure > 140/90 mm Hg
4. Bleeding and clotting disorders
5. Acute or chronic infection (such as TB, HIV or Hepatitis)
6. Renal insufficiency (eGFR<60), nephritis, or chronic kidney disease
7. Thyroid dysfunction (suppressed TSH, elevated TSH <10 µIU/ml if symptomatic or elevated TSH >10 µIU/ml if asymptomatic)
8. Liver disease (liver function tests > 2 x normal; including NASH/NAFLD)
9. Gastrointestinal disorders (including inflammatory bowel disease or malabsorption, swallowing disorders, suspected or known strictures, fistulas or physiological/mechanical GI obstruction, history of gastrointestinal surgery, Crohn's disease or diverticulitis)
10. Past or present history of eating disorder (including binge eating)
11. Past or present history of psychiatric disease, including major depressive illness or bipolar disorder, as well as claustrophobia since part of the protocol will involve being confined to a small room for whole-body indirect calorimetry
12. Unwilling or unable to eat the foods provided in the study diet
13. A positive urine drug test for illicit drugs.
14. Any malignancy not considered cured, except basal cell carcinoma and squamous cell carcinoma of the skin (a participant is considered cured if there has been no evidence of cancer recurrence in the previous 5 years)
15. Pregnant or nursing females or females less than 6 months postpartum from the scheduled date of collection
16. Regular smoking or regular nicotine use of any kind including chewing tobacco, snuff and vaping
17. Presence of any condition that, in the opinion of the Investigator, compromises participant safety or data integrity or the participant's ability to complete study days.
18. History of regular alcohol consumption exceeding 7 drinks/week for female participants or 14 drinks/week for male participants (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months before screening.
19. Donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit.
20. Anemia (hemoglobin <12 g/dl in men, <11 g/dl in women)

Excluded medications include, but are not limited to:

1. Any prescription medication or other drug that may influence metabolism (e.g. diet/weight-loss medication, psychiatric medications, corticosteroids, or other medications at the discretion of the PI and/or study team)
2. Anti-diabetic agents
3. Recent change to medication and/or dosing in the past 3 months
4. Blood thinner prescription medication
5. Chronic use of aspirin or other non-steroidal anti-inflammatory drugs, including COX-2 inhibitors (a single aspirin daily if prescribed for cardioprotection will be allowed as will occasional use of aspirin and other non-steroidal drugs, provided that they are used for < 3 consecutive days and not during the period of metabolic testing)