PHROG

Type 1 diabetes cohort:

1. Age 20-60 years

2. Diagnosis of T1DM according to American Diabetes Association (ADA) criteria continuously requiring insulin for survival

3. Diabetes diagnosis performed more than 5 years before enrollment

4. Fasting C-peptide levels < 0.7 ng/mL with a concurrent plasma glucose concentration > 90 mg/dL (Labs may need to be repeated if the Plasma glucose is < 90 mg/dL)

5. For female participants: must be > 6 months post-partum and not lactating and agrees not to become pregnant during the study and for at least 2 weeks after the last dose of the study medication. For male participants: agrees not to donate sperm or not to get a woman pregnant during the study and for at least 2 weeks after the last dose of the study medication.

Healthy subject cohort:

1. Age 20-60 years

2. General good health

3. Creatinine clearance >80 mL/min based on CKD-EPI equation

4. Fasting blood glucose (FBG) >70 mg/dL and <100 mg/dL

5. No history of diabetes

6. For female participants: must be > 6 months post-partum and not lactating and agrees not to become pregnant during the study

1. BMI >35 kg/m2 and <18.5 kg/m2 for females and BMI >35 kg/m2 and <20 kg/m2 for males.

2. Increase or decrease body weight greater than 3kg in the 3 months before enrollment.

3. Evidence by history, ECG or exams of clinically significant cardiovascular disease (unstable angina, myocardial infarction or coronary revascularization within 6 months, clinically significant abnormalities on ECG, presence of cardiac pacemaker, implanted cardiac defibrillator)

4. Evidence of autonomic neuropathy

5. Liver disease (AST or ALT >2.5 times the upper limit of normal)

6. Kidney disease (creatinine >1.6 mg/dl or estimated GFR <60 ml/min).

7. Dyslipidemia, including triglycerides >500 mg/dl, LDL >200 mg/dl or unstable hyperlipidemia. Treatment with a single lipid lowering agents is allowed if stable within the previous 3 months.

8. Anemia (hemoglobin <12 g/dl in men, <11 g/dl in women)

9. Thyroid dysfunction (suppressed TSH, elevated TSH <10 µIU/ml if symptomatic or elevated TSH >10 µIU/ml if asymptomatic)

10. Uncontrolled hypertension (BP >160 mmHg systolic or >100 mmHg diastolic) or treatment with more than 2 antihypertensive medications.

11. Current use of beta-adrenergic blocking agents or their use was stopped less than one month before recruitment

12. History of cancer within the last 5 years (skin cancers, with the exception of melanoma, may be acceptable)

13. History of organ transplant

14. History of HIV, active Hepatitis B or C, or Tuberculosis

15. Pregnancy, lactation or 6 months postpartum from the scheduled date of screening lab collection

16. Females of childbearing potential (any female except those with tubal ligation, hysterectomy, or absence of menses >2 years) unwilling to use an approved method of contraception (one medically accepted method of contraception with ≥99% effectiveness when used consistently and correctly). Male participants: he or he and his partner unwilling to use an approved method of contraception with ≥99% effectiveness when used consistently and correctly

17. History of Major Depression in the last 5 years

18. History of an eating disorder

19. History of bariatric surgery

20. History of drug or alcohol abuse (> 3 drinks per day) within the last 5 years

21. Self-report of marijuana use ≥3 days/week in any form

22. Psychiatric disease prohibiting adherence to study protocol

23. Current use of oral or injectable anti-hyperglycemic agents: metformin, sulfonylureas, DPP IV inhibitors, SGLT-2 inhibitors, thiazolidinediones, acarbose, GLP-1 analogs

24. Initiation or change in hormone replacement therapy within the past 3 months (including, but not limited to thyroid hormone or estrogen replacement therapy). Hormone based contraception is acceptable.

25. Use of any medications known to influence glucose, fat and/or energy metabolism (e.g., growth hormone therapy, glucocorticoids [steroids], prescribed medications for weight loss, etc.). Patients on medications with acute effects on glucose metabolism used for other indications (certain antidepressants, ADHD and antiepileptic medications) may be enrolled if they have been on chronic, stable doses (≥6 months)

26. Uncontrolled seizure disorder

27. Current night shift worker

28. 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 visits

29. Unwilling and/or unable to follow and comply with scheduled visits and protocol requirements

Additional exclusion Criteria for the type 1 diabetes cohort:

1. HbA1c >9%

2. Insulin dose less than 0.3 U/kg or low carbohydrate diet

3. History of T2DM or any form of diabetes other than T1DM

4. Hypoglycemia unawareness as assessed using the GOLD score

5. Using a predictive low blood glucose suspend mode on an insulin pump or a hybrid closed loop algorithm for insulin delivery. For those applying these strategies for everyday management of blood glucose and willing to participate, the algorithm will be stopped at enrollment.

6. Two or more episodes of severe hypoglycemia (Hypoglycemia requiring help from a third party) per month in the past six months

7. One or more DKA episodes in the past 3 months

8. QTcF >450 msec for males and >470 msec for females

9. Using non-insulin agents to control blood glucose levels

10. History or evidence of moderate or severe end-organ diabetic complications of retinopathy, nephropathy or neuropathy. Proliferative diabetic retinopathy. Non-proliferative retinopathy and microalbuminuria will be allowed.

Additional exclusion Criteria for the healthy cohort:

1. Insulin treatment