Effects of Single Doses of Liraglutide and Dapagliflozin on Hyperglycemia and Ketogenesis in Type 1 Diabetes
Effects of Single Doses of Liraglutide and Dapagliflozin on Hyperglycemia and Ketogenesis in Type 1 Diabetes
1. To compare levels of ketone bodies (beta-hydroxybutyrate and acetoacetate) in plasma and
 urine following a single dose treatment of either liraglutide 1.8mg,dapagliflozin 10mg
 or placebo in insulinopenic state.

 2. To compare plasma levels of free fatty acid, glucagon, hs-CRP, Il-6 and IL-1 before and
 after administration of liraglutide/Dapagliflozin/placebo.
Diabetic ketoacidosis is an important cause of mortality and morbidity in type 1 patients.
 The decreased ratio of insulin to glucagon in insulin deficient subjects promotes
 ketogenesis. In patients with type 1 diabetes, the suppressive effect of hyperglycemia and
 the paracrine inhibitory effect of insulin and GABA from the β cell on α cell are absent.
 Thus, plasma glucagon concentrations are elevated and in combination with insulin deficiency,
 lead to lipolysis, increased plasma FFA concentrations and an increased fatty acid supply to
 the liver. Thus, both fatty acid oxidation and ketogenesis are enhanced.

 Our recent work has shown that liraglutide, a GLP 1 agonist, improves glycemic control and
 reduces glycemic excursions in patients with type 1 diabetes within a few days of the
 initiation of treatment.

 With this background, the investigators hypothesize that suppression of glucagon with
 liraglutide in patients with type 1 diabetes may protect them from lipolysis, increased
 bio-availability of FFAs, ketogenesis and ketoacidosis. On the other hand, addition of SGLT 2
 inhibitor can shift these biochemical changes to other direction thus increasing ketogenesis
 /ketoacidosis.

 It is essential to investigate this area further as there are no prior studies that have
 investigated the acute effects of liraglutide/Dapagliflozin on FFAs or ketogenesis. This
 study will be the first randomized controlled prospective study investigating the effect of
 liraglutide/dapagliflozin on ketogenesis. Also, it would be important to measure the
 mediators of inflammation at the same time to investigate whether there is a concomitant
 changes of inflammatory factors in parallel with the lipolysis and ketogenesis.

 After the screening visit, subjects who meet the inclusion and exclusion criteria will be
 randomized to receive a single dose of either liraglutide, dapagliflozin or placebo and will
 be monitored for a total of 8 hours. The same patient (as described in 8.3, cross over
 study), will get the other 2 treatments in random order in the following 2 visits (one week
 apart) for a total participation of 2 weeks+1 day.
Inclusion Criteria:

 1. Type 1 Diabetes on continuous subcutaneous insulin infusion (CSII, also known as
 insulin pump).

 2. Undetectable c peptide (c-peptide < 0.1 ng/ml).

 3. HbA1c of less than or equal to 8.5%.

 4. Age 18-75 inclusive

 Exclusion Criteria:

 1. Type 1 diabetes for less than 12 months

 2. Coronary event/ procedure (MI, Unstable angina, CABG, PCI) in the last four weeks

 3. Hepatic disease (Transaminase > 3 times normal) or Cirrhosis

 4. Renal impairment (serum eGFR <30ml/min/1.73m2)

 5. HIV or Hepatitis B or C positive status

 6. History of pancreatitis, i.e., history of gallstones, alcohol abuse and
 hypertriglyceridemia

 7. Pregnancy

 8. Inability to give informed consent

 9. History of Gastroparesis

 10. Personal or Family History of medullary thyroid carcinoma or MEN 2 syndrome

 11. Alcoholism

 12. Hypertriglyceridemia (>500 mg/dl).

 13. Those with history of bladder cancer , diabetic ketoacidosis