Effects of Single Doses of Liraglutide and Dapagliflozin on 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, Ll-6 and IL-1 before and after administration of liraglutide/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.

It is essential to investigate this area further as there are no prior studies that have investigated the acute effects of liraglutide on FFAs or ketogenesis. This study will be the first randomized controlled prospective study investigating the effect of liraglutide 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.

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