Involvement of Dipeptidyl Peptidase-4 and Sodium-glucose Co-transporter-2 in Extrapancreatic Glucagon Secretion

Conditions

• Diabetes After Total Pancreatectomy

Eligibility Criteria

Sex

ALL

Age

18 Years - 85 Years

Healthy Volunteers

Accepted

Interventions

• Sitagliptin 100mg — DRUG
  2 tablets of sitagliptin 100 mg. Standardized liquid meal Standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g \[U-13C6\]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
• Empagliflozin 25 MG — DRUG
  2 tablets of empagliflozin 25 mg.
• Placebo tablet — OTHER
  2 placebo tablets. Standardized liquid meal Standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g \[U-13C6\]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.

Study Details

Glucagon is a 29-amino acid peptide hormone of essential importance for glucose homeostasis. Hitherto glucagon has been believed to be secreted only from the pancreas, but recent studies show that glucagon is also secreted from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data). This has fundamentally changed the understanding of glucagon physiology and provides new avenues for the investigation of several metabolic disorders in which hyperglucagonaemia represents a common and important pathophysiological characteristic (including type 2 diabetes). To delineate the physiological role of gut-derived glucagon and its potential pathophysiological implications, and thereby clear the way for new treatment modalities targeting gut glucagon, it is of importance to understand how glucagon secretion from the gut is regulated. In contrast to the regulation of pancreatic glucagon secretion, very little is known about the regulation of gut-derived glucagon. Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4) which under normal circumstances degrades, and thereby inactivates the two gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), has been shown to decrease pancreatic glucagon secretion. This is most likely brought about by increased levels of intact, active GLP-1, which is known to suppress pancreatic glucagon secretion. Furthermore, the sodium-glucose transporter 2 (SGLT-2) seems to be implicated in pancreatic glucagon secretion as inhibitors of SGLT-2 have been shown to increase the secretion of pancreatic glucagon secretion. The present project will employ further investigations of totally pancreatectomised patients to delineate the regulation of gut-derived glucagon secretion with focus on the well-known modulators of pancreatic glucagon secretion, the enzyme DPP-4 and the sodium-glucose co-transporter SGLT-2, respectively. The study is designed as a randomised, double-blinded, crossover study. 10 healthy persons and 10 totally pancreatectomized patients will be subjected to 3 experimental days. All participants will undergo a screening visit and three experimental days (day A (meal test during DPP-4 inhibition), B (meal test during SGLT-2 inhibition) and C (meal test with placebo)). A liquid meal test will be followed by a fasting period and finished off with an ad libitum meal.

Key Dates

Start date

Apr 2, 2019

Status verified

Sep 2019

Primary completion

Aug 20, 2019

Completion

Aug 20, 2019

Study Design

Enrollment

20 participants (actual)

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

BASIC_SCIENCE

Arms

• Placebo Comparator: Pancreatectomized + Placebo
  During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g \[U-13C6\]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol. Before the meal (1 h and 12 h) 1+1 placebo tablets will be administered orally.
• Active Comparator: Pancreatectomized + DPP-4 inhibitor
  During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g \[U-13C6\]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol. Before the meal (1 h and 12 h) 1+1 DPP4-inhibitor tablets will be administered orally.
• Active Comparator: Pancreatectomized + SGLT-2 inhibitor
  During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g \[U-13C6\]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol. Before the meal (1 h and 12 h) 1+1 SGLT-2 tablets will be administred orally.
• Placebo Comparator: Healthy + Placebo
  During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g \[U-13C6\]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
• Active Comparator: Healthy + DPP-4 inhibitor
  During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g \[U-13C6\]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.
• Active Comparator: Healthy + SGLT-2 inhibitor
  During the experimental day the participant will ingest a standardized liquid meal (200 ml) containing: 1,650 KJ, (394 kcal), carbohydrate 50%, protein 15%, fat 35% consisting of glucose (47.2 g + 2.8 g \[U-13C6\]-glucose), rapeseed oil (14.1 g), whey protein (15.2 g) and 1.5 g paracetamol.

Primary Outcome Measure

glucagon excursions measured as incremental area under the curve (iAUC) [ Time Frame: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]