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

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from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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.

Study Overview

• Status: Completed
• Conditions: Diabetes After Total Pancreatectomy
• Intervention / Treatment: Other: Placebo tablet; Drug: Sitagliptin 100mg; Drug: Empagliflozin 25 MG

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Capital Region
    • Hellerup, Capital Region, Denmark, 2900
      • Center for Clinical Metabolic Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Pancreatectomised patients

• Caucasian above 30 years of age who have undergone total pancreatectomy
• Blood haemoglobin >7.0 mmol/l for males and >6.5 mmol/l for females
• Informed consent

Non-diabetic control subjects

• Normal fasting plasma glucose and normal HbA1c (according to the World Health Organization (WHO) criteria)
• Normal blood haemoglobin
• Caucasian above 30 years of age
• Informed consent

Exclusion Criteria:

Pancreatectomised patients

• Pancreatectomy within the last 3 months
• Ongoing chemotherapy or chemotherapy within the last 3 months
• Treatment with GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors within the last 3 months
• eGFR<60 ml/min/1,73m2 and/or albuminuria
• Known liver disease (excluding simple steatosis) and/or serum alanine aminotransferase (ALAT) and/or serum aspartate aminotransferase (ASAT) >3 × upper normal limit)
• Pregnancy and/or breastfeeding
• Age above 85 years
• Uncontrolled hypertension and/or significant cardiovascular disease
• Any condition that the investigator feels would interfere with trial participation

Non-diabetic control subjects

• Diabetes or prediabetes (according to WHO criteria)
• First-degree relatives with diabetes
• eGFR<60 ml/min/1,73m2 and/or albuminuria
• Known liver disease (excluding simple steatosis) and/or serum ALAT and/or serum ASAT >3 × upper normal limits)
• Pregnancy and/or breastfeeding
• Age above 85 years
• Uncontrolled hypertension and/or significant cardiovascular disease
• Any condition that the investigator feels would interfere with trial participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Other: Placebo tablet; 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.
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.	Drug: Sitagliptin 100mg; 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.
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.	Drug: Empagliflozin 25 MG; 2 tablets of empagliflozin 25 mg.
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.	Other: Placebo tablet; 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.
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.	Drug: Sitagliptin 100mg; 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.
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.	Drug: Empagliflozin 25 MG; 2 tablets of empagliflozin 25 mg.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PPG excurions measured as incremental area under the curve (iAUC)		-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
endogenous glucose production	Using intravenous and oral tracers	-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
GLP-1, gastrin, cholecystokinin, GIP, oxyntomodulin	excurions measured as incremental area under the curve (iAUC)	-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
Differences in gastric emptying, meassurement of s-paracetamol	measurement of time to peak and incremental area under the curve (iAUC)	-120-180 minutes
satiety, appetite, thirst,	assesed by a visual analougue scale (VAS)	-30, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
Resting energy expenditure (REE)	measured by indirect calorimetry	-90, 150 and 150 minutes
p-glucose mmol/L		-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
s-peptide pmol/l		-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
s-insulin		-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
Pulse and blood pressure	will be measured every 30th min	-120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes
food intake	the ad libitum meal will be weighed before after ingestion.	180 and 210 minutes

Collaborators and Investigators

• Sponsor: University Hospital, Gentofte, Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): April 2, 2019
• Primary Completion (Actual): August 20, 2019
• Study Completion (Actual): August 20, 2019

Study Registration Dates

• First Submitted: August 15, 2019
• First Submitted That Met QC Criteria: August 16, 2019
• First Posted (Actual): August 19, 2019

Study Record Updates

• Last Update Posted (Actual): September 4, 2019
• Last Update Submitted That Met QC Criteria: September 2, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Diabetes; Pancreatectomy; glucagon; DPP4 inhibitor; SGLT-2 inhibitor
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Empagliflozin; Sitagliptin Phosphate
• Other Study ID Numbers: H-19000992

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No