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

NCT ID: NCT04061473

Last Updated: 2019-09-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-04-02
• Study Completion Date: 2019-08-20

Brief Summary

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from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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

Conditions

Diabetes After Total Pancreatectomy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: PLACEBO_COMPARATOR

Placebo tablet

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Sitagliptin 100mg

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Empagliflozin 25 MG

Intervention Type: DRUG

2 tablets of empagliflozin 25 mg.

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.

Group Type: PLACEBO_COMPARATOR

Placebo tablet

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Sitagliptin 100mg

Intervention Type: 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.

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.

Group Type: ACTIVE_COMPARATOR

Empagliflozin 25 MG

Intervention Type: DRUG

2 tablets of empagliflozin 25 mg.

Interventions

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.

Intervention Type: DRUG

Empagliflozin 25 MG

2 tablets of empagliflozin 25 mg.

Intervention Type: DRUG

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.

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University Hospital, Gentofte, Copenhagen

OTHER

Sponsor Role: lead

Responsible Party

Filip Krag Knop

Consultant endocrinologist, Professor of Clinical Endocrinology and Director of Center for Clinical Metabolic Research

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Center for Clinical Metabolic Research

Hellerup, Capital Region, Denmark

Countries

Denmark

Other Identifiers

H-19000992

Identifier Type: -

Identifier Source: org_study_id