NCT04061473

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from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
20

participants targeted

Target at below P25 for not_applicable

Timeline
Completed

Started Apr 2019

Shorter than P25 for not_applicable

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

April 2, 2019

Completed
5 months until next milestone

First Submitted

Initial submission to the registry

August 15, 2019

Completed
4 days until next milestone

First Posted

Study publicly available on registry

August 19, 2019

Completed
1 day until next milestone

Primary Completion

Last participant's last visit for primary outcome

August 20, 2019

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

August 20, 2019

Completed
Last Updated

September 4, 2019

Status Verified

September 1, 2019

Enrollment Period

5 months

First QC Date

August 15, 2019

Last Update Submit

September 2, 2019

Conditions

Diabetes After Total Pancreatectomy

Keywords

PancreatectomyDiabetesSGLT-2 inhibitorDPP4 inhibitorglucagon

Outcome Measures

Primary Outcomes (1)

  • 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 Outcomes (11)

  • 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

    -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes

  • GLP-1, gastrin, cholecystokinin, GIP, oxyntomodulin

    -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes

  • Differences in gastric emptying, meassurement of s-paracetamol

    -120-180 minutes

  • satiety, appetite, thirst,

    -30, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes

  • +6 more secondary outcomes

Study Arms (6)

Pancreatectomized + Placebo

PLACEBO COMPARATOR

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

Pancreatectomized + DPP-4 inhibitor

ACTIVE COMPARATOR

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

Pancreatectomized + SGLT-2 inhibitor

ACTIVE COMPARATOR

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

Healthy + Placebo

PLACEBO COMPARATOR

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

Healthy + DPP-4 inhibitor

ACTIVE COMPARATOR

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

Healthy + SGLT-2 inhibitor

ACTIVE COMPARATOR

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

Interventions

Sitagliptin 100mgDRUG

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 + DPP-4 inhibitorPancreatectomized + DPP-4 inhibitor
Empagliflozin 25 MGDRUG

2 tablets of empagliflozin 25 mg.

Healthy + SGLT-2 inhibitorPancreatectomized + SGLT-2 inhibitor
Placebo tabletOTHER

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 + PlaceboPancreatectomized + Placebo

Eligibility Criteria

Age18 Years - 85 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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)
  • +4 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Center for Clinical Metabolic Research

Hellerup, Capital Region, 2900, Denmark

Location

MeSH Terms

Conditions

Diabetes Mellitus

Interventions

Sitagliptin Phosphateempagliflozin

Condition Hierarchy (Ancestors)

Glucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesEndocrine System Diseases

Intervention Hierarchy (Ancestors)

TriazolesAzolesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsPyrazines

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
DOUBLE
Who Masked
PARTICIPANT, INVESTIGATOR
Purpose
BASIC SCIENCE
Intervention Model
CROSSOVER
Model Details: The study is designed as a randomised, double-blinded, crossover study.
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Consultant endocrinologist, Professor of Clinical Endocrinology and Director of Center for Clinical Metabolic Research

Study Record Dates

First Submitted

August 15, 2019

First Posted

August 19, 2019

Study Start

April 2, 2019

Primary Completion

August 20, 2019

Study Completion

August 20, 2019

Last Updated

September 4, 2019

Record last verified: 2019-09

Locations

DK(1)