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Trial record 33 of 751 for:    Area Under Curve AND meal

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

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ClinicalTrials.gov Identifier: NCT04061473
Recruitment Status : Completed
First Posted : August 19, 2019
Last Update Posted : September 4, 2019
Sponsor:
Information provided by (Responsible Party):
Filip Krag Knop, University Hospital, Gentofte, Copenhagen

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from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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


Condition or disease Intervention/treatment Phase
Diabetes After Total Pancreatectomy Drug: Sitagliptin 100mg Drug: Empagliflozin 25 MG Other: Placebo tablet Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: The study is designed as a randomised, double-blinded, crossover study.
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Involvement of Dipeptidyl Peptidase-4 and Sodium-glucose Co-transporter-2 in Extrapancreatic Glucagon Secretion
Actual Study Start Date : April 2, 2019
Actual Primary Completion Date : August 20, 2019
Actual Study Completion Date : August 20, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Glucagon

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.




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. PPG excurions measured as incremental area under the curve (iAUC) [ Time Frame: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]
  2. endogenous glucose production [ Time Frame: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]
    Using intravenous and oral tracers

  3. GLP-1, gastrin, cholecystokinin, GIP, oxyntomodulin [ Time Frame: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]
    excurions measured as incremental area under the curve (iAUC)

  4. Differences in gastric emptying, meassurement of s-paracetamol [ Time Frame: -120-180 minutes ]
    measurement of time to peak and incremental area under the curve (iAUC)

  5. satiety, appetite, thirst, [ Time Frame: -30, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]
    assesed by a visual analougue scale (VAS)

  6. Resting energy expenditure (REE) [ Time Frame: -90, 150 and 150 minutes ]
    measured by indirect calorimetry

  7. p-glucose mmol/L [ Time Frame: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]
  8. s-peptide pmol/l [ Time Frame: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]
  9. s-insulin [ Time Frame: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]
  10. Pulse and blood pressure [ Time Frame: -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes ]
    will be measured every 30th min

  11. food intake [ Time Frame: 180 and 210 minutes ]
    the ad libitum meal will be weighed before after ingestion.



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04061473


Locations
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Denmark
Center for Clinical Metabolic Research
Hellerup, Capital Region, Denmark, 2900
Sponsors and Collaborators
University Hospital, Gentofte, Copenhagen

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Responsible Party: Filip Krag Knop, Consultant endocrinologist, Professor of Clinical Endocrinology and Director of Center for Clinical Metabolic Research, University Hospital, Gentofte, Copenhagen
ClinicalTrials.gov Identifier: NCT04061473     History of Changes
Other Study ID Numbers: H-19000992
First Posted: August 19, 2019    Key Record Dates
Last Update Posted: September 4, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Filip Krag Knop, University Hospital, Gentofte, Copenhagen:
Pancreatectomy
Diabetes
SGLT-2 inhibitor
DPP4 inhibitor
glucagon
Additional relevant MeSH terms:
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Acetaminophen
Sitagliptin Phosphate
Empagliflozin
Dipeptidyl-Peptidase IV Inhibitors
Sodium-Glucose Transporter 2 Inhibitors
Glucagon
Glucagon-Like Peptide 1
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antipyretics
Gastrointestinal Agents