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Completed

NCT Number: NCT04061473

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

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from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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

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Key information

Conditions

Diabetes After Total Pancreatectomy Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Center for Clinical Metabolic Research

Hellerup, Capital Region, 2900, Denmark

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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.

Primary outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

University Hospital, Gentofte, Copenhagen

Other

Registry information

Acronym: Px-Meal

Important dates

Study start
2019
Primary completion
2019
Study completion
2019
First posted
Aug 19, 2019
Registry last updated
Sep 4, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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