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

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from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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

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

Conditions
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Diabetes After Total Pancreatectomy

Intervention / Treatment
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* Drug: Sitagliptin 100mg
* Drug: Empagliflozin 25 MG
* Other: Placebo tablet


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study is designed as a randomised, double-blinded, crossover study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Pancreatectomized + Placebo<br>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<br>* 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.<br>|
| Active Comparator: Pancreatectomized + DPP-4 inhibitor<br>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<br>* 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.<br>|
| Active Comparator: Pancreatectomized + SGLT-2 inhibitor<br>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<br>* 2 tablets of empagliflozin 25 mg.<br>|
| Placebo Comparator: Healthy + Placebo<br>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<br>* 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.<br>|
| Active Comparator: Healthy + DPP-4 inhibitor<br>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<br>* 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.<br>|
| Active Comparator: Healthy + SGLT-2 inhibitor<br>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<br>* 2 tablets of empagliflozin 25 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatectomy, Diabetes, SGLT-2 inhibitor, DPP4 inhibitor, glucagon