Diabetes After Total Pancreatectomy
Conditions
Keywords
Pancreatectomy, Diabetes, SGLT-2 inhibitor, DPP4 inhibitor, glucagon
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from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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.
Interventions
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.
DRUGEmpagliflozin 25 MG
2 tablets of empagliflozin 25 mg.
OTHERPlacebo 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.
Sponsors
University Hospital, Gentofte, Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Intervention model description
The study is designed as a randomised, double-blinded, crossover study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| endogenous glucose production | -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes | Using intravenous and oral tracers |
| GLP-1, gastrin, cholecystokinin, GIP, oxyntomodulin | -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes | excurions measured as incremental area under the curve (iAUC) |
| Differences in gastric emptying, meassurement of s-paracetamol | -120-180 minutes | measurement of time to peak and incremental area under the curve (iAUC) |
| satiety, appetite, thirst, | -30, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes | assesed by a visual analougue scale (VAS) |
| Resting energy expenditure (REE) | -90, 150 and 150 minutes | measured by indirect calorimetry |
| PPG excurions measured as incremental area under the curve (iAUC) | -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 | -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes | will be measured every 30th min |
| food intake | 180 and 210 minutes | the ad libitum meal will be weighed before after ingestion. |
| p-glucose mmol/L | -120, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150 and 180 minutes | — |
Countries
Denmark
Outcome results
None listed