Involvement of Dipeptidyl Peptidase-4 and Sodium-glucose Co-transporter-2 in Extrapancreatic Glucagon Secretion
Condition: Diabetes After Total Pancreatectomy
Study type: Interventional

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      enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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.
    


Intervention name(s): Sitagliptin 100mg; Empagliflozin 25 MG; Placebo tablet
Intervention type(s): Drug; Drug; Other
Intervention description(s): 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.; 2 tablets of empagliflozin 25 mg.; 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.
Intervention MeSH terms: Sitagliptin Phosphate; Empagliflozin
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
Keywords: Pancreatectomy; Diabetes; SGLT-2 inhibitor; DPP4 inhibitor; glucagon