Involvement of Dipeptidyl Peptidase-4 and Sodium-glucose Co-transporter-2 in Extrapancreatic Glucagon Secretion
Status:
Completed
Trial end date:
2019-08-20
Target enrollment:
Participant gender:
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enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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.