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from an extra pancreatic origin - most likely from enteroendocrine cells in the intestinal epithelium (Baekdal et al., unpublished data).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


Eligibility Criteria:
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