Clinical trial NCT01666223: Effect of Bile Acids on GLP-1 Secretion
Official title: Effect of Bile Acids in the Gut on GLP-1 Secretion in Healthy Subjects and Patients With Type 2 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes
Obesity
Keywords: Type 2 diabetes
GLP-1
Bile acid
TGR-5
Lead sponsor: University Hospital, Gentofte, Copenhagen
Sponsor class: OTHER
First posted: 2012-08-16
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to describe the physiological, pathophysiological and potentially therapeutic implications of bile-induced glucagon-like peptide-1 (GLP-1) secretion in human glucose homeostasis.

Detailed description: The investigators hypothesize that even modest increments in endogenous GLP-1 secretion will elicit important antidiabetic effects of GLP-1. To evaluate whether bile acids have such effects, the investigators plan to perform intraduodenal infusion of two different bile acids and placebo.

Eligibility criteria: Patients with type 2 diabetes

Inclusion Criteria:

* danish caucasian ethnicity
* normal haemoglobin
* BMI \> 25 kg/m2
* HbA1c \< 9%
* informed consent

Exclusion Criteria:

* liver disease(ALT and AST \> upper reference limit)
* gastrointestinal disease
* liver and biliary tract disease
* nephropathy (serum creatinine \> 150 μM, and/or albuminuria)
* treatment with insulin, glp-1 analogues and/ or DPP-4 inhibitors
* treatment with medicine that can not be paused for 12 hours
* previous abdominal surgery eg. cholecystectomy
* BMI \< 18,5 kg/m2 or \> 35 kg/m2

Healthy Volunteers

Inclusion Criteria:

* danish caucasian ethnicity
* normal haemoglobin
* HbA1c \< 6,0 (American Diabetes Association guidelines)
* informed consent

Exclusion Criteria:

* liver disease(ALT and AST \> upper reference limit)
* gastrointestinal disease
* liver and biliary tract disease
* nephropathy (serum creatinine \> 150 μM, and/or albuminuria)
* treatment with medicine that can not be paused for 12 hours
* previous abdominal surgery eg. cholecystectomy
* BMI \< 18,5 kg/m2 or \> 35 kg/m2
* first degree relatives diagnosed with diabetes
* previously diagnosed with diabetes, or treated with antidiabetic agents

Primary outcomes:
measure: Change in GLP-1
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
Secondary outcomes:
measure: Change in insulin
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in C-peptide
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in glucagon
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in glucagon-like-peptide 2 (GLP-2)
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in glucose-dependent insulinotropic polypeptide (GIP)
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in peptide YY (PYY)
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in oxyntomodulin
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in bile acids
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in gastrin
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in CCK
timeFrame: At baseline, and at 5, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150 and 180 minutes
measure: Change in appetite, satiety and prospective food consumption
timeFrame: At baseline, and 30, 60, 90, 120 and 180 minutes
measure: Change in gallbladder volume
timeFrame: -30, 0 (baseline), 30, 60, 120 og 180 minutes
measure: Change in basal metabolic rate
timeFrame: At -30, 60 og 150 minutes
measure: Change in bile acid composition
timeFrame: At -30, 0, 30, 60, 120 og 180 minutes
Other outcomes:
Locations:
city: Hellerup
country: Denmark
facility: Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen
state: Copenhagen
Study officials:
affiliation: Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, University of Copenhagen
name: Morten Hansen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, Nakamura T, Itadani H, Tanaka K. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002 Nov 15;298(5):714-9. doi: 10.1016/s0006-291x(02)02550-0.
citation: Adrian TE, Ballantyne GH, Longo WE, Bilchik AJ, Graham S, Basson MD, Tierney RP, Modlin IM. Deoxycholate is an important releaser of peptide YY and enteroglucagon from the human colon. Gut. 1993 Sep;34(9):1219-24. doi: 10.1136/gut.34.9.1219.
citation: Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun. 2005 Apr 1;329(1):386-90. doi: 10.1016/j.bbrc.2005.01.139.
citation: Rafferty EP, Wylie AR, Hand KH, Elliott CE, Grieve DJ, Green BD. Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R(-/-) mice. Biol Chem. 2011 Apr;392(6):539-46. doi: 10.1515/BC.2011.050. Epub 2011 Apr 27.