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The purpose of this study is do determine the functional significance of the G protein-coupled receptor TGR5 in the secretion of GI satiation peptides by using natural bile acids and oleanolic acid (triterpenoid compound of plant origin) as TGR5 agonists.
TGR5 is expressed in GLP-1-secreting cell lines and L cells from mice; gain- and loss-of-function models suggest a physiological role for TGR5 activation on GLP-1 secretion in rodents. TGR5 signaling showed improved postprandial glucose tolerance in obese mice, associated with marked postprandial GLP-1 release and insulin secretion. In contrast, TGR5-/- mice exhibited reduced glucose tolerance. In animals, TGR5 activation has been shown for natural bile acids (BAs) and triterpenoid compounds of plant origin, such as oleanolic acid (OA), suggesting a role for postprandial BAs in modulating nutrient-induced GLP-1 secretion. We therefore hypothesized that intraduodenal (ID) perfusions of TGR5 agonists (BAs and OA) stimulate the secretion of GLP-1 with respective changes in the glucose metabolism of healthy humans.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ID saline | Placebo Comparator | ID saline by feeding tube |
|
| ID saline + CDCA (5 mmol/L) | Active Comparator | CDCA = chenodeoxycholic acid (primary bile acid) |
|
| ID + CDCA (15 mmol/L) | Active Comparator | CDCA = chenodeoxycholic acid (primary bile acid) |
|
| ID saline + oleanolic acid (1 mmol/L) | Active Comparator |
| |
| ID saline + CDCA (5 mmol/L) + oleic acid | Active Comparator |
| |
| ID saline + oleic acid (20 mmol/L) | Placebo Comparator |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| saline | Other | intraduodenal perfusion |
|
| Measure | Description | Time Frame |
|---|---|---|
| Gastrointestinal satiation peptide secretion | Assessment of plasma GLP-1, PYY and CCK release to BA and OA stimulation | 3 hours blood sampling |
| Measure | Description | Time Frame |
|---|---|---|
| Serum bile acids | Assessment of serum bile acids levels to BA and OA stimulation | 3 hours blood sampling |
| Appetite perceptions during 3 hours using visual analogue scales | Assessment of the following appetite perceptions markers: feelings of hunger, feelings of prospective food consumption, feelings of fullness and feelings of satiety using validated visual analogue scales |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Christoph Beglinger, MD | University Hospital Basel, Phase 1 Research Unit, Basel Switzerland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Basel, Phase 1 Research Unit | Basel | 4031 | Switzerland |
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| ID | Term |
|---|---|
| D004455 | Echolocation |
| ID | Term |
|---|---|
| D000819 | Animal Communication |
| D001522 | Behavior, Animal |
| D001519 | Behavior |
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| ID | Term |
|---|---|
| D012965 | Sodium Chloride |
| D001647 | Bile Acids and Salts |
| D002635 | Chenodeoxycholic Acid |
| D009828 | Oleanolic Acid |
| D019301 | Oleic Acid |
| D005227 | Fatty Acids |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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| bile acid (CDCA, chenodeoxycholic acid) | Other | intraduodenal perfusion |
|
|
| oleanolic acid | Other | intraduodenal perfusion |
|
|
| oleic acid | Dietary Supplement | intraduodenal perfusion |
|
|
| 3 hours |
| Glucose and insulin secretion | Assessment of plasma glucose and insulin levels to BA and OA stimulation | 3 hours blood sampling |
| D017670 |
| Sodium Compounds |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D003840 | Deoxycholic Acid |
| D002793 | Cholic Acids |
| D002757 | Cholanes |
| D053978 | Pentacyclic Triterpenes |
| D014315 | Triterpenes |
| D013729 | Terpenes |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D012502 | Sapogenins |
| D009829 | Oleic Acids |
| D005229 | Fatty Acids, Monounsaturated |
| D005231 | Fatty Acids, Unsaturated |
| D008055 | Lipids |