Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery.
The glucose-dependent secretion of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) is a critical step in the regulation of glucose homeostasis. Two molecular mechanisms have separately been suggested as the primary mediator of intestinal glucose-stimulated GLP-1 secretion (GSGS): one is a metabotropic mechanism requiring the sweet taste receptor type 2 (T1R2) + type 3 (T1R3) while the second is a metabolic mechanism requiring ATP-sensitive K(+) (K(ATP)) channels. By quantifying sugar-stimulated hormone secretion in receptor knockout mice and in rats receiving Roux-en-Y gastric bypass (RYGB), we found that both of these mechanisms contribute to GSGS; however, the mechanisms exhibit different selectivity, regulation, and localization. T1R3(-/-) mice showed impaired glucose and insulin homeostasis during an oral glucose challenge as well as slowed insulin granule exocytosis from isolated pancreatic islets. Glucose, fructose, and sucralose evoked GLP-1 secretion from T1R3(+/+), but not T1R3(-/-), ileum explants; this secretion was not mimicked by the K(ATP) channel blocker glibenclamide. T1R2(-/-) mice showed normal glycemic control and partial small intestine GSGS, suggesting that T1R3 can mediate GSGS without T1R2. Robust GSGS that was K(ATP) channel-dependent and glucose-specific emerged in the large intestine of T1R3(-/-) mice and RYGB rats in association with elevated fecal carbohydrate throughout the distal gut. Our results demonstrate that the small and large intestines utilize distinct mechanisms for GSGS and suggest novel large intestine targets that could mimic the improved glycemic control seen after RYGB.
Division of Endocrinology, Diabetes, and Nutrition, Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Maartje C P
MC
Geraedts
Tatsuyuki
T
Takahashi
Stephan
S
Vigues
Michele L
ML
Markwardt
Andongfac
A
Nkobena
Renee E
RE
Cockerham
Andras
A
Hajnal
Cedrick D
CD
Dotson
Mark A
MA
Rizzo
Steven D
SD
Munger
D000818:Animals; D002478:Cells, Cultured; D005243:Feces / Q000737:chemistry; D005632:Fructose / Q000494:pharmacology; D015390:Gastric Bypass; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007420:Intestine, Large / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism; D051379:Mice; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013395:Sucrose / Q000031:analogs & derivatives / Q000494:pharmacology; D013650:Taste Buds / Q000187:drug effects / Q000378:metabolism*
D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D043562:Receptors, G-Protein-Coupled; C431926:taste receptors, type 1; D005632:Fructose; D013395:Sucrose; D052216:Glucagon-Like Peptide 1; C026285:trichlorosucrose; D005947:Glucose; D005905:Glyburide