Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery

Maartje C.P. Geraedts, Tatsuyuki Takahashi, Stephan Vigues, Michele L. Markwardt, Andongfac Nkobena, Renee E. Cockerham, Andras Hajnal, Cedrick D. Dotson, Mark A. Rizzo, Steven D. Munger

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52 Scopus citations

Abstract

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+ (KATP) 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 KATP 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 KATP channeldependent 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.

Original languageEnglish (US)
Pages (from-to)E464-E474
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume303
Issue number4
DOIs
StatePublished - 2012

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Geraedts, M. C. P., Takahashi, T., Vigues, S., Markwardt, M. L., Nkobena, A., Cockerham, R. E., Hajnal, A., Dotson, C. D., Rizzo, M. A., & Munger, S. D. (2012). Transformation of postingestive glucose responses after deletion of sweet taste receptor subunits or gastric bypass surgery. American Journal of Physiology - Endocrinology and Metabolism, 303(4), E464-E474. https://doi.org/10.1152/ajpendo.00163.2012