Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion

Yan, Shijun; Conley, Jason M.; Reilly, Austin M.; Stull, Natalie D.; Abhyankar, Surabhi D; Ericsson, Aaron C.; Kono, Tatsuyoshi; Molosh, Andrei I.; Kubal, Chandrashekhar A.; Evans‐Molina, Carmella; Ren, Hongxia

doi:10.1016/j.celrep.2021.110179

Cited by 8 publications

(2 citation statements)

References 92 publications

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“…Unlike pancreatic β-cells, in which insulin secretion is mainly coupled to circulating glucose levels, enteroendocrine cells evolved to secrete hormones in response to the large variety of different compounds typically found in digested chyme, including glucose, fatty acids, amino acids and bile. Although glucose-stimulated GLP-1 release is coupled to membrane depolarization through SGLT-1 co-transporter function and voltage-gated Ca 2+ channels, GPCR pathway activation and cAMP-mediated regulation of exocytosis also play major roles in coupling GLP-1 with the arrival of fatty acids, amino acids and bile in the small intestine ( Yan et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor Antagonists Increase the Release of GLP-1 From Gut Endocrine Cells

et al. 2022

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Type 2 diabetes mellitus (T2DM) remains one of the most pressing health issues facing modern society. Several antidiabetic drugs are currently in clinical use to treat hyperglycaemia, but there is a need for new treatments that effectively restore pancreatic islet function in patients. Recent studies reported that both murine and human pancreatic islets exhibit enhanced insulin release and β-cell viability in response to N-methyl-D-aspartate (NMDA) receptor antagonists. Furthermore, oral administration of dextromethorphan, an over-the-counter NMDA receptor antagonist, to diabetic patients in a small clinical trial showed improved glucose tolerance and increased insulin release. However, the effects of NMDA receptor antagonists on the secretion of the incretin hormone GLP-1 was not tested, and nothing is known regarding how NMDA receptor antagonists may alter the secretion of gut hormones. This study demonstrates for the first time that, similar to β-cells, the NMDA receptor antagonist MK-801 increases the release of GLP-1 from a murine L-cell enteroendocrine model cell line, GLUTag cells. Furthermore, we report the 3′ mRNA expression profiling of GLUTag cells, with a specific focus on glutamate-activated receptors. We conclude that if NMDA receptor antagonists are to be pursued as an alternative, orally administered treatment for T2DM, it is essential that the effects of these drugs on the release of gut hormones, and specifically the incretin hormones, are fully investigated.

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Section: Discussionmentioning

confidence: 99%

NMDA Receptor Antagonists Increase the Release of GLP-1 From Gut Endocrine Cells

et al. 2022

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“…Within the last 10 years, a wide-range of organoid-based disease models have been developed. This includes models to reproduce inflammatory and metabolic diseases,135–137 infection and cancer 1 3 5 138–140…”

Section: Introductionmentioning

confidence: 99%

Organoids in gastrointestinal diseases: from experimental models to clinical translation

Günther

Winner

Stappenbeck

2022

Gut

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We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut–brain axis or gut–liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.

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Illuminating the druggable genome: Pathways to progress

Sharma,

Colvis,

Rodgers

et al. 2024

Drug Discovery Today

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Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion

Cited by 8 publications

References 92 publications

NMDA Receptor Antagonists Increase the Release of GLP-1 From Gut Endocrine Cells

NMDA Receptor Antagonists Increase the Release of GLP-1 From Gut Endocrine Cells

Organoids in gastrointestinal diseases: from experimental models to clinical translation

Illuminating the druggable genome: Pathways to progress

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