Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying

Yujiro Hayashi, Yoshitaka Toyomasu, Siva Arumugam Saravanaperumal, Michael R. Bardsley, John A. Smestad, Andrea Lorincz, Seth T. Eisenman, Gianluca Cipriani, Molly H. Nelson Holte, Fatimah J. Al Khazal, Sabriya A. Syed, Gabriella B. Gajdos, Kyoung Moo Choi, Gary J. Stoltz, Katie E. Miller, Michael L. Kendrick, Brian P. Rubin, Simon J. Gibbons, Adil E. Bharucha, David R. LindenLouis James Maher, Gianrico Farrugia, Tamas Ordog

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Background & Aims Depletion of interstitial cells of Cajal (ICCs) is common in diabetic gastroparesis. However, in approximately 20% of patients with diabetes, gastric emptying (GE) is accelerated. GE also occurs faster in obese individuals, and is associated with increased blood levels of glucose in patients with type 2 diabetes. To understand the fate of ICCs in hyperinsulinemic, hyperglycemic states characterized by rapid GE, we studied mice with mutation of the leptin receptor (Leprdb/db), which in our colony had accelerated GE. We also investigated hyperglycemia-induced signaling in the ICC lineage and ICC dependence on glucose oxidative metabolism in mice with disruption of the succinate dehydrogenase complex, subunit C gene (Sdhc). Methods Mice were given breath tests to analyze GE of solids. ICCs were studied by flow cytometry, intracellular electrophysiology, isometric contractility measurement, reverse-transcription polymerase chain reaction, immunoblot, immunohistochemistry, enzyme-linked immunosorbent assays, and metabolite assays; cells and tissues were manipulated pharmacologically and by RNA interference. Viable cell counts, proliferation, and apoptosis were determined by methyltetrazolium, Ki-67, proliferating cell nuclear antigen, bromodeoxyuridine, and caspase–Glo 3/7 assays. Sdhc was disrupted in 2 different strains of mice via cre recombinase. Results In obese, hyperglycemic, hyperinsulinemic female Leprdb/db mice, GE was accelerated and gastric ICC and phasic cholinergic responses were increased. Female KitK641E/+ mice, which have genetically induced hyperplasia of ICCs, also had accelerated GE. In isolated cells of the ICC lineage and gastric organotypic cultures, hyperglycemia stimulated proliferation by mitogen-activated protein kinase 1 (MAPK1)- and MAPK3-dependent stabilization of ets variant 1—a master transcription factor for ICCs—and consequent up-regulation of v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) receptor tyrosine kinase. Opposite changes occurred in mice with disruption of Sdhc. Conclusions Hyperglycemia increases ICCs via oxidative metabolism-dependent, MAPK1- and MAPK3-mediated stabilization of ets variant 1 and increased expression of KIT, causing rapid GE. Increases in ICCs might contribute to the acceleration in GE observed in some patients with diabetes.

Original languageEnglish (US)
Pages (from-to)521-535.e20
JournalGastroenterology
Volume153
Issue number2
DOIs
StatePublished - Aug 2017

Keywords

  • ERK
  • Gastrointestinal Motility
  • Mesenchymal Cells
  • Signal Transduction

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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