Yaling Yi1, Xingshen Sun1, Bo Liang1, Nan He1, Katherine N Gibson-Corley2, Andrew W Norris3, John F Engelhardt4, Aliye Uc5. 1. Department of Anatomy and Cell Biology, Iowa City, IA, USA. 2. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. 3. Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA; Department of Pediatrics, lowa City, IA, USA; Department of Biochemistry, Iowa City, IA, USA. 4. Department of Anatomy and Cell Biology, Iowa City, IA, USA; Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA. 5. Fraternal Order of Eagles Diabetes Research Center, Iowa City, IA, USA; Department of Pediatrics, lowa City, IA, USA; Department of Radiation Oncology; University of Iowa, Iowa City, IA, USA. Electronic address: aliye-uc@uiowa.edu.
Abstract
BACKGROUND: / Objectives: The pathogenesis of hyperglycemia during acute pancreatitis (AP) remains unknown due to inaccessibility of human tissues and lack of animal models. We aimed to develop an animal model to study the mechanisms of hyperglycemia and impaired glucose tolerance in AP. METHODS: We injected ferrets with intraperitoneal cerulein (50 μg/kg, 9 hourly injections) or saline. Blood samples were collected for glucose (0, 4, 8, 12, 24h); TNF-α, IL-6 (6h); amylase, lipase, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) (24h). Animals underwent oral glucose tolerance test (OGTT), mixed meal tolerance test (MMTT) at 24h or 3 months, followed by harvesting pancreas for histopathology and immunostaining. RESULTS: Cerulein-injected ferrets exhibited mild pancreatic edema, neutrophil infiltration, and elevations in serum amylase, lipase, TNF-α, IL-6, consistent with AP. Plasma glucose was significantly higher in ferrets with AP at all time points. Plasma glucagon, GLP-1 and PP were significantly higher in cerulein-injected animals, while plasma insulin was significantly lower compared to controls. OGTT and MMTT showed abnormal glycemic responses with higher area under the curve. The hypoglycemic response to insulin injection was completely lost, suggestive of insulin resistance. OGTT showed low plasma insulin; MMTT confirmed low insulin and GIP; abnormal OGTT and MMTT responses returned to normal 3 months after cerulein injection. CONCLUSIONS: Acute cerulein injection causes mild acute pancreatitis in ferrets and hyperglycemia related to transient islet cell dysfunction and insulin resistance. The ferret cerulein model may contribute to the understanding of hyperglycemia in acute pancreatitis.
BACKGROUND: / Objectives: The pathogenesis of hyperglycemia during acute pancreatitis (AP) remains unknown due to inaccessibility of human tissues and lack of animal models. We aimed to develop an animal model to study the mechanisms of hyperglycemia and impaired glucose tolerance in AP. METHODS: We injected ferrets with intraperitoneal cerulein (50 μg/kg, 9 hourly injections) or saline. Blood samples were collected for glucose (0, 4, 8, 12, 24h); TNF-α, IL-6 (6h); amylase, lipase, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) (24h). Animals underwent oral glucose tolerance test (OGTT), mixed meal tolerance test (MMTT) at 24h or 3 months, followed by harvesting pancreas for histopathology and immunostaining. RESULTS: Cerulein-injected ferrets exhibited mild pancreatic edema, neutrophil infiltration, and elevations in serum amylase, lipase, TNF-α, IL-6, consistent with AP. Plasma glucose was significantly higher in ferrets with AP at all time points. Plasma glucagon, GLP-1 and PP were significantly higher in cerulein-injected animals, while plasma insulin was significantly lower compared to controls. OGTT and MMTT showed abnormal glycemic responses with higher area under the curve. The hypoglycemic response to insulin injection was completely lost, suggestive of insulin resistance. OGTT showed low plasma insulin; MMTT confirmed low insulin and GIP; abnormal OGTT and MMTT responses returned to normal 3 months after cerulein injection. CONCLUSIONS: Acute cerulein injection causes mild acute pancreatitis in ferrets and hyperglycemia related to transient islet cell dysfunction and insulin resistance. The ferret cerulein model may contribute to the understanding of hyperglycemia in acute pancreatitis.
Authors: Phil A Hart; Melena D Bellin; Dana K Andersen; David Bradley; Zobeida Cruz-Monserrate; Christopher E Forsmark; Mark O Goodarzi; Aida Habtezion; Murray Korc; Yogish C Kudva; Stephen J Pandol; Dhiraj Yadav; Suresh T Chari Journal: Lancet Gastroenterol Hepatol Date: 2016-10-12
Authors: Xingshen Sun; Alicia K Olivier; Yaling Yi; Christopher E Pope; Hillary S Hayden; Bo Liang; Hongshu Sui; Weihong Zhou; Kyle R Hager; Yulong Zhang; Xiaoming Liu; Ziying Yan; John T Fisher; Nicholas W Keiser; Yi Song; Scott R Tyler; J Adam Goeken; Joann M Kinyon; Matthew C Radey; Danielle Fligg; Xiaoyan Wang; Weiliang Xie; Thomas J Lynch; Paul M Kaminsky; Mitchell J Brittnacher; Samuel I Miller; Kalpaj Parekh; David K Meyerholz; Lucas R Hoffman; Timothy Frana; Zoe A Stewart; John F Engelhardt Journal: Am J Pathol Date: 2014-03-15 Impact factor: 4.307
Authors: Jami L Saloman; Kathryn M Albers; Zobeida Cruz-Monserrate; Brian M Davis; Mouad Edderkaoui; Guido Eibl; Ariel Y Epouhe; Jeremy Y Gedeon; Fred S Gorelick; Paul J Grippo; Guy E Groblewski; Sohail Z Husain; Keane K Y Lai; Stephen J Pandol; Aliye Uc; Li Wen; David C Whitcomb Journal: Pancreas Date: 2019-07 Impact factor: 3.327
Authors: Xingshen Sun; Hongshu Sui; John T Fisher; Ziying Yan; Xiaoming Liu; Hyung-Ju Cho; Nam Soo Joo; Yulong Zhang; Weihong Zhou; Yaling Yi; Joann M Kinyon; Diana C Lei-Butters; Michelle A Griffin; Paul Naumann; Meihui Luo; Jill Ascher; Kai Wang; Timothy Frana; Jeffrey J Wine; David K Meyerholz; John F Engelhardt Journal: J Clin Invest Date: 2010-08-25 Impact factor: 14.808
Authors: Alexandra Zauner; Petra Nimmerrichter; Christian Anderwald; Martin Bischof; Mark Schiefermeier; Klaus Ratheiser; Bruno Schneeweiss; Christian Zauner Journal: Metabolism Date: 2007-01 Impact factor: 8.694