title: Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes.
abstract: We compared the evolution of insulin resistance, hyperglycemia, and pancreatic β-cell dysfunction in the Nile rat (Arvicanthis niloticus), a diurnal rodent model of spontaneous type 2 diabetes (T2D), when maintained on regular laboratory chow versus a high-fiber diet. Chow-fed Nile rats already displayed symptoms characteristic of insulin resistance at 2 months (increased fat/lean mass ratio and hyperinsulinemia). Hyperglycemia was first detected at 6 months, with increased incidence at 12 months. By this age, pancreatic islet structure was disrupted (increased α-cell area), insulin secretion was impaired (reduced insulin secretion and content) in isolated islets, insulin processing was compromised (accumulation of proinsulin and C-peptide inside islets), and endoplasmic reticulum (ER) chaperone protein ERp44 was upregulated in insulin-producing β-cells. By contrast, high-fiber-fed Nile rats had normoglycemia with compensatory increase in β-cell mass resulting in maintained pancreatic function. Fasting glucose levels were predicted by the α/β-cell ratios. Our results show that Nile rats fed chow recapitulate the five stages of progression of T2D as occurs in human disease, including insulin-resistant hyperglycemia and pancreatic islet β-cell dysfunction associated with ER stress. Modification of diet alone permits long-term β-cell compensation and prevents T2D.
authors.affiliation: Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Kaiyuan
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of PhysiologyUniversity of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gotzmann
authors.affiliation: Department of Ophthalmology and Visual SciencesUniversity of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sharee
authors.initials: S
authors.lastname: Kuny
authors.affiliation: Department of PhysiologyUniversity of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of PhysiologyUniversity of Alberta, Edmonton, Alberta, Canada Department of Ophthalmology and Visual SciencesUniversity of Alberta, Edmonton, Alberta, Canada ysauve@ualberta.ca.
authors.forename: Yves
authors.initials: Y
authors.lastname: Sauvé
authors.affiliation: Department of AgriculturalFood and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada Department of PhysiologyUniversity of Alberta, Edmonton, Alberta, Canada.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Chan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000178:diet therapy / Q000209:etiology / Q000503:physiopathology*; D004043:Dietary Fiber / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D008297:Male; D051189:Murinae
chemical_list: D001786:Blood Glucose; D004043:Dietary Fiber; D007328:Insulin
keywords: animal model; endoplasmic reticulum stress; insulin processing; insulin resistance; type 2 diabetes