Progressive Erosion of β-Cell Function Precedes the Onset of Hyperglycemia in the NOD Mouse Model of Type 1 Diabetes
Diego Ize-Ludlow,Yaíma L. Lightfoot,Matthew Parker,Song Xue,Clive Wasserfall,Michael J. Haller,Desmond A. Schatz,Dorothy J. Becker,Mark A. Atkinson,Clayton E. Mathews +9 more
Reads0
Chats0
TLDR
There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes.Abstract:
OBJECTIVE A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice—the prototypic model for human type 1 diabetes.
RESEARCH DESIGN AND METHODS Morning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6–14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests.
RESULTS During prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity.
CONCLUSIONS There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive β-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease.read more
Citations
More filters
Journal ArticleDOI
Mechanisms of Insulin Action and Insulin Resistance
TL;DR: This work aims to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response.
Journal ArticleDOI
Islet β-Cell Endoplasmic Reticulum Stress Precedes the Onset of Type 1 Diabetes in the Nonobese Diabetic Mouse Model
Sarah A. Tersey,Yurika Nishiki,Andrew T. Templin,Susanne M. Cabrera,Natalie D. Stull,Stephanie C. Colvin,Carmella Evans-Molina,Jenna L. Rickus,Bernhard Maier,Raghavendra G. Mirmira +9 more
TL;DR: It is concluded that β-cells of prediabetic NOD mice display dysfunction and overt ER stress that may be driven by NF-κB signaling, and strategies that attenuate pathways leading to ER stress may preserve β-cell function in type 1 diabetes.
Journal ArticleDOI
Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice
Alexandra E. Livanos,Thomas U. Greiner,Pajau Vangay,Wimal Pathmasiri,Delisha A. Stewart,Susan McRitchie,Huilin Li,Jennifer Chung,Jiho Sohn,Sara Kim,Zhan Gao,Cecily M. Barber,Joanne Kim,Sandy Ng,Arlin B. Rogers,Susan Sumner,Xue-Song Zhang,Ken Cadwell,Dan Knights,Alexander V. Alekseyenko,Fredrik Bäckhed,Fredrik Bäckhed,Martin J. Blaser,Martin J. Blaser +23 more
TL;DR: Findings show that early-life antibiotic treatments alter the gut microbiota and its metabolic capacities, intestinal gene expression and T-cell populations, accelerating T1D onset in non-obese diabetic mice.
Journal ArticleDOI
The diabetes susceptibility gene Clec16a regulates mitophagy.
Scott A. Soleimanpour,Scott A. Soleimanpour,Aditi Gupta,Marina Bakay,Alana M. Ferrari,David N. Groff,João Fadista,Lynn A. Spruce,Jake A. Kushner,Leif Groop,Steven H. Seeholzer,Brett A. Kaufman,Hakon Hakonarson,Hakon Hakonarson,Doris A. Stoffers +14 more
TL;DR: It is reported that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1 that controls β cell function and prevents diabetes by controlling mitophagy.
Journal ArticleDOI
High‐energy diets may induce a pre‐diabetic state altering testicular glycolytic metabolic profile and male reproductive parameters
Luís Rato,Marco G. Alves,Tânia R. Dias,G. Lopes,José E. Cavaco,Sílvia Socorro,Pedro Oliveira +6 more
TL;DR: It is suggested that HED induces a pre‐diabetic state that may impair reproductive function by modulating overall testicular metabolism and the first report on testicular metabolic features and mechanisms related with the onset of a pre-di diabetic state is reported.
References
More filters
Journal ArticleDOI
Type I diabetes mellitus. A chronic autoimmune disease.
TL;DR: Evidence has suggested that progressive loss of first-phase insulin secretion precedes diabetes, and immunologic findings have suggested that selection of selected assays for islet-cell antibodies has been defined.
Journal ArticleDOI
Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.
Bart Keymeulen,Evy Vandemeulebroucke,Anette-G. Ziegler,Chantal Mathieu,Leonard Kaufman,Geoff Hale,Frans Gorus,Michel Goldman,M Walter,Sophie Candon,Liliane Schandené,Laurent Crenier,Christophe De Block,Jean-Marie Seigneurin,Pieter De Pauw,Denis Pierard,Ilse Weets,Peppy Rebello,Pru Bird,Eleanor Berrie,Mark Frewin,Herman Waldmann,Jean-François Bach,Daniel Pipeleers,Lucienne Chatenoud +24 more
TL;DR: Short-term treatment with CD3 antibody preserves residual beta-cell function for at least 18 months in patients with recent-onset type 1 diabetes, as suggested by the results of a phase 1 study.
Journal ArticleDOI
Rituximab, B-Lymphocyte Depletion, and Preservation of Beta-Cell Function
Mark D. Pescovitz,Carla J. Greenbaum,Heidi Krause-Steinrauf,Dorothy J. Becker,Stephen E. Gitelman,Robin Goland,Peter A. Gottlieb,Jennifer B. Marks,Paula McGee,Antoinette Moran,Philip Raskin,Henry Rodriguez,Desmond A. Schatz,Diane K. Wherrett,Darrell M. Wilson,John M. Lachin,Jay S. Skyler +16 more
TL;DR: The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition.
Journal ArticleDOI
A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes
Kevan C. Herold,Stephen E. Gitelman,Umesh Masharani,William Hagopian,Brygida Bisikirska,David Donaldson,Kristina I. Rother,Beverly Diamond,David M. Harlan,Jeffrey A. Bluestone +9 more
TL;DR: It is concluded that treatment with the anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.
Journal ArticleDOI
GAD treatment and insulin secretion in recent-onset type 1 diabetes
Johnny Ludvigsson,Maria Faresjö,Maria Hjorth,Stina Axelsson,Mikael Chéramy,Mikael Pihl,Outi Vaarala,Gun Forsander,Sten A. Ivarsson,Calle Johansson,Agne Lindh,Nils-Östen Nilsson,Jan Åman,Eva Örtqvist,Peter Zerhouni,Rosaura Casas +15 more
TL;DR: GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement.