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Deletion of Carboxypeptidase E in β-Cells Disrupts Proinsulin Processing but Does Not Lead to Spontaneous Development of Diabetes in Mice

Journal Article · · Diabetes
DOI:https://doi.org/10.2337/db22-0945· OSTI ID:2203041
 [1];  [1];  [2];  [2];  [3];  [1];  [4];  [4];  [1];  [1];  [3];  [2];  [1]
  1. University of British Columbia, Vancouver, BC (Canada); BC Children’s Hospital Research Institute, Vancouver, BC (Canada)
  2. Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
  3. University of Alberta, Edmonton, AB (Canada)
  4. BC Children’s Hospital Research Institute, Vancouver, BC (Canada)
+ Show Author Affiliations
Carboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers of CPE mutations have elevated plasma proinsulin and develop severe obesity and hyperglycemia. We aimed to determine whether loss of Cpe in pancreatic β-cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic β-cell–specific Cpe knockout mice (βCpeKO; Cpefl/fl x Ins1Cre/+) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in βCpeKO islets remained intact. High-fat diet–fed βCpeKO mice showed weight gain and glucose tolerance comparable with those of Wt littermates. Notably, β-cell area was increased in chow-fed βCpeKO mice and β-cell replication was elevated in βCpeKO islets. Transcriptomic analysis of βCpeKO β-cells revealed elevated glycolysis and Hif1α-target gene expression. On high glucose challenge, β-cells from βCpeKO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced MafA, and elevated Aldh1a3 transcript levels. Following multiple low-dose streptozotocin injections, βCpeKO mice had accelerated development of hyperglycemia with reduced β-cell insulin and Glut2 expression. In conclusion, these findings suggest that Cpe and proper proinsulin processing are critical in maintaining β-cell function during the development of hyperglycemia.
Research Organization:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); Natural Sciences and Engineering Research Council of Canada (NSERC); Canadian Institutes of Health Research (CIHR); National Institutes of Health (NIH)
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
2203041
Report Number(s):
PNNL-SA--186901
Journal Information:
Diabetes, Journal Name: Diabetes Journal Issue: 9 Vol. 72; ISSN 0012-1797
Publisher:
American Diabetes AssociationCopyright Statement
Country of Publication:
United States
Language:
English

References (52)

Beta-Cell Apoptosis is Responsible for the Development of iddm in the Multiple Low-Dose Streptozotocin Model journal February 1996
Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity journal January 2001
PAM haploinsufficiency does not accelerate the development of diet- and human IAPP-induced diabetes in mice journal January 2020
Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic beta-cells. Potential role in nutrient sensing. journal February 1994
Biological Activity of Proinsulin and Related Polypeptides in the Fat Tissue journal June 1973
Neuropeptidomic Analysis of a Genetically Defined Cell Type in Mouse Brain and Pituitary journal January 2021
Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration journal February 2020
The dynamic plasticity of insulin production in β-cells journal September 2017
Enhancing Top-Down Proteomics of Brain Tissue with FAIMS journal April 2021
Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice journal August 2016
Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing journal July 2017
Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity journal June 1995
Publisher Correction: IAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function journal July 2019
Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing journal August 2022
MNK2 deficiency potentiates β-cell regeneration via translational regulation journal June 2022
Distinct Levels of Reactive Oxygen Species Coordinate Metabolic Activity with Beta-cell Mass Plasticity journal June 2017
The insulin-secretory-granule carboxypeptidase H. Purification and demonstration of involvement in proinsulin processing journal July 1987
Carboxypeptidase E mediates palmitate-induced β-cell ER stress and apoptosis journal June 2008
Dual and opposing roles of the unfolded protein response regulated by IRE1  and XBP1 in proinsulin processing and insulin secretion journal May 2011
Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells journal May 2014
Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3 journal July 2002
Internal cleavage of the inhibitory 7B2 carboxyl-terminal peptide by PC2: a potential mechanism for its inactivation. journal May 1996
Incomplete Processing of Proinsulin to Insulin Accompanied by Elevation of Des-31,32 Proinsulin Intermediates in Islets of Mice Lacking Active PC2 journal February 1998
Hydrogen Peroxide Alters Mitochondrial Activation and Insulin Secretion in Pancreatic Beta Cells journal September 1999
Characterization of Phospholipids in Insulin Secretory Granules and Mitochondria in Pancreatic Beta Cells and Their Changes with Glucose Stimulation journal April 2015
Role of the Connecting Peptide in Insulin Biosynthesis journal April 2003
The Identification of Potential Factors Associated with the Development of Type 2 Diabetes journal August 2008
A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic β-cells journal February 2020
High-fat diet-induced β-cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice journal April 2015
Normal and defective pathways in biogenesis and maintenance of the insulin storage pool journal January 2021
Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice journal September 2011
Inactivation of specific β cell transcription factors in type 2 diabetes journal July 2013
Insulin demand regulates β cell number via the unfolded protein response journal September 2015
The Carboxypeptidase E Knockout Mouse Exhibits Endocrinological and Behavioral Deficits journal December 2004
Role of Carboxypeptidase E in Processing of Pro-Islet Amyloid Polypeptide in β-Cells journal April 2005
Revisiting PC1/3 Mutants: Dominant-Negative Effect of Endoplasmic Reticulum-Retained Mutants journal July 2015
The β Cell in Diabetes: Integrating Biomarkers With Functional Measures journal June 2021
The Metabolic Effects of Biosynthetic Human Proinsulin in Individuals with Type I Diabetes* journal June 1984
Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism journal June 2015
SUMOylation Regulates Insulin Exocytosis Downstream of Secretory Granule Docking in Rodents and Humans journal February 2011
Unbiased Profiling of the Human Proinsulin Biosynthetic Interaction Network Reveals a Role for Peroxiredoxin 4 in Proinsulin Folding journal May 2020
Heterogeneous Development of β-Cell Populations in Diabetes-Resistant and -Susceptible Mice journal June 2022
Quantification of the Relationship Between Insulin Sensitivity and β-Cell Function in Human Subjects: Evidence for a Hyperbolic Function journal November 1993
The Prohormone Convertase Enzyme 2 (PC2) Is Essential for Processing Pro-Islet Amyloid Polypeptide at the NH2-Terminal Cleavage Site journal March 2001
Role of β-Cell Prohormone Convertase (PC)1/3 in Processing of Pro-Islet Amyloid Polypeptide journal January 2004
Five Stages of Evolving Beta-Cell Dysfunction During Progression to Diabetes journal November 2004
Oxidative Stress Leads to β-Cell Dysfunction Through Loss of β-Cell Identity journal November 2021
Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass journal February 2019
Differential regulation and localization of carboxypeptidase D and carboxypeptidase E in human and mouse β-cells journal July 2011
A New Cause of Obesity Syndrome Associated with a Mutation in the Carboxypeptidase Gene Detected in Three Siblings with Obesity, Intellectual Disability and Hypogonadotropic Hypogonadism journal February 2021
Proinsulin misfolding is an early event in the progression to type 2 diabetes journal June 2019
Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2 journal November 2020

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Type 1 diabetes
carboxypeptidase
insulin
insulin-secretion
prohormone
protein processing