Abstract:Direct in vivo assessment of pancreatic islet-cells for the study of the pathophysiology of diabetes in humans is hampered by anatomical and technological hurdles. To date, most of the information that has been generated is derived from histological studies performed on pancreatic tissue from autopsy, surgery, in vivo biopsy or organ donation. Each approach has its advantages and disadvantages (as summarised in this commentary); however, in this edition of Diabetologia, Kusmartseva et al (https://doi. org/10.1… Show more
“…iPSCs were cultured in Matrigel-coated plates (Corning) in E8 medium as previously described (61,62). Four YIPF5 mutant cell lines (2 clones from each Human pancreata not suitable for clinical purposes were collected from nondiabetic, brain-dead organ donors after written informed consent from next of kin, and handled as described (64) with the approval of the Ethical Committee, University of Pisa.…”
Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the
YIPF5
gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy.
YIPF5
is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (
YIPF5
silencing in EndoC-βH1 cells,
YIPF5
knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which
YIPF5
loss of function affects β cells. Loss of
YIPF5
function in stem cell–derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial
YIPF5
silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress–induced apoptosis. We report recessive
YIPF5
mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of
YIPF5
in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.
“…iPSCs were cultured in Matrigel-coated plates (Corning) in E8 medium as previously described (61,62). Four YIPF5 mutant cell lines (2 clones from each Human pancreata not suitable for clinical purposes were collected from nondiabetic, brain-dead organ donors after written informed consent from next of kin, and handled as described (64) with the approval of the Ethical Committee, University of Pisa.…”
Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the
YIPF5
gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy.
YIPF5
is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (
YIPF5
silencing in EndoC-βH1 cells,
YIPF5
knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which
YIPF5
loss of function affects β cells. Loss of
YIPF5
function in stem cell–derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial
YIPF5
silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress–induced apoptosis. We report recessive
YIPF5
mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of
YIPF5
in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.
“…Human pancreata not suitable for clinical purposes were collected from nondiabetic, brain-dead organ donors after obtaining written informed consent from next of kin and handled as described (80) with the approval of the Ethical Committee, University of Pisa, in Pisa.…”
“…Newer initiatives, including the European INNODIA consortium and a Medical Research Council (MRC)-funded pancreas collection (the Quality in Organ Donation [QUOD] Biobank; coordinated from the University of Newcastle, UK) promise to deliver high-quality samples in the future. Further study of pancreas biobanks remains paramount for an improved understanding of diabetes [ 15 ]. Fig.…”
Type 1 diabetes is increasing in incidence in many parts of the world and it might be imagined that the pathological processes that underlie disease progression are firmly understood. However, this is not the case; rather, our collective understanding is still surprisingly rudimentary. There are various reasons for this but one of the most important is that the target organ (the pancreas) has been examined at, or soon after, diagnosis in only a small number of cases worldwide over the past half a century. This review provides a summary of some of the insights gained from these studies and highlights areas of ongoing uncertainty. In particular, it considers the process of insulitis (a form of islet inflammation that occurs characteristically in type 1 diabetes) and discusses the factors that may influence the access of immune cells to the beta cells. Attention is also drawn to recent evidence implying that two distinct profiles of insulitis exist, which occur differentially in people who develop type 1 diabetes at increasing ages. Emphasis is also placed on the emerging (and somewhat surprising) consensus that the extent of beta cell loss is variable among people with type 1 diabetes and that many (especially those who are older at onset) retain significant numbers of insulin-producing cells long after diagnosis. We conclude by emphasising the importance of renewed efforts to study the human pancreas at disease onset and consider how the current insights may inform the design of future strategies to slow or halt the rate of beta cell loss.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4731-y) contains a slideset of the figures for download, which is available to authorised users.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
