Type 1 Diabetes: Cellular, Molecular & Clinical
ImmunologyChapter 2 - The Pancreatic Beta-CellSuparna A. Sarkar,
3/1/2012 Update of chapter by Kirstine Juhl, John C. Hutton and
George S. EisenbarthCell Therapy of Diabetes PowerPoint slide
set-Updated 7/06Proprotein Processing and Pancreatic Islet Function
PowerPoint slide set-Updated 11/06Stimulus-Secretion Coupling in
the Pancreatic Beta-Cell PowerPoint slide set- Updated 7/08Human
Fetal Pancreas Development slide setUpdated 03/12IntroductionThe
two most common forms of diabetes in man (Type 1A and Type 2) have
very different etiologies and different clinical presentation1.
Nevertheless, the underlying loss of islet beta cell function has
similar consequences in terms of glycemic control and the emergence
of long-term complications. type 1 Diabetes (T1D) is a polygenic
T-cell dependent autoimmune disease, characterized by the selective
destruction of the -cells of the islets of Langerhans1-6and that
susceptible individuals have inherent defects in critical
immunomodulatory mechanisms7that increase the risk of a pathogenic
rather than protective immune response to self6, 8, 9. Type 2
Diabetes is typically linked to dysmetabolism or metabolic syndrome
and the presence of insulinresistance, however a large subset of
T1D patients routinely exhibits insulin resistance10-13contributing
to the metabolic distress in islets.With the rising incidence of
T1D and T2D, it is now being argued that both T1D and T2D are
essentially disorders of altered insulin resistance set against the
backdrop of genetic susceptibility14and the inflammatory process;
in T1D brought about by the autoimmune component of the disease
process15.In type 1A (autoimmune diabetes) the loss of beta cells
is often close to absolute with less than 1% of beta cells
remaining in patients with long-term diabetes16-18with prolonged C
peptide production19.In most patients with almost no remaining beta
cells, essentially all of the islets are devoid of beta cells while
islets contain cells expressing glucagon and somatostatin. Such
islets are termed pseudoatrophic islets20. Nevertheless, some beta
cells remain often as scattered single cells in the parenchyma and
ducts.In a small subset of patients, even with long-term type 1A
diabetes, significant C-peptide is present and lobules of pancreas
remain where all the islets contain beta cells and appear
essentially normal in terms of expression of insulin while the rest
of the pancreas is devoid of beta cells in islets20-22. The figure
below illustrates a section of one such pancreas from the nPOD
collection (jdrfnpod.org) where the pancreatic lobule on the right
is stained dark and at higher power one can observe that all of the
islets in this lobule lack insulin23.In contrast to the lobule on
the left, all of the islets contain insulin.The dark staining of
the right lobule likely results from pancreatic acinar atrophy that
occurs with severe loss of pancreatic insulin.Shrinkage in overall
pancreatic mass in patients with type 1 diabetes has long been
noted24-26. Analysis of decreased pancreatic volume was recently
combined with imaging of iron particle pancreatic accumulation to
help distinguish patients with type 1 diabetes from normal
controls27-29.In fact,C-peptide secretion in long-standing diabetic
patients has now been explained by two different patterns of beta
cell survival, which possibly reflect different subsets of type 1
diabetes.In a recent study20associatedPattern A with type 1A
diabetes that histologically had lobular retention of islet areas
with abnormal beta cells producing the apoptosis inhibitor BIRC5
(survivin) and HLA class I. In pattern B, 100% of all islets
contained normal-appearing but quantitatively reduced beta cells
without survivin or HLA class I.Baculoviral IAP repeat 5 BiRC530is
anapoptosis inhibitor that is produced in the beta cells of fetal
human pancreas31, but not in adult islets. It is also found in the
beta cells in areas of pancreatitis32. The presence of survivin, in
all surviving islet beta cells Pattern A patients, may result from
1) inflammatory changes that did not result in beta cell
destruction of a subset of islets or 2) be protected from
destruction and further lymphocytic infiltration. An alternative
hypothesis extended by the authors is that lobular regions with
beta cells of Pattern A pancreas represent areas of beta cell
regeneration. Althoughthe sudden onset of type 1A belies the fact
that the underlying loss of beta cell mass is the culmination of
many years of gradual and progressive loss of beta cells in the
face of autoimmune attack which is first evident with the
appearance of autoantibodies to islet proteins in the preceding
years (see other chapters)33-38. In the NOD mouse the infiltration
of the islets with immune and inflammatory cells that initiates the
disease first appears in the islets of the pancreatic periphery,
affects a subpopulation of islets and is possibly benign or at
least kept in check by the presence of regulatory T cells39-42. The
invasive insulitis seen in NOD mice closer to disease onset may
reflect a change in the balance of destructive and protective
responses in favor of the former. The histological changes in man
are comparatively mild and may reflect the slower progression of
the disease or possibly a different immune process. The islet tends
to be viewed as the source of autoantigen that supports or
initiates the immune attack and ultimately the victim of the
crime.Histopathological examination of pancreata from diabetic
organ donors procured from nPOD was examined with the goal to
provide a foundation for the informed selection of potential
therapeutic targets within the chemokine/receptor family43. CCL5,
CCL8, CCL22, CXCL9, CXCL10 and CX3CL1 were the major chemokines
transcribed and translated by human islet cells in response toin
vitroinflammatory stimuli. CXCL10 was identified as the dominant
chemokine expressedin vivoin the islet environment of prediabetic
animals and T1D patients, while CCL5, CCL8, CXCL9 and CX3CL1
proteins were present at lower levels in the islets of both
species. Importantly, additional expression of the same chemokines
in human acinar tissues emphasized an underappreciated involvement
of the exocrine pancreas in the natural course of T1D that will
require consideration for further T1D pathogenesis and immune
intervention studies.Undoubtedly, much more needs to be learned
about the reaction of the islet to cytokine mediators of the immune
response and about how the beta cell manages to survive so long or
replenish its population from progenitor cells in the pancreas.
Since the mechanism of autoimmune destruction by effector cells may
be mediated by CD4+ cells, and thus indirect, there is also the
question of whether the beta cell is uniquely susceptible to oxygen
and nitrogen free radicals or cytokine mediators of cell death
which may account for the fact that other islet cells exposed to
same molecules survive while the beta cell dies.The focus of the
following review is to discuss the wealth of information regarding
the physiological and pathophysiological responses of the islet to
nutrient secretagogues and pharmacological agents and to emphasize
how the beta cell differs from its neighbors and from other
endocrine tissues and how it may participate in its own demise in
type 1 diabetes. The review also illustrates the challenges faced
by investigators wishing to genetically engineer non-cells for
cellular therapy of type 1 diabetes or wanting to introduce
specific genes into the beta cell population to afford it greater
protection from autoimmune attack.
Development of the Human PancreasSimilar to the mouse pancreas,
the human pancreas develops from two endodermal diverticula, the
dorsal and ventral44, which fuses around 56 days post coitum of
development45. The pancreas comprises of 3 important cell lineages:
Endocrine, acinar and ductal (which together make up the exocrine
pancreas). The morphogenesis of the endocrine tissue, however, is
unlikely to be equivalent given the differences in gestation (260
vs 20 days) and the larger relative volume of the human
pancreas46.Human fetal pancreases obtained at gestational ages
923weeks were processed in parallel for immunohistochemistry and
gene expression profiling by Affymetrix microarray47. At 911weeks,
the pancreas was made up principally of mesenchymal tissue
interspersed with PDX1 positive branched epithelial structures
containing scattered hormone-negative neurogenin3-positive
endocrine cells. Protoacinar structures marked by carboxy esterase
lipase (CEL) expression were noted by 1519weeks, along with
clusters of endocrine cells producing either glucagon or insulin.
By 2023weeks, vascularized islet-like structures appeared. Analysis
of Ki67 immunoreactivity showed that the replicative rate of
endocrine cells was low and suggested that the endocrine expansion
was derived from hormone-negative precursors. Insulin, glucagon,
somatostatin, ghrelin and pancreatic polypeptide transcripts were
present at 910weeks as confirmed by quantitative PCR and increased
progressively, commensurate with the expansion of endocrine cell
volume. The human equivalent of a mouse endocrine secondary
transition was not evident, neither in terms of morphology nor in
dramatic changes in endocrine-specific transcriptional regulators.
By contrast, exocrine genes showed a marked transition at around
11weeks, associated with a greater than six-fold increase in
exocrine gene transcripts.The terminal differentiation of human
endocrine tissue into late gestation and the presence of NEUROG3
are in contrast with findings in the mouse, where neurog3 is
transiently expressed from e12.5e15.5. This indicates that the
human fetal pancreas could provide an abundant islet precursor cell
population that could be expanded ex vivo for therapeutic
transplantation for the treatment of brittle and unstable type 1
diabetes. The ductal cells also develop from the PDX1 expressing
primordial pancreatic epithelium and expresses Cytokeratin 19
(CK19), cystic fibrosis transmembrane receptor, DBA lectin,
Carbonic anhydrase 248. (For images of the human fetal pancreas
development,please refer to power-point slides).Physiology of the
islet of Langerhans
The endocrine pancreas is arranged in clusters of secretory
cells the Islets of Langerhans scattered throughout the exocrine
glandular tissue (Fig. 1)49, 50. In man, the pancreas contains
around one million islets that comprise 1-2% of the total mass of
the gland. The islets are separated from the exocrine tissue by a
capsule made up of connective tissue fibers and by glial like cells
and human islets vary in size from less than 50 up to several
thousand cells. Four different endocrine cell types are contained
in the islets; beta cells, which produce insulin and constitute
60-80% of the endocrine cell mass, glucagon secreting a-cells
(10-20%), somatostatin producing d-cells (~5%) and pancreatic
polypeptide secreting PP-cells (