Biomedical Engineering Reference
In-Depth Information
transplantation was already being investigated in the late twentieth century [
7
], the
success of the procedure was highly limited with only 8 % individuals remaining
insulin independent at one year [
8
]. The hope in clinical islet transplantation
increased after the group of J. Shapiro, at Edmonton University, showed increased
islet graft survival and achievement of insulin independence in seven patients
using a glucocorticoid-free immunosuppressive regimen [
9
]. Afterwards, the
Edmonton protocol was evaluated at multiple centers around the world with
variable success rates. In the most experienced centers about 90 % insulin-inde-
pendence rate was noticed [
10
]. However, long-term follow-up showed that graft
function decreases over time requiring subsequent islet transplants. Therefore, the
major goal of islet transplantation is now limited to avoid severe hypoglycemia
and to achieve near-normal glycemic control rather than complete insulin inde-
pendence [
3
]. Just like pancreas transplantation, islet transplantation faces a
shortage of donors, as in the Edmonton protocol one patient required islets from at
least two donor pancreas [
9
]. This shortage of donor pancreas/islets, therefore,
emphasizes the need to understand and promote endogenous regeneration of
pancreas in order to combat the disease without or with minimal number of
external islets. In parallel to that, efforts must be directed in a way to generate
b cells in vitro for transplantation or to generate b cells in vivo from other cell
types, e.g., by means of gene therapy. Finally, xenotransplantation of humanized
and encapsulated islets can be a therapeutic possibility as well. In the following
sections, these issues are discussed individually.
9.3 Endogenous Pancreas Regeneration
Based on numerous studies done in rodents as well as in humans, it is now well
known that the pancreas has the ability to regenerate under certain conditions.
Pancreatic b cell mass undergoes compensatory changes in response to changes in
the metabolic demand. Physiologically, b cell mass can expand in response to
increased insulin demand, e.g., during pregnancy or obesity. Such adaptive
expansion may involve increase in b cell replication, decrease in b cell death,
increase in b cell size (hypertrophy) and insulin secretion, and possibly also b cell
neogenesis, that is, differentiation of b cells from some kind of progenitors.
9.3.1 Expansion of b Cell Mass During Pregnancy
In rodents, the b cell mass increases 2-5-fold during pregnancy. This compensa-
tory expansion is achieved through hypertrophy and enhanced b cell proliferation
[
11
-
14
] and comes back to normal after birth, mainly through increased apoptosis
[
15
]. Compensatory changes in b cell mass during pregnancy are, therefore,
reversible and well regulated. In contrast to rodents not much data is available
