Islet transplantation in type 1 diabetes

Kort, et al present a review of the current status of islet
transplantation in Type 1 diabetes, and interestingly found no randomised
controlled trials (RCTs) or at least trials with appropriate control
groups that were intensively managed by insulin using modern treatment
regimens (1). No wonder the American Diabetes Association (ADA)
recommends performing islet transplantation only in the context of
controlled research studies (2), and until results of RCTs become
available, islet transplantation should be considered just an experimental
procedure (3). That clearly implies that islet transplantation, despite
its two decades history since the first transplantation in humans, hasn't
been established unequivocally better than conventional insulin therapy in
Type 1 diabetics. Yet the Kort review presents islet transplant as a
treatment option, and advice risk-benefit analysis when there isn't a
single RCT that suggests whether achieving temporary insulin independence
with islet transplantation justifies chronic exposure to immunosuppressive
drugs and their related side-effects. How is risk benefit analysis
possible in absence of any RCT evidence? We know of no other instance in
evidence based medicine where a procedure is recommended as a treatment
option without going through RCTs.

Having said that, it is incumbent upon us to evolve new strategies to
fill the half empty glass (4) of cell-based therapies for diabetes.
Firstly, we have to acknowledge the fact that islet transplantation is
likely to be antiquated in very near future by the beta-cell surrogates
such as autologous stem cells, their derivatives or modified cell lines
that do not pose the graft rejection problems and may not require chronic
immunosuppressive treatment. Secondly, strategies for inhibition of islet
apoptosis in the immediate post transplant period and graft tolerance may
not only reduce the amount and intensity of current anti-rejection
therapies (5), but also assist in successful translation of the existing
transplant approaches in development into effective treatment options for
diabetics.

Recent advances in stem cell technology and our own understanding of
the inflammatory pathways that trigger apoptosis open up new possibilities
for countering the shortcomings. Apoptic beta-cell death is central to
the pathogenesis of Type 1 diabetes and in islet graft rejection. beta-
cell specific activation of NF-kappa B has been shown to be a key event in
the progressive loss of beta-cell in diabetes, and inhibition of this
process non-invasively and non-toxically could be a potentially effective
strategy for beta-cell protection (6). Recent discovery of an innate
phenomenon of remote ischaemic preconditioning that non-invasively
modulates NF-Kappa B (7) and related apoptotic and inflammatory pathways
(8) holds out a new promise to afford beta-cell protection and reduce or
eliminate the need for immunosuppressive drugs. Optimal remote ischaemic
preconditioning is a safe, non-invasive procedure that can be conveniently
used as an adjunct in islet/stem cell transplant for minimizing beta-cell
apoptosis, transplant rejection and long term immune-suppression, thus
facilitating quick progression of effective cell based therapies for
diabetes through RCTs.

References:

1. Kort H, Koning EJ, Rabelink TJ, Bruijn JA, and Bajema IM. Islet
transplantation in type 1 diabetes. BMJ 2011;342:d247.

2. American Diabetes Association. Pancreas and islet transplantation
in type 1 diabetes (Position Statement). Diabetes Care 2006;29:935.

3. Ruggenenti P, Remuzzi A, Remuzzi G. Decision time for pancreatic
islet-cell transplantation. Lancet 2008;371:883-884.

4. Robertson RP. Islet transplantation a decade later and strategies
for filling a half-full glass. Diabetes. 2010;59(6):1285-1291.

5. Emamaullee JA, Shapiro AMJ. Interventional Strategies to Prevent
Beta-Cell Apoptosis in Islet Transplantation. Diabetes. 2006; 55(7):1907-
1914.

6. Melloul D. Role of NF-kappaB in beta-cell death. Biochem Soc
Trans. 2008;36(Pt 3):334-9.

7. Konstantinov C, Redington AN. Linking gene expression, nuclear
factor kappa B, remote ischemic preconditioning, and transplantation: A
quest for an elusive Holy Grail or a road to an amazing discovery? J.
Thorac. Cardiovasc. Surg., 2006; 131(2): 507-509.

8. Konstantinov IE, Arab S, Kharbanda RK, et al. The remote ischemic
preconditioning stimulus modifies inflammatory gene expression in humans.
Physiol Genomics 2004;19:143-150.