Key words
diabetes mellitus - hypoglycemia - unawareness - insulin deficiency
Introduction
The major therapeutic goals in the treatment of diabetes mellitus type 1 (T1DM) are
near-normal glycemic control without hypoglycemia, the avoidance of diabetes-associated
complications, and an acceptable quality of life [1]. Despite substantial improvements in pharmacological diabetes therapy and technically
advanced aids for blood glucose monitoring and insulin application, a subset of patients
fail to meet the target parameters by far [2]
[3]. The reasons are manifold and include impaired counterregulatory mechanisms and
severe autonomous neuropathy, psychological barriers such as coping with the disease,
repeated experience of hypoglycemia, deficient patient education, and most importantly
the inherent limitations of exogenous insulin therapy.
In our specialized type 1 diabetes outpatient clinic, we have therefore pursued individualized
treatment regimens that comprehend the current clinically available options including
intensive insulin therapy (ICT), insulin pump therapy (CSII), sensor assisted blood
glucose monitoring (CGMS), intraperitoneal insulin infusion (CIPII), and beta-cell
replacement therapy by pancreas or islet transplantation.
Here, we report on our 5 years’ experience with implementing single islet transplantation
as a treatment option in patients with T1DM and high metabolic lability with frequent
severe hypoglycemia. All patients were recruited from the own outpatient clinic assuring
for exhausted conventional treatment regimen and compliance.
Although islet transplantation is a very promising approach in this subset of patients,
it is not widely available due to a number of limitations. Irrespective of the persistent
shortage of donor organs, the successful application of this technique requires a
specialized infrastructure and highly skilled and trained personnel. Due to the small
number of cases worldwide, the amount of data regarding islet transplantation is still
very limited and registry data as well as single-center studies are an important contribution
to foster the data base and evaluate the most suitable indications and clinical effectiveness
of this therapeutic approach [4,5]. At present, the university medical center at Carl Gustav Carus in Dresden runs
the only active islet transplantation program in Germany. Here, we present our 5 year
experience with respect to glycemic control and graft function after single islet
transplantation in metabolically critical T1DM patients and evaluate the potential
of islet transplantation to achieve the major treatment goals in this subset of patients.
Subjects and Methods
Subjects
Since 2008, 10 patients with a mean age of 46±9 years and long standing T1DM (mean
diabetes duration of 29±14 years) received a single islet transplantation at the Dresden
transplantation center. Demographic data are summarized in [Table 1]. All patients had a complete loss of islet function prior to transplantation as
determined by negative stimulated C-peptide and a history of highly problematic diabetes
control, including hypoglycemia unawareness, and severe metabolic lability characterized
by distinct blood glucose excursions.
Table 1 Baseline demographic data for islet recipients.
|
Patient #
|
Age (years)
|
Gender (M/F)
|
BMI (kg/m²)
|
Diabetes duration (years)
|
Insulin requirement pre-Tx (units/day)
|
HbA1c pre-Tx mmol/mol (%)
|
Diabetes management pre-Tx
|
|
1
|
55
|
F
|
24
|
51
|
25
|
69 (8.5)
|
CSII
|
|
2
|
27
|
M
|
22
|
26
|
68
|
77 (9.2)
|
CSII
|
|
3
|
55
|
M
|
24
|
38
|
30
|
73 (8.8)
|
CSII
|
|
4
|
48
|
F
|
28
|
38
|
30
|
66 (8.2)
|
CSII
|
|
5
|
50
|
F
|
29
|
40
|
50
|
81 (9.6)
|
CSII
|
|
6
|
49
|
F
|
28
|
36
|
43
|
60 (7.6)
|
CSII
|
|
7
|
42
|
F
|
24
|
12
|
32
|
61 (7.7)
|
CSII
|
|
8
|
36
|
F
|
24
|
17
|
44
|
66 (8.2)
|
CSII
|
|
9
|
53
|
F
|
27
|
17
|
38
|
62 (7.8)
|
CSII
|
|
10
|
47
|
M
|
26
|
11
|
33
|
63 (7.9)
|
CSII
|
BMI: Body mass index; T1DM: Diabetes mellitus type 1; CSII: Continuous subcutaneous
insulin infusion
Islet isolation and transplantation
Human pancreata were obtained through organ allocation by eurotransplant with consent
obtained for tissue processing. Islets were isolated using a modification of the automated
Ricordi method [6]. Briefly, Collagenase NB1, neutral protease (Serva Electrophoresis, Heidelberg,
Germany), and Pulmozyme (Roche, Grenzach, Germany,) were infused into the main pancreatic
duct. Islets were separated from exocrine tissue by centrifugation on a continuous
Biocoll gradient (Biochrom AG, Berlin, Germany) in a COBE 2991 cell processor (Lakewood,
CO, USA). Islets were cultured in CMRL 1066 (Mediatech, Herndon, VA, USA) containing
2.5% human serum albumin at 37°C in a 5% CO2 incubator prior to transplantation. Donor and isolation characteristics are summarized
in [Table 2]. Islet transplantation was performed intraportally via minilaparatomy over a 30-min
period under continuous monitoring of portal vein pressure. All patients received
only a single islet transplant.
Table 2 Donor and isolation/transplant characteristics.
|
Transplant #
|
Donor age (years)
|
Donor BMI (kg/m²)
|
CIT (h:min)
|
Number of IEQ transplanted
|
Total IEQ/kg T1DM
|
In vitro islet SI
|
|
1
|
48
|
36
|
08:40
|
350 835
|
5.482
|
2.5
|
|
2
|
41
|
31
|
08:00
|
932 000
|
14.563
|
4.5
|
|
3
|
36
|
35
|
5:55
|
642 650
|
10.041
|
2.3
|
|
4
|
48
|
30
|
10:29
|
642 150
|
10.034
|
3.8
|
|
5
|
41
|
33
|
8:27
|
976 500
|
15.258
|
4.3
|
|
6
|
28
|
49
|
09:00
|
719 850
|
11.248
|
4.5
|
|
7
|
56
|
25
|
06:30
|
400 050
|
6.251
|
3.2
|
|
8
|
45
|
31
|
04:03
|
400 770
|
6.263
|
2.8
|
|
9
|
57
|
25
|
07:00
|
376 800
|
5.888
|
3.2
|
|
10
|
37
|
26
|
08:31
|
540 000
|
6.429
|
3.8
|
BMI: Body mass index; CIT: Cold ischemia time; IEQ: Islet equivalents; T1DM: Diabetes
mellitus type 1; SI: Stimulation index
Immunosuppression
For induction therapy, an interleukin 2 receptor antagonist (Daclizumab/Basilixumab)
was used and a combination of calcineurin inhibitor (Tacrolimus) and inosine monophosphate
dehydrogenase inhibitor (mycophenolic acid) was applied for maintenance of immunosuppression.
In addition, an inhibitor of TNF-α (Etanercept) was given as anti-inflammatory therapy.
Post transplantation follow-up
Upon transplantation, patients were treated by i. v.-insulin for 24 h and CSII, adapted
to metabolic requirements, was continued thereafter. Glycemic control was documented
by self-monitoring blood glucose and regular determination of HbA1c. Graft function
was tested by frequent sampling of i. v.-glucose tolerance test (dextrose 0.5 g/kg
body weight applied by bolus injection) at 3 and 6 months after transplantation and
yearly thereafter. Metabolic stability was assessed on the basis of blood glucose
self-measurements by calculation of the lability index (LI-score) according to Ryan
et al. at regular intervals [7].
Data analysis
Data processing was performed using GraphPad Prism 4 (GraphPad Software, La Jolla,
CA, USA). Student’s t-test was used to establish comparisons between groups. Results are shown as mean±SD.
Significance was established at a p-value of <0.05.
Results
Glycemic control
Prior to islet transplantation, the mean HbA1c under CSII was 68±7 mmol/mol (8.4±0.7%).
After transplantation, all patients showed a fast and persistent reduction of HbA1c
within a therapeutically optimal range of below 55 mmol/mol (7.2%), indicating a sustained,
robust and adequate glycemic control ([Fig. 1]). This normalization of HbA1c was achieved without any hypoglycemic episodes following
transplantation that might influence HbA1c.
Fig. 1 Changes in glycemic control following islet transplantation. HbA1c levels of individual
patients, pre- and after single islet transplantation.
The metabolic stability was assessed by calculation of the lability index (LI-Score),
which is the most accepted measure for blood glucose fluctuations ([Fig. 2]). Based on this method, blood glucose instability was highly pronounced prior to
transplantation with a mean LI-Score of 422±58. Following transplantation, the LI-Score
was reduced significantly in all patients and was maintained throughout the follow-up
period. Severe hypoglycemia was prevented in all patients after transplantation.
Fig. 2 The LI-scores for pre- and post-transplants. Post-transplant scores for years 1–5
were significantly improved compared to pre-transplant values (*p<0.05). Data are
expressed as mean±SD.
Graft function
In order to analyze graft function, intravenous glucose tolerance tests were performed
with determination of blood glucose, insulin and C-peptide. During the follow-up period
of up to 5 years, all patients showed a return of blood glucose values to pre-stimulation
levels within 3 h ([Fig. 3]). However, the kinetic profile of insulin and C-peptide secretion following supraphysiological
glucose challenge was delayed compared to healthy controls (data not shown).
Fig. 3 Intravenous glucose tolerance test in islet transplant recipients at 12 months post-transplant
(n=10). Blood glucose levels in all patients returned to pre-stimulation levels within
180 min after stimulation accompanied by slightly delayed C-peptide release. Data
are expressed as mean±SD.
Post transplantation diabetes management
Following islet transplantation, all patients were initially treated by i. v.-insulin
for 24 h and returned to CSII thereafter. Insulin dose was adjusted according to metabolic
needs and optimal blood glucose control including post-prandial glucose levels. Reduction
of insulin requirement ranged from 95% to 20% compared to pre-transplantation regimen.
After frequent and as needed visits during the early post transplantation period,
all patients were seen once in 8 weeks during follow-up in order to allow for optimal
diabetes management and subtle adjustment of immunosuppressive therapy. Throughout
the observation period, no single episode of severe hypoglycemia requiring third party
assistance was reported.
Discussion and Conclusions
Discussion and Conclusions
Patients with T1DM live longer and experience less or later diabetes associated complications
due to significant advances in diabetes therapy over the last decades [8]
[9]. Therefore, therapeutic regimens must focus more on quality of life and compatibility
with work and social life. However, this development also creates an increasing number
of patients with very long diabetes duration and very specific challenges such as
metabolic lability and hypoglycemic unawareness. Underlying factors are often defective
counterregulatory mechanisms and autonomous neuropathy [10]. In these patients, a reliable synchronization of carbohydrate intake, and insulin
application and action is barely feasible. The results are hyperinsulinemia or insulin
deficiency often with fatal consequences. These conditions have tremendous impact
on quality of life and can often be life threatening. While patients with solitary
hypoglycemia unawareness may benefit from a glucose sensor assisted therapy, patients
with additional high metabolic lability ultimately can only be stabilized by reconstitution
of endogenous regulated insulin secretion.
Despite highly promising advances in novel approaches for beta cell generation and
regeneration, pancreas and islet transplantation are still the only clinically available
options for beta cell replacement therapy [11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]. While simultaneous pancreas/kidney transplantation is the gold standard for patients
with T1DM and end-stage renal disease [20], single islet transplantation has evolved into a viable treatment option for this
subset of critically instable patients with T1DM and normal kidney function. Stabilization
of blood glucose and prevention of hypoglycemia are established therapeutic goals
and thereby the avoidance or stabilization of diabetes associated complications. Interestingly,
these beneficial effects are independent of achieving insulin independence after transplantation
[4]
[21]
[22]
[23].
Here, we report on our experience with single islet transplantation as a therapeutic
approach in this critical subset of patients. The main indication was metabolic lability
complicated by severe hypoglycemia despite an optimal diabetes management. The primary
therapeutic goal was defined as stabilization of blood glucose profile and avoidance
of hypoglycemia rather than insulin independence. With respect to the need for chronic
immunosuppression, a thorough risk benefit analysis has been undertaken in all cases.
We could demonstrate a consistent reduction of HbA1c in all transplanted patients
and the complete elimination of severe episodes of hypoglycemia. Besides a major impact
on quality of life, these achievements represent an important benefit on micro- and
macrovascular complications and patient survival [24]. No major procedure or immunosuppression related complications were seen. For most
patients, the most important experience after islet transplantation was the achievement
of blood glucose stability and predictability of blood glucose trends. From the 10
patients described here, 50% were drastically restricted in their working ability
prior to transplantation and achieved partly or complete capacity to return to their
profession afterwards. This may represent a crucial perspective of islet transplantation
that should be considered substantially during selection and evaluation of candidate
patients.
However, achievement of long-term insulin independency is a legitimate therapeutic
goal of most patients and doctors. Islet transplantation has been shown to be capable
to reach insulin independence mainly after repeated islet infusions and an immunosuppressive
regimen that includes T-cell depletion and anti-inflammatory agents [4]
[25]. In fact, the comparison of pancreas alone and islet transplantation in respect
to insulin independence has been shown to be equally effective after 5 years [5]. In respect to the safe and minimally invasive procedure of islet transplantation,
adapted and more “islet-friendly” donor selection and allocation algorithms are considered
or already implemented in various countries [26]
[27]
[28]
[29]. In the German environment with critical lack of donor organs in general and a rather
hostile regulatory environment for islet transplantation in particular, multiple transplantations
for one patient are virtually not feasible. However, our positive results on reliable
reconstitution of insulin secretion, stabilization of metabolic control, and significant
impact on quality of life after single islet transplantation may help to promote this
therapeutic approach also in our system.
In conclusion, careful identification of patients that will benefit from this therapy
and a clear definition of therapeutic goals are an essential prerequisite for success.
Ideally, islet transplantation should be carried out in a center that provides various
alternative treatment options and state of the art technical assistance especially
for “the difficult patient”. In our experience, islet transplantation is an excellent
treatment option for selected patients with T1DM to reliably reconstitute endogenous
insulin secretion and prevent acute and chronic complications.
