Prevention of Diabetes for up to 13 Years by Autoislet Transplantation After Pancreatectomy for Chronic Pancreatitis
R. Paul Robertson,
Karla J. Lanz,
David E.R. Sutherland, and
David M. Kendall
From the Pacific Northwest Research Institute and the University of
Washington, Seattle, Washington; and the University of Minnesota, Minneapolis,
Minnesota.
Address correspondence and reprint requests to R. Paul Robertson, MD,
Director, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA
98122. E-mail:
rpr{at}u.washington.edu
.
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ABSTRACT
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Patients with chronic pancreatitis who undergo total pancreas resection
inevitably become diabetic unless their islets are autotransplanted to prevent
diabetes. We studied patients who underwent this procedure to assess its
long-term efficacy in providing stable glucose regulation. Six patients were
followed for up to 13 (6.2 ± 1.7) years after intrahepatic islet
autotransplantation. From 290,000 to 678,000 islets were transplanted and no
patients received drugs to control glucose levels postoperatively. Islet
function was assessed by measurements of fasting plasma glucose (FPG),
intravenous glucose disappearance rate (KG),
HbA1c, insulin responses to intravenous glucose and to arginine,
and insulin secretory reserve. Patients were studied two to four times each to
obtain longitudinal data. Five of six patients remained free of insulin
treatment and maintained FPG <126 mg/dl and HbA1c levels
<6.5%. As a group, they maintained stable insulin secretary reserve, but
insulin responses to glucose tended to decrease over time in three patients.
KG values correlated significantly with the number of
islets originally transplanted. These data indicate that intrahepatic
autoislet transplantation can successfully maintain stable ß-cell
function and normal levels of blood glucose and HbA1c for up to 13
years after total pancreatectomy as treatment for chronic painful
pancreatitis. This usually overlooked procedure of intrahepatic islet
transplantation designed to prevent diabetes in patients undergoing
pancreatectomy for chronic pancreatitis should be considered more often.
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INTRODUCTION
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The association of chronic pancreatitis and diabetes has been known for
more than 200 years and was instrumental in the discovery of insulin by
Banting and Best (1). Although
a major etiological factor leading to chronic pancreatitis is alcohol
consumption, most alcoholics do not develop pancreatitis
(2), and extensive lists of
many other etiologies can be found in standard textbooks of medicine
(3,4).
Cardinal features of relapsing chronic pancreatitis include recurrent
abdominal pain that is exacerbated by ingestion of alcohol or a heavy meal,
especially one rich in fat. This syndrome leads to weight loss, abnormal
stools, and other signs or symptoms consistent with malabsorption. Treatment
of chronic pancreatitis is directed toward the major problems of pain control
and malabsorption. Pain often leads to frequent use of narcotics and a
compromised lifestyle that interferes with child care and employment, and may
require surgical intervention. Surgery is generally performed upon discovery
of a pseudocyst or localized ductal obstruction. In the most extreme cases,
total or near-total pancreatic resection is performed for relief of
unrelenting pain.
Diabetes inevitably accompanies chronic pancreatitis once sufficient
pancreatic tissue has been destroyed. It also occurs in nondiabetic
pancreatitis patients who undergo 80-90% pancreatectomy for relief of pain.
Uncommonly, islets isolated from the extirpated pancreas have been crudely
isolated and autotransplanted into the liver without need for
immunosuppression, in an attempt to prevent diabetes
(5,6,7).
Despite the success of this procedure, it surprisingly is not even mentioned
in leading textbooks of internal medicine
(3,4).
On the other hand, the most recently published International Islet Transplant
Registry (8) reports an overall
50% rate of diabetes prevention after pancreatectomy and immediate
intrahepatic autotransplantion of the patient's own pancreatic islets.
However, no data have been reported that address the stability of ß-cell
function and glycemic control over time after autotransplantation of islets in
humans. Consequently, we conducted longitudinal studies in six patients for
1-13 years after transplantation.
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RESEARCH DESIGN AND METHODS
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Patients. Six successful recipients of intrahepatic autoislet
transplantation were admitted on multiple occasions to the University of
Minnesota General Clinical Research Center. After an overnight fast and at bed
rest, intravenous catheters were placed into arm veins into which 0.45N saline
was infused to maintain patency. One intravenous line was used for infusion of
test substances; the other was used to draw samples of blood for
determinations of glucose, HbA1c, and insulin. All patients
underwent total or at least 99% pancreatectomy for pain relief. While the
patients were still in the operating room, their extirpated pancreata were
taken to a laboratory where they were subjected to enzymatic digestion and
partial separation of islets from exocrine tissue under sterile conditions
(7). The islet/exocrine mixture
was brought back to the operating room within 2 h and slowly infused into the
recipient's portal venous system over 30 min with close monitoring of the
portal venous pressure.
Metabolic studies. Intravenous glucose disappearance rate
(KG) and acute insulin response to intravenous glucose
(AIRg) were determined by drawing samples of blood 5 and 0 min
before and 3, 4, 5, 7, 10, 15, 20, 25, and 30 min after a 20-g intravenous
injection of glucose. AIRg was calculated as the mean of the 3, 4,
and 5 min values from which was substracted the mean of the -5 and 0 min
values. KG was calculated as the slope of time in minutes
and the natural log of glucose concentration using the data collected between
10 and 30 min after the glucose injection. The acute insulin response to
arginine (AIRa) was determined by drawing samples of blood 15, 5,
and 0 min before and 2, 3, 4, and 5 min after a 5-g intravenous injection of
arginine. AIRa was calculated as the mean of the 2, 3, and 4 min
values, from which was subtracted the mean of the -10, -5, and 0 min values.
ß-Cell insulin secretory reserve (AIRaMAX) was determined by
the method of glucose potentiation of arginine-induced insulin responses. This
method uses an infusion of intravenous glucose at a rate of 900 mg/min by
intravenous pump, a rate that results in maximal potentiation of
arginine-induced insulin secretion
(9).
Statistics. Statistical comparisons were performed by Student's
paired t tests and linear correlation analysis was performed by
Pearson product moment.
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RESULTS
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Patients. Of the six recipients, four were female
(Table 1). None of the patients
was diabetic before pancreatectomy and all patients underwent at least 99%
pancreatectomy. The number of islets transplanted varied from 290,000 to
678,000 islet equivalents. None of the etiologies involved chronic
alcoholism.
Metabolic studies. None of the patients was treated with insulin at
the time of study. Patients were studied from two to four times each at yearly
intervals ranging from 1 to 13 years after pancreatectomy and intrahepatic
autoislet transplantation. Of 16 fasting plasma glucose (FPG) levels, 14 were
<126 mg/dl; the two higher values were obtained from the same patient 2 and
4 years after transplantation (Fig.
1). This patient received the fewest islets (290,000).
HbA1c values were <6% in 13 of the 16 samples measured; 2 of the
elevated samples were in the same patient who also had elevated FPG levels and
low glucose disappearance rates (Fig.
2). AIRg tended to decrease over time in three of the
six patients (Fig. 3).
Intravenous glucose disappearance rates were >1.0%/min in 6 of the 16
studies (Fig. 4).
KG correlated significantly with the number of islets
transplanted (Fig. 5). The
AIRa values (Fig. 6)
and insulin secretory reserve, assessed by measuring AIRaMAX
(Fig. 7), were generally stable
in all recipients throughout the study.

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FIG. 1. FPG levels in six recipients (A-F) of intrahepatic autoislet
transplantation over 1-13 years after transplantation. Dashed line represents
upper limit of normal values. Numbers of islets transplanted are given next to
initials A-F.
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FIG. 2. HbA1c levels in the six recipients (A-F) of intrahepatic
autoislet transplantation over 1-13 years after transplantation. Dashed line
represents upper limit of normal values. Number of islets transplanted:
, 290,000; , 337,000; , 420,000; , 470,000; ,
652,000; , 678,000.
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FIG. 3. Acute insulin responses to 20-g intravenous injection of glucose (AIRg)
in six recipients (A-F) of intrahepatic autoislet transplantation over 1-13
years after transplantation. Number of islets transplanted: , 290,000;
, 337,000; , 420,000; , 470,000; , 652,000; ,
678,000.
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FIG. 4. Glucose disappearance rates after 20-g intravenous injection of glucose
(KG) in the six recipients (A-F) of intrahepatic autoislet transplantation
over 1-13 years after transplantation. Dashed line represents lower limit of
normal values. Number of islets transplanted: , 290,000; , 337,000;
, 420,000; , 470,000; , 652,000; , 678,000.
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FIG. 5. Correlation between the number of islet equivalents transplanted and
KG (KG). KG of 1.0%/min correlated to
500,000 islets.
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FIG. 6. Acute insulin responses to 5-g intravenous injection of arginine (AIRa)
in the six recipients (A-F) of intrahepatic autoislet transplantation over
1-13 years after transplantation. Number of islets transplanted: ,
290,000; , 337,000; , 420,000; , 470,000; , 652,000;
, 678,000.
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FIG. 7. Insulin secretory reserve (AIRaMAX) in six recipients (A-F) of
intrahepatic autoislet transplantation over 1-13 years after transplantation.
Number of islets transplanted: , 290,000; , 337,000; ,
420,000; , 470,000; , 652,000; , 678,000.
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DISCUSSION
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We studied six patients two to four times at yearly intervals who had
undergone near-total or total pancreatectomy because of chronic, unrelentingly
painful pancreatitis. They would have become diabetic had they not been
autotransplanted with a crude preparation of their own islets within hours of
pancreatectomy. Only one of the six patients developed clinical diabetes with
mild fasting hyperglycemia. This patient used small amounts of NPH insulin to
maintain HbA1c levels as close to 7% as possible, but no other
patient used insulin or other treatment for hyperglycemia. HbA1c
values were generally within the normal range with two exceptionsbut
even these two were in the range that would be considered excellent glycemic
control in diabetic patients receiving treatment. The patient who became
frankly diabetic received the fewest islets (290,000), whereas the patient who
received 337,000 islets has maintained normal fasting glucose and
HbA1c levels. Insulin responses to glucose appear to have
deteriorated over the course of the study, whereas insulin responses to
arginine and insulin-secretory reserve remained stable for as long as 13
years. However, as we have reported previously
(9), these insulin responses
are generally of a smaller magnitude than normal and the magnitude of the
responses correlates significantly with the numbers of islets transplanted.
Intravenous glucose disappearance rates correlated significantly with the
number of islets transplanted. This correlation suggests that
500,000
islets should be sufficient to normalize glucose tolerance.
Diabetes is not an infrequent complication of chronic pancreatitis. Larsen
(2) reported that in unselected
patients with chronic pancreatitis, roughly one-third developed type 1
diabetes and another third developed type 2 diabetes or glucose intolerance.
Total or near-total pancreatectomy inevitably leads to insulin-dependent
diabetes, because at least 20-30% of the normal complement of pancreatic
islets must be functioning to maintain normal glucose levels. Wahoff et al.
(7) reported cross-sectional
data indicating that the success rate for insulin independence for >2 years
was 74% for 14 patients who received >300,000 autotransplanted islets. In
this series of 48 patients, the surgical complication rate was 25%, the rate
of significant pain relief was 80%, and one perioperative death (colon
perforation and sepsis) occurred. The six patients reported herein are a
subset of this series, but they are the only ones with functioning islets whom
we have been able to study longitudinally. These findings overall underscore
the need to evaluate early in the course of chronic pancreatitis whether and
when the patient is likely to develop diabetes. Factors such as family history
of diabetes and the extent of pancreatic injury and previous surgery are
likely to be important variables. Earlier pancreatectomy and maximal recovery
of islets are two important variables that favor successful prevention of
hyperglycemia after autoislet transplantation. The difficult clinical choice
is when to discontinue temporizing procedures such as removal of pseudocysts
or use of stents as opposed to removing the diseased organ and
autotransplanting islets with the intent of relieving abdominal pain and
preventing the eventual development of diabetes. It would seem that the
standard practice in the U.S. probably errs on waiting too long, since the
concept of autotransplantation of pancreatic islets after pancreatectomy is
not even mentioned in standard textbooks of internal medicine
(3,4).
Although the success rate is very encouraging, the potential lethality of this
procedure was underscored by Froberg et al.
(10), who published a case
report of fatal disseminated intravascular coagulation immediately after
autoislet transplantation.
The success of autotransplantation of pancreatic islets stands in stark
contrast to the success rates of alloislet transplantation in type 1 diabetic
patients. The most recently published edition of the International Islet
Transplant Registry reports an 8% success rate of islet allografts in type 1
diabetic patients, defined as insulin independence for >1 year after
transplantation (8). The
longest instance of success appears to have been the case reported by Ferreria
et al. (11), who reported
normalization or near-normalization of HbA1c levels without insulin
treatment in two type 1 diabetic patients for 9 years. It remains an enigma
why the same immunosuppressive drugs that are effective in protecting
whole-organ pancreas allografts
(12) are not nearly as
effective in protecting islets after allotransplantation, although most of
these drugs have been known for years to adversely affect ß-cells
(13,14,15,16,17,18,19,20,21).
Another potentially important variable is that patients receiving intrahepatic
islet transplants usually have type 1 diabetes, whereas patients with chronic
pancreatitis have had no such previous autoimmune-directed pressure on their
pancreatic islets. The adverse effect of glucocorticoids used for
immunosuppression on ß-cell survival may be a very important factor, as
recently reported by Shapiro et al.
(21), who reported 100%
success for an average of 1 year in seven allo-transplant recipients treated
with a steriod-free regimen.
In conclusion, our data indicate that long-term function of
autotransplanted islets and prevention of diabetes is possible in patients who
have undergone pancreas resection because of chronic pancreatitis. This
procedure should be routinely considered when patients with chronic
pancreatitis are scheduled to undergo pancreatectomy.
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ACKNOWLEDGMENTS
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This work was supported by NIH-R01-39994 and the University of Minnesota
General Clinical Research Center.
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FOOTNOTES
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AIRa, acute insulin response to arginine; AIRaMAX,
insulin secretory reserve; AIRg, acute insulin response to glucose;
FPG, fasting plasma glucose; KG, glucose disappearance
rate.
Received for publication June 12, 2000
and accepted in revised form September 8, 2000
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