Metabolic Effects of Restoring Partial ß-Cell Function After Islet Allotransplantation in Type 1 Diabetic Patients
Livio Luzi,
Gianluca Perseghin,
Mathias D. Brendel,
Ileana Terruzzi,
Alberto Battezzati,
Michael Eckhard,
Daniel Brandhorst,
Heide Brandhorst,
Schirin Friemann,
Carlo Socci,
Valerio Di Carlo,
Lucia Piceni Sereni,
Stefano Benedini,
Antonio Secchi,
Guido Pozza, and
Reinhard G. Bretzel
From the Departments of Medicine and Surgery (L.L., G.Pe., I.T., A.B.,
C.S., V.D.C., L.P.S., S.B., A.S., G.P.), Istituto Scientifico H. San Raffaele
and the University of Milan, Milan, Italy; and the Center of Internal Medicine
(M.D.B., M.E., D.B., H.B., S.F., R.G.B.), Justus-Liebig
Universität, Giessen, Germany.
Address correspondence and reprint requests to Dr. Livio Luzi, Head, Amino
Acid and Stable Isotope Laboratory, Istituto Scientifico H. San Raffaele, via
Olgettina 60, 20132 Milan, Italy. E-mail:
luzi.livio{at}hsr.it
.
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ABSTRACT
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Successful intraportal islet transplantation normalizes glucose metabolism
in diabetic humans. To date, full function is not routinely achieved after
islet transplantation in humans, with most grafts being characterized by only
partial function. Moreover, the duration of full function is variable and
cannot be sufficiently predicted with available methods. In contrast, most
grafts retain partial function for a long time. We hypothesized that partial
function can restore normal protein and lipid metabolism in diabetic
individuals. We studied 45 diabetic patients after islet transplantation.
Labeled glucose and leucine were infused to assess whole-body glucose and
protein turnover in 1) 6 type 1 diabetic patients with full function
after intraportal islet transplantation (FF group; C-peptide > 0.6 nmol/l;
daily insulin dosage 0.03 ± 0.02 U · kg-1 body wt
· day-1; fasting plasma glucose < 7.7 mmol/l;
HbA1c
6.5%), 2) 17 patients with partial function (PF
group; C-peptide > 0.16 nmol/l; insulin dosage < 0.4 U ·
kg-1 body wt · day-1), 3) 9 patients
with no function (NF group; C-peptide < 0.16 nmol/l; insulin dosage >
0.4 U · kg-1 body wt · day-1), and
4) 6 patients with chronic uveitis as control subjects (CU group).
Hepatic albumin synthesis was assessed in an additional five PF and five
healthy volunteers by means of a primed-continuous infusion of
[3,3,3-2H3]leucine. The insulin requirement was 97%
lower than pretransplant levels for the FF group and 57% lower than
pretransplant levels for the PF group. In the basal state, the PF group had a
plasma glucose concentration slightly higher than that of the FF (P =
0.249) and CU groups (P = 0.08), but was improved with respect to the
NF group (P < 0.01). Plasma leucine (101.1 ± 5.9 µmol/l)
and branched-chain amino acids (337.6 ± 16.6 µmol/l) were similar in
the PF, FF, and CU groups, and significantly lower than in the NF group
(P < 0.01). During insulin infusion, the metabolic clearance rate
of glucose was defective in the NF group versus in the other groups
(P < 0.01). Both the basal and insulin-stimulated proteolytic and
proteosynthetic rates were comparable in the PF, FF, and CU groups, but
significantly higher in the NF group (P = 0.05). In addition, the PF
group had a normal hepatic albumin synthesis. Plasma free fatty acid
concentrations in the PF and FF groups were similar to those of the CU group,
but the NF group showed a reduced insulin-dependent suppression during the
clamp. We concluded that the restoration of
60% of endogenous insulin
secretion is capable of normalizing the alterations of protein and lipid
metabolism in type 1 diabetic kidney recipients, notwithstanding chronic
immunosuppressive therapy. The results of the present study indicate that
"success" of islet transplantation may be best defined by a number
of metabolic criteria, not just glucose concentration/metabolism alone.
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INTRODUCTION
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We have recently shown that successful intraportal islet transplantation
can normalize hepatic glucose production and insulin action in type 1 diabetic
patients with a kidney transplant
(1). This procedure, now
performed in several centers worldwide
(2,3,4,5,6),
is relatively safe, noninvasive (percutaneous puncture of the liver), and
repeatable. The major factors limiting the large-scale application of islet
graft in diabetic patients receiving chronic immunosuppression for a kidney
graft are 1) the low percentage of patients reaching insulin
independence and a complete normalization of glucose homeostasis
(1) and 2) the limited
survival of fully successful grafts. Most diabetic patients receiving an islet
graft achieve only partial function and a reduction of the pretransplant
insulin requirement
(2,3,4,5,6);
they are characterized by fasting C-peptide concentrations in the near-normal
range, but frankly abnormal fasting glucose and GHb values
(1,2,3,4,5,6).
In the last decade, we
(7,8,9,10)
and others
(11,12)
found that protein and lipid metabolism had greater sensitivity to acutely
infused insulin than did glucose metabolism, both in diabetes and uremia.
Conventional insulin administration (one or two insulin injections per day
according to the Diabetes Control and Complications Trial criteria) was also
shown to normalize protein and lipid metabolism but left glucose homeostasis
mildly altered (7). Insulin
treatment does not replace normal plasma concentrations of other peptides
commonly cosecreted with insulin, such as C-peptide and proinsulin. Very
recent data in diabetic rodents
(13) have suggested a
biological activity for the C-peptide, namely the restoration of the
Na+-K+ ATPase pump activity. This effect of C-peptide
may play an important role in the delay and prevention of microvascular
complications of diabetes
(14,15).
At present, islet and pancreas transplantation are the only available
treatments for type 1 diabetes that replace the whole ß-cell function. To
test whether a partial function induced by intraportally implanted islets can
normalize protein turnover and intermediary metabolism, we selected three
groups of diabetic kidney recipients after an associated intraportal islet
graft (full function, partial function, and no function; representative of
diabetic patients after islet transplantation) and studied them with glucose
and leucine tracers to quantify glucose and protein turnover in the basal and
insulin-stimulated state. Our results demonstrated that the achievement of
partial function permits the normalization of protein and lipid homeostasis in
immunosuppressed type 1 diabetic patients, with the persistence of a mild
alteration of glucose homeostasis, similar to that observed in type 1 diabetic
patients on conventional insulin therapy. It is noteworthy that this result
was obtained notwithstanding the fact that the islet recipients were on
immunosuppressive drugs.
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RESEARCH DESIGN AND METHODS
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Subjects. Table 1 shows
the clinical and biochemical data of the study groups. All diabetic patients
enrolled in this study were kidney graft recipients on chronic
immunosuppressive treatment receiving the islet along with or after the
kidney. After islet transplantation, diabetic subjects were usually treated
with subcutaneous injections of regular insulin (three injections per day)
eventually combined with intermediate insulin (one to two injections per day),
when necessary. Table 2
summarizes the classification criteria for full, partial, and no function (FF,
PF, and NF). Postabsorptive C-peptide concentrations and daily insulin dosage
were considered major criteria. Glucose and HbA1c were classified
as minor criteria because in PF and NF patients they were determined by the
intensity of insulin treatment (HbA1c) in the 4 weeks preceding the
study.
Experimental protocol. In the 2 weeks before the study, all subjects
consumed an isocaloric diet containing at least 250 g carbohydrate and 70-90 g
protein per day. All studies were performed while patients were hospitalized.
Patients were admitted to the Department of Internal Medicine I of the
Istituto Scientifico H San Raffaele (Milan, Italy) or to the Third Department
of Medicine of the Justus-Liebig Universität
(Giessen, Germany) for the execution of the insulin clamp 1-2 days before the
study. Patients on subcutaneous insulin treatment received the last doses of
intermediate and short-acting insulin 18 and 12 h, respectively, before the
experimental procedure. The next morning, after a 10-h overnight fast, two
indwelling catheters were placed in an antecubital vein for the infusions and
retrogradely in the wrist vein of the opposite arm for blood sampling, as
previously described (1).
Arterialization was obtained via a heated box at the sampling site. Subjects
received [3-3H]glucose and [1-14C]leucine (in Milan,
Italy) and [6,6-2H2]glucose and
[1-13C]leucine (in Giessen, Germany) as boluses followed by
continuous infusions to assess whole-body rates of glucose and protein
metabolism for 300 min
(1,16,17,18).
After a 150-min tracer equilibration period, a 40 mU · m-2
· min-1 insulin infusion was given while maintaining
euglycemia via a 20% dextrose solution
(1). Indirect calorimetry was
performed in the basal postabsorptive condition and during the last 45 min of
the clamp, as previously described
(16,17,18,19,20).
Blood samples were taken every 10 min in the last hour of the equilibration
period and throughout the insulin/glucose infusion for the measurement of
tracer enrichments and specific activities as well as substrate and hormone
concentrations. Breath samples were collected every 10 min in the last hour of
each the basal state and the insulin/glucose infusion for the measurement of
14CO2 radioactivity
(17,21)
and 13CO2 enrichment
(22). We also studied five
additional type 1 diabetic patients with partial function and five healthy
volunteers to assess plasma albumin synthetic rates in the postabsorptive
condition. These subjects received a primed-continuous infusion of
[3,3,3-2H3]leucine (bolus 7 µmol/kg; continuous
infusion 7 µmol · kg-1 · h-1 for 5 h).
Blood samples were taken before the infusion of the isotope and every 30 min
thereafter. All bedside studies were directly supervised by Dr. Livio Luzi
(both in Italy and Germany), and all tracer measurements were carried out in
Dr. Luzi's laboratory. The protocol was approved by the Institutional Ethical
Committees of San Raphael Scientific Institute, Milan, Italy and the
Justus-Liebig University, Giessen, Germany; informed consent was given by all
study subjects.
Analytical determinations and calculations. Plasma glucose was
measured at bedside with a Beckman glucose analyzer
(1); free insulin, C-peptide,
glucagon, free fatty acid (FFA), tritiated glucose-specific activity,
14C-leucine-specific activity, 14C-ketoisocaproate
(KIC)-specific activity, and deuterated glucose enrichment were measured as
previously described
(16,17,18,19,21).
-Ketoacid enrichments were measured by means of electron impact gas
chromatography-mass spectrometry (GC-MS) using a derivatization with
boroacetylation (1).
14CO2-specific activity in breath was measured by
ß-scintillation as previously described
(17,21).
The 13CO2/12CO2 isotope ratio in
expired air was measured by isotope ratio MS
(22). Endogenous glucose
production and peripheral glucose disposal were measured as previously
described
(1,16,19).
Endogenous leucine flux (proteolytic rate), nonoxidative leucine disposal
(protein synthetic rate), and leucine oxidation were calculated using both the
leucine- and the
-ketoisocaproic acid-specific activity/enrichment, as
previously described
(17,21,22).
Isolation of plasma albumin was performed according to the method of Korner
and Debro (23). Plasma was
deproteinized with 10% trichloroacetic acid and centrifuged. The supernatant
was discarded and the pellet was resuspended in pure ethanol. The samples were
centrifuged and the supernatant containing albumin was retained. The purity of
each of the albumin preparations was tested in an aliquot of the supernatant
by SDS-PAGE after evaporation under nitrogen stream and resuspension in
distilled water. Hydrolysis of albumin was performed in a second aliquot of
the supernatant that was evaporated under nitrogen and heated in 6N HCl for 24
h. The hydrolysate was filtered and then derivatized to the
N-heptafluorobutyryl-N-propyl amino acid esther derivative
as previously described (18).
The enrichment of [3,3,3-2H3]leucine incorporated in
albumin was measured in quadruplicate by GC-MS, as previously described
(18). The incorporation rate
of [3,3,3-2H3]leucine into albumin was expressed as mole
percent excess/day, calculated by least-squares regression analysis, and was
linear between the first and fifth hour of the study. The daily fractional
synthetic rate (FSR) of albumin (expressed as the percentage of the protein
pool renewed each day) was calculated by dividing the mean tracer
incorporation rate into albumin by the precursor enrichment. The plasma
enrichment of [3,3,3-2H3]KIC was assumed to represent
the intracellular precursor pool enrichment for albumin synthesis. The
absolute rate of albumin synthesis (mg · kg-1 ·
h-1) was calculated as the product of FSR and the albumin
concentration, assuming a distribution volume of 40 ml/kg.
Statistical analysis. Data are given as group means ± SE.
Statistical differences among groups were performed using Student's t
test and analysis of variance, with Scheffe's post hoc testing when
appropriate.
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RESULTS
|
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Postabsorptive condition. FF, PF, and NF patients
(Table 1) had 100, 57, and 13%
reductions, respectively, in required insulin dosage compared with their
pretransplant condition (Table
2). NF patients had significantly higher levels of glucose
(P < 0.01) compared with the FF and PF patients and patients with
chronic uveitis (CU; control subjects) (Table
2) and higher levels of branched-chain amino acids (P
< 0.01) and leucine (P < 0.01) with respect to the FF and PF
patients (Table 3). Plasma FFA
and glycerol were comparable among groups. PF patients had a slightly higher
glucose concentration (P = 0.08)
(Table 2), but normal leucine and
branchedchain amino acids (with a trend for lower values; P = 0.07)
(Table 3) and normal FFA
(Table 3) and glycerol (108
± 27, 136 ± 23, 125 ± 45, and 86 ± 27 in the NF,
PF, FF, and CU groups, respectively; P = 0.605) concentrations with
respect to the CU group. FF patients had normal plasma glucose, lower plasma
leucine (P = 0.07) and branched-chain amino acids (P <
0.01), and normal FFA and glycerol concentrations compared with the CU group.
In the postabsorptive state, triglyceride concentration was comparable in the
NF (115 ± 12), PF (133 ± 18), FF (180 ± 44), and CU
groups (180 ± 26 mg/dl). Total cholesterol was higher in the NF (218
± 7), PF (243 ± 15), and FF groups (257 ± 18) compared
with the CU group (162 ± 13 mg/dl; P = 0.05) and HDL
cholesterol was higher in the NF (65 ± 7; P = 0.05), PF (72
± 6; P = 0.05), and FF groups (50 ± 9; P =
0.08) compared with the CU group (39 ± 11 mg/dl).
Insulin clamp condition. During insulin infusion, the plasma glucose
concentration was maintained at the basal level in the FF and CU groups
(
5 mmol/l), but allowed to decrease to
8 mmol/l in the NF group (a
value comparable with the postabsorptive level of the PF group), then
subsequently clamped via a 20% dextrose infusion at those levels. Plasma
leucine and branched-chain amino acids decreased to similar concentrations in
the NF, PF, FF, and CU groups during the clamp
(Table 3). In contrast, FFA
concentration was not suppressed in a similar fashion in the NF group in
comparison to the PF (P = 0.03), FF (P = 0.03), and CU
groups (P = 0.05) (Table
3).
Pancreatic peptides. Fasting plasma free insulin levels were
comparable in all study groups (65 ± 18, 73 ± 9,59 ± 12,
and 78 ± 14 pmol/l in FF, PF, NF, and CU, respectively). However, the
C-peptide concentration was different in the NF and PF groups, but not in the
FF group when compared with the CU group, as the C-peptide concentration was
considered a criterion for classification of subgroups
(Table 2). Postabsorptive plasma
glucagon concentration was comparable among groups (107 ± 20, 120
± 18, 94 ± 14, and 119 ± 11 pg/ml in the NF, PF, FF, and
CU groups, respectively). During hyperinsulinemia (plateau insulin
concentrations of 441 ± 46, 435 ± 29, 378 ± 39, and 488
± 25 pmol/l in the FF, PF, NF, and CU groups, respectively), the
C-peptide concentrations remained low in the NF group and became
physiologically suppressed in the NF (0.056 ± 0.02 nmol/l; P =
0.03 vs. basal), PF (0.30 ± 0.04 nmol/l; P < 0.01 vs.
basal), and FF groups (0.57 ± 0.14 nmol/l; P = 0.01 vs. basal)
compared with the CU group (0.57 ± 0.09; P < 0.01 vs.
basal). Similarly, the plasma glucagon concentration in all groups decreased
during the clamp (12 ± 6, 29 ± 9, 28 ± 14, and 18
± 5% in the NF, PF, FF, and CU groups, respectively).
Glucose and protein turnovers. Postabsorptive endogenous glucose
production (EGP) was higher in the NF group when compared with the PF, FF, and
CU groups (P = 0.01) (Table
4). In contrast, the PF and FF groups showed similar rates when
compared with the CU group (P = 0.71). Also, the insulin-dependent
suppression of EGP during the clamp was defective in the NF group (P
< 0.01); the PF and FF groups showed a normal pattern of suppression in
comparison with the CU group (Table
4). Insulin-stimulated glucose metabolism calculated during the
last hour of the clamp study did not show any differences among groups
(P = 0.306), albeit it did show a trend for lower rates in the NF
group (P = 0.101). The metabolic clearance rate of glucose was lower
in the NF group than in the other groups (P < 0.01).
Postabsorptive endogenous leucine flux was higher in the NF group than in the
other groups, using either the primary or reciprocal pool model (P =
0.05) (Table 4). Endogenous
leucine flux decreased to similar values during the clamp in all groups
(Table 4). Basal leucine
oxidation and nonoxidative leucine disposal (index of protein synthesis) were
higher in the NF (P < 0.05) than in the other groups; during
insulin infusion, both parameters decreased similarly in all groups
(Table 4). Using either the
primary or reciprocal pool model, data were comparable and differences among
groups were similar. For the FF group, data on only the endogenous leucine
flux were available, due to technical difficulties in collecting expired
breath samples in Giessen.
Lipid oxidation. Postabsorptive lipid oxidation was increased in the
NF group (1.710 ± 0.462 mg · kg-1 ·
min-1; P = 0.03) versus all other groups (0.826 ±
0.229, 1.130 ± 0.158, and 1.183 ± 0.181 mg ·
kg-1 · min-1 in the FF, PF, and CU groups,
respectively). During the insulin clamp, lipid oxidation was suppressed
similarly in the CU, FF, and PF groups (0.487 ± 0.041, 0.489 ±
0.296, and 0.607 ± 0.184 mg · kg-1 ·
min-1, respectively), but was still persistently higher in the NF
group (1.200 ± 0.474 mg · kg-1 ·
min-1; P = 0.01).
Albumin synthetic rate. Type 1 diabetic patients with intraportal
islet transplantation had a normal albumin concentration (38.3 ± 1.4
vs. 40.8 ± 2.3 g/l; P = 0.416), hepatic albumin synthetic rate
(7.0 ± 0.8 vs. 8.2 ± 0.9 mg · kg-1 ·
h-1; P = 0.670) and albumin fractional synthetic rate
(11.16 ± 1.56 vs. 12.08 ± 0.58%; P = 0.855) when
compared with that of normal healthy subjects.
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DISCUSSION
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Intrahepatic islet transplantation entails the injection of
1-2 ml of
packed islet tissue in the portal vein under angiographical guide. The
procedure is minimally invasive, relatively safe, and repeatable
(1). However, the success rate
1 year after islet transplantation is considerably lower than after
whole-pancreas transplantation
(24). The aim of the present
study was to examine the metabolic effects of the full and partial islet
functions (based on criteria given in Table
2) with special regard to intermediary metabolism and pancreatic
peptides secretion. This study showed that the restoration of partial function
(with an
60% reduction of pretransplant insulin requirement) normalized
postabsorptive and insulin-mediated protein and lipid metabolism. In contrast,
glucose homeostasis remained mildly abnormal. A full function of the islet
allograft (with an
100% reduction of pretransplant insulin requirement)
can also normalize glucose homeostasis. Our findings are particularly
important in light of the high prevalence of partial function in experienced
centers. Table 5 represents the
percentage of FF and PF patients in the Milan (n = 23 patients) and
Giessen (n = 22 patients) populations during the first 4 years after
the transplantation. Based on the present data, 81% of patients in the 1st
year, 43% in the 2nd year, 29% in the 3rd year, and 16% in the 4th year had
either full or partial function, and therefore normal lipid and protein
homeostasis.
Analysis of studies in which the amino acid and lipid concentrations were
measured in type 1 diabetic patients on conventional or intensive insulin
treatment
(25,26)
suggests that the metabolic abnormalities of islet-transplanted patients with
partial function are comparable with those of type 1 diabetic patients on
insulin treatment. If one considers that in grafted patients insulin is
secreted intrahepatically, undergoing the first-pass cleavage by the liver and
avoiding peripheral hyperinsulinemia, islet transplantation is seen as being
even more efficacious, even in conditions characterized by only partial
function. Moreover, the degree of metabolic compensation of type 1 diabetic
patients with an islet transplant is obtained notwithstanding the chronic
immunosuppressive treatment. This observation is noteworthy in light of the
fact that all the immunosuppressive drugs are administered orally, therefore
having a major firstpass effect on hepatic metabolism as well as an adverse
effect on islet secretory capacity. The finding that type 1 diabetic patients
with only partial function had a normal albumin secretion rate underlines the
efficacy of such a procedure in restoring normal hepatic glucose and protein
metabolism. Furthermore, it is striking to note that the NF patients were all
on intensified insulin therapy, but with immunosuppression; this regimen may
have been responsible for the increased proteolytic rates in NF patients when
compared with insulin-treated type 1 diabetic patients
(7). Interestingly, FF patients
showed a normalization of glucose homeostasis and low plasma concentration of
amino acids. This clinical pattern resembles the pattern of type 1 diabetic
patients on intensive treatment
(25,26,27).
However, in the latter group, metabolic control was obtained at the expense of
a high prevalence of hypoglycemia
(27), whereas no hypoglycemic
episode was seen in islet-transplanted patients. This finding is very likely
secondary to the near-physiological insulin secretion of islet allografts in
FF patients.
Kahn et al. (28) proposed a
disposition index for glucose metabolism, correlating insulin secretion and
BMI with insulin sensitivity
(28). Although such additional
analysis of data would have been appropriate for our PF and FF patients,
extending the correlation to protein and lipid metabolism and permitting the
definition of discrete insulin regulatory thresholds for protein, glucose, and
lipid metabolism, it was not possible to do so with the small number of
available subjects (n = 23) in this study.
The high value of residual EGP during the insulin clamp
(Table 4) confirmed our previous
findings in type 1 diabetic patients with islet transplantation
(1). Because an appropriate
steady state of specific activities/enrichments of tracers was achieved after
100 min of insulin infusion, other factors, such as increased intrahepatic
glucagon delivery, variability of the islet reinnervation pattern, and local
effect of immunosuppressive drugs may explain the EGP values.
Recent reports have suggested a physiological role for the C-peptide
molecule also, mainly via activation of the Na+-K+
ATPase pump
(13,14).
C-peptide was shown to affect both metabolism
(29,30,31)
and diabetic complications
(14,32,33).
Overall, the new set of data on C-peptide function may help to explain the
good metabolic control of type 1 diabetic patients with a partially
functioning graft. A positive effect of pancreas transplantation (yielding the
same levels of plasma C-peptide as PF patients) is already established for
diabetic neuropathy (34). In
addition, a reversal of the morphological lesions of diabetic nephropathy
after 10 years of successful pancreas transplantation has been shown recently
(35). We hypothesize that this
effect might be linked to the restoration of C-peptide and proinsulin
secretion along with insulin
(36). Finally, we recently
found higher postabsorptive C-peptide levels in type 1 diabetic patients
without renal complications than in patients with micro- and macroalbuminuria
(37). Our data did not
demonstrate a cause-effect relationship between C-peptide level and the
described metabolic effects, as it is likely that the results would have been
similar with aggressive insulin treatment.
In conclusion, restoring partial function to the secretory capacity of
ß-cells can lead to the normalization of protein and lipid metabolism,
leaving glucose metabolism only moderately impaired The present study
indicates that the "success" of islet transplantation may best be
defined by a number of metabolic criteria, not just glucose
concentration/metabolism alone.
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ACKNOWLEDGMENTS
|
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This work was supported by Juvenile Diabetes Foundation Research Grant
Award 194153 (L.L.), grants from the San Raphael Scientific Institute (PZ708,
L.L) and the Bundesministerium für Forschung und
Technologie (FKZ-07024806, R.G.B.), a Juvenile Diabetes Foundation
International Research Grant (R.G.B.), and the Fondazione Vigoni.
We wish to thank Van Chuong Phan, Paola Sandoli, and Sabrina Costa for the
skilled work with radioimmunoassay assessments.
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FOOTNOTES
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CU, chronic uveitis; EGP, endogenous glucose production; FF, full function
group; FFA, free fatty acid; FSR, fractional synthetic rate; GC, gas
chromatography; KIC, ketoisocaproate; MS, mass spectrometry; NF, no function
group; PF, partial function group.
Received for publication January 24, 2000
and accepted in revised form October 6, 2000
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