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Journal of Gastrointestinal Surgery
ISSN 1091-255X
J Gastrointest Surg
DOI 10.1007/s11605-013-2283-5
Distal Gastrectomy in
Pancreaticoduodenectomy is Associated
with Accelerated Gastric Emptying,
Enhanced Postprandial Release of GLP-1,
and Improved Insulin Sensitivity
Stefan Harmuth, Marlene Wewalka, Jens
Juul Holst, Romina Nemecek, Sabine
Thalhammer, Rainer Schmid, Klaus
Sahora, Michael Gnant, et al.
1 23
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2013 SSAT PLENARY
Distal Gastrectomy in Pancreaticoduodenectomy is Associated
with Accelerated Gastric Emptyin g, Enhanced Postprandial
Release of GLP-1, and Improved Insulin Sensitivity
Stefan Harmuth & Marlene Wewalka & Jens Juul Holst &
Romina Nemecek & Sabine Thalhammer & Rainer Schmid &
Klaus Sahora & Michael Gnant & Johannes Miholić
Received: 19 April 2013 / Accepted: 2 July 2013
#
2013 The Society for Surgery of the Alimentary Tract
Abstract
Objective This study aims to investigate the relationship between gastric emptying, postprandial GLP-1 and insulin sensitivity
after pancreaticoduodenectomy (PD).
Background Abnormal glucose regulation is highly prevalent in patients with pancreatic neoplasm and resolves in some after
PD, the cause of which is unclear. The procedure is carri ed out with pylorus preservation (PPPD) or with distal gastrectomy
(Whipple procedure). Accelerated gastric emptying and ensuing enhanced release of glucagon-like peptide-1 (GLP-1)
conceivably play a role in glucose metabolism after PD. It was the purpose of this study to shed light on the relationship
between gastric emptying, GLP-1 and glycemic control after PPPD and the Whipple procedure.
Methods A 75-g oral glucose tolerance test was carried out in 13 patients having undergone PPPD and in 13 after the Whipple
procedure, median age 61 (range, 32–70) years, following an interval of 23 (range, 5–199) months. Gastric emptying was
measured by the paracetamo l absorption method. Plasm a concentrations of glucose, insulin, GLP-1 and paracetamol were
measured at baseline, 10, 20, 30 60, 90, 120, 150 and 180 min. Homeostasis model assessment-estimated insulin resistance
(HOMA-IR) and oral glucose insulin sensitivity were calculated from glucose and insulin concentrations.
Results Patients with Whipple procedure as compared to PPPD had accelerated gastric emptying (p=0.01) which correlated
with early (0–30 min) integrated GLP-1 (AUC
30
; r
2
=0.61; p=0.02) and insulin sensitivity (r
2
=0.41; p=0.026) and inversely
with HOMA-IR (r
2
=0.17; p=0.033). Two of 13 Whipple patients (15 %) as compared to seven of 13 after PPPD (54 %) had
postload glucose concentrations (i.e. 120 min postmeal) ≥200 mg/dl (p<0.05). None of 13 (0 %) after Whipple procedure but
four of 13 patients (31 %) after PPPD had fasting glucose concentrations ≥126 mg/dl (p<0.05)
Conclusions Gastric emptying was accelerated after Whipp le procedure as compared to patients who have undergone PPPD,
resulting in higher postprandial GLP-1 concentrations and insulin sensitivity and improved glycemic control.
Presented at the 54th Annual Meeting of the SSAT in conjunction with
DDW at the Orange County Convention Center in Orlando, FL, USA,
May 18–21, 2013.
SSAT Presidential Plenary B (Plenary Session II)
S. Harmuth
:
R. Nemecek
:
K. Sahora
:
M. Gnant
:
J. Miholić (*)
Department of Surgery, Allgemeines Krankenhaus (AKH),
Medical University of Vienna, Währinger Gürtel 18,
1090 Vienna, Austria
e-mail: johannes.miholic@meduniwien.ac.at
M. Wewalka
Department of Internal Medicine III, Gastroenterology
and Hepatology, Medical University of Vienna, Vienna, Austria
J. J. Holst
Department of Medical Physiology, Panum Institute,
University of Copenhagen, Copenhagen, Denmark
S. Thalhammer
Department of Surgery, Kaiser Franz-Josef-Krankenhaus (KFJ),
Vienna, Austria
R. Schmid
Institute of Medical and Chemical Laboratory Diagnostics,
Medical University of Vienna, Vienna, Austria
J Gastrointest Surg
DOI 10.1007/s11605-013-2283-5
Author's personal copy
Keywords Pancreaticoduodenectomy
.
Diabetes mellitus
.
Gastric emptying. Glucagon-like peptide 1
.
Insulin resistance
Background
Partial pancreaticoduodenectomy (PD) is the standard pro-
cedure for the resection of pancreatic head and ampullary
neoplasms. It is carried out with distal gastrectomy and
pylorus resection (Whipple procedure) or as pylorus preserv-
ing PD (PPPD), both of which offer similar long- and short-
term outcomes.
1–5
However, PPPD has become the more
frequently used approach not only due to shorter operation
times but also following an intention to preserve unaffected
organs and function.
5
Impaired glucose tolerance and overt diabetes mellitus
(DM) are highly prevalent in pancreatic cancer patients, with
a great proportion of new-onset DM.
6,7
Insulin sensitivity
improves after tumor resection,
8
and diabetes even resolves
in a great proportion of patients with recent-onset DM after
PD,
9
the reason for which is not entirely clear. Apart from
increased insulin secretion and utilization, the enhanced
release of glucagon-like peptide-1 (GLP-1), which has an
antidiabetic effect, might contribute to the improved glyce-
mic state. Gastric emptying of nutrients triggers the release
of GLP-1 from the distal small bowel, which in turn en-
hances insulin release
10–12
and attenuates hepatic glucose
production.
13
Moreover, GLP-1 inhibits apoptosis of islet
cells and stimulates the proliferation of beta-cells and their
differentiation from precursors in rodents.
14
These mecha-
nisms are thought to be crucial in the improvement of DM
after gastric resections and after bariatric surgery before
significant weight loss has been achieved
15,16
and might
also play a role in improved glucose regulation after PD.
Conceivably, gastric emptying is accelerated after PD
with pylorus resection and partial gastrectomy.
17
Therefore,
the choice of surgical procedure with or without pylorus
preservation and ensuing gastric emptying and GLP-1 re-
lease might act upon glucose homeostasis. It was the purpose
of this study to shed light on the relationship between gastric
emptying, ensui ng GLP-1 release and glycemic control in
patients who have undergone PPPD and Whipple procedure.
Patients and Methods
Patients who have undergone partial PD were retrieved from
the records of two participating institutions (AKH, KFJ) and
contacted. A tota l of 57 patients were screened for eligibility
during a visit at the outpatient clinic. Only tum or-free pa-
tients up to 70 years old, with stable body weight (weight
gain or loss ≤ 2 kg during the preceding 3 months), were
included. There were 13 patients after PPPD and 13 who
have undergone Whipple procedure who agreed to partici-
pate and gave informed written consent (Table 1). The Ethics
Review Board of the Medical University of Vienna has
approved the study protocol.
Body Compos ition Measurement
Weight was measured to the nearest 0.5 kg and height to the
nearest 0.5 cm, and bioelectrical impedance recordings were
used to estimate lean body mass from resistance and reac-
tance as described previously, using a BIA 103 impedance
analyzer (RJL Systems, Detroit, MI, USA).
18,19
OGTT and Paracetamol Absorption Test
The study patients were asked to adhere to a diet rich in
carbohydrates for 3 days and to fast for 12 h prior to their
study visit. On the day of the visit, an indwelling catheter
was inserted into the forearm vein for blood sampling. After
measurement of baseline glucose, insulin, GLP-1, and para-
cetamol, 1 g of aqueous paracetamol solution was ingested
simultaneously with a solution of 75 g glucose in 300 ml
water (oral glucose tolerance test [OGTT]) within 1 min.
Consequently, glucose, insulin, GLP-1, and paracetamol
were sampled at 10, 20, 30, 60, 90, 120, 150 and 180 min
after the end of ingestion. Gastric emptying was estimated by
calculating the area under the curve from 0 to 30 min
(AUC
30
) from seri al measurements of plasma paracetamol
concentrations,
20
using a specific homogenous immunoas-
say with CEDIA-technology (Microgenics GmbH, Passau,
Germany). The postprandial plasma concentrations of para-
cetamol, which is absorbed in the small intestine but not in
stomach, have frequently been used as a measure of gastric
emptying and have been validated against other methods
such as scintigraphy.
20
Modeling Analysis
Insulin sensitivity was derived from a mathematical model of
plasma glucose and insulin concentrations.
21
It is calculated as
the oral glucose insulin sensitivity (OGIS) index which esti-
mates plasma glucose clearance at a level of hyperinsulinemia
in the range of that achieved during a standard euglycemic–
hyperinsulinemic clamp, against which this index has been
validated.
21
The calculations used the glucose measurements
at 0, 120 and 180 min and the insulin concentrations at 0 and
120 min. The homeostasis model assessment was applied to
determine homeostasis model assessment-estimated insulin
resistance (HOMA-IR).
22
HOMA-IR was calculated as fasting
plasma glucose (mg/dl) × fasting serum insulin (μIU/ml)/405.
J Gastrointest Surg
Author's personal copy
Laboratory Analysis
Plasma glucose concentrations were measured by the glucose
oxidase method. Blood samples for hormone measurements
were collected in pre-frozen tubes containing 7.3 mmol/l
EDTA, centrifuged in the cold, and stored at −70 °C.
GLP-1 plasma concentrations were measured after extrac-
tion of plasma with 70 % ethanol (vol/vol, final concentra-
tion). The plasma concentrations of GLP-1 were measured
against standards of synthetic GLP-1 (7–36 amide) using
antiserum code no. 89390, which is specific for the amidated
C-terminus of GLP-1 and therefore reacts mainly with GLP-1
of intestinal origin. The sensitivity of this assay was below
1 pmol/l, the intra-assay coefficient of variation was below
6 % at 20 pmol/l and the recovery of the standard, added to the
plasma before extraction, was about 100 % when corrected for
losses inherent in the plasma extraction procedure.
Statistics
Continuous variables are presented as median and range,
unless stated otherwise. The integrated values of concentra-
tions were retrieved by the trapezoidal rule. Continuous
variables were compared and tested for significance using
the Wilcoxon test, frequencies by one-sided Fisher’s exact
test, unless stated otherwise. Univariate and multivariate
linear regression was carried out where appropriate, using
JMP version 9.0.1 (SAS Institute Inc.). A p-value of ≤ 0.05
was consi dered to be significant.
Results
The paracetamol plasma concentrations peaked earlier, and the
early integrated concentrations (AUC
30
)—used throughout as
measure of gastric emptying
20
—were significantly higher after
Whipple procedure as compared to PPPD (T able 2;Fig.1).
Paracetamol and GLP-1 correlated significantly (Fig. 2). Cor-
respondingly, GLP-1 plasma concentrations peaked higher, and
the early (AUC
30
) and total integrated concentrations (AUC
180
)
of GLP-1 were significantly higher in Whipple subjects. The
BMIandearlyintegratedGLP-1(AUC
30
) correlated inversely
(r=−0.41; p=0.039).
The integrated concentrations of insulin were similar be-
tween the two surgical procedures (Table 2; Fig. 1). The
early and total integrated (AUC
0–30
and AUC
0–180
) plasma
glucose levels were not different between Whipples and
PPPD. The fasting value and the measurement at 180 min
were, however, significantly lower in Whipple subjects
(p<0.02 and p<0.05, respectively; Fig. 3a; Table 2). None
of the Whipples but four (31 %) of PPPD subjects had a
fasting glucose above 126 mg/dl (p=0.0484), the WHO
cutoff defining diabetes mellitus.
23,24
The concentrations at
120 min (also termed postload glucose) were above
200 mg/dl in significantly more subjects after PPPD
(p=0.0478; Table 2). Six of 13 Whipples (46 %) and three
of 13 (23 %) PPPD subjects suffered glucose concentrations
≤70 mg/dl (NS) and two of each group ≤ 50 mg/dl during the
observation period.
25
The HOMA-IR was lower (Fig. 3b) and the insulin sen-
sitivity (OGIS
180
) was significantly higher after Whipple
procedure as compared to patients with PPPD (Table 2).
In order to identify factors independently associated with
insulin sensitivity in addition to the type of operation, mul-
tiple linear regression was applied (Fig. 4). The type of
operation (p=0.0014) and % body fat (inverse correlation;
p=0.0138) were the only significant “predictors” of insulin
sensitivity, whereas preoperative DM, age, gender, interval
since operation and BMI did not yield additional significance
(r=0.68; p<0.002).
Discussion
A great proportion of patients with pancreatic neoplasms are
found to have impaired glucose regulation or even overt
DM, which often improves substantially after undergoing
pancreaticoduode nectomy.
9
Accelerated gastric emptying and
Table 1 Patient characteristics
Whipple PPPD P-value
Age (year) 61 (32– 70) 62 (48–66) 0.918
Gender (M/F ratio) 6:7 11:2 0.097
Interval since surgery (months) 31 (7–199) 19 (5–107) 0.218
Underlying disease Pancreatitis, 1
Neoplasia, 11
Trauma, 1
Pancreatitis, 1
Neoplasia, 12
0.593
Body mass index 22.6 (16.6–36.1) 25.4 (18.4–31.2) 0.72
% body fat 23.8 (7.1–45.8) 24.9 (2.0–34.1) 0.938
DM before surgery (fasting glucose ≥126 mg/dl) 2/13 (15 %) 4/13 (30 %) 0.189
J Gastrointest Surg
Author's personal copy
consequently enhanced postprandi al release of GLP-1 have
been observed after various surgical procedures including gas-
trectomy, gastric bypass, esophageal resection and fundo-
plication.
11,12,26
The rapid transport of unabsorbed nutrients to
the distal bowel triggers an enhanced release of GLP-1, resul-
ting not only in improved glycemic control and even remission
of overt DM but also in reactive hypoglycemia and late
dumping.
15,27,28
Since removal of the pylorus likely accelerates
gastric emptying,
17
we wanted to investigate whether the
Whipple procedure shows enhanced postprandial GLP-1 con-
centrations and possibly improved glycemic control.
Paracetamol absorption testing was chosen to study gas-
tric emptying for the method’s ease of use and because it has
been validated against scintigraphic measurements of gastric
emptying.
20
Median gastric emptying was significantly
faster after Whipple procedure than in PPPD (Table 2), in
which procedure delayed gastric emptying is recognized as a
common side effect.
29–31
The time to peak paracetamol
concentration—10 min after Whipple and 20 min after
PPPD—was much shorter than the reported 60 min in
healthy controls, showing accelerated gastric emptying for
glucose solution after both types of PD.
32
Rapid emptying
was closely associated with ensuing GLP-1 relea se. Whereas
in healthy men during OGTT GLP-1 peak concentrations
were the twofold fasting values,
33
in Whipple subjects the
peak GLP-1 concentrations were 11 times and in PPPD were
6.5 times the fasting value. Hence, PD subjects experience
faster gastric emptying and exaggerated concentrations of
GLP-1 when compared to healthy controls.
We observed that regardless which type of operation was
carried out, gastric emptying was closely correlated to GLP-1
release (Fig. 2), which corresponds well with previous find-
ings after other gastric operations.
11,12
This is in accordance
with the early (AUC
30
) and total (AUC
180
) integrated
concentrations of GLP-1 being significantly higher in Whip-
ple subjects (Table 2).
This enhanced release of GLP.1 was in correspondence
with a lower percentage of subjects with a postload glucose
≥200 mg/dl, one of the definitions of DM. Moreover, the
fasting glucose concentrations were also lower in the
Whipples, which is in correspondence with the lower
HOMA-IR in this group.
GLP-1 improves insulin sensitivity via enhanced stimula-
tion of insulin release, inhibition of glucagon and ensuing
Table 2 Paracetamol, glucose, insulin, and GLP-1 measured during the procedure and insulin resistance and sensitivity calculated from OGTT
Whipple PPPD P-value
Paracetamol
Peak concentration (μg/ml) 24 (14 43) 15 (11–32) 0.009
Time to peak concentration (min) 10 (10– 20) 20 (10–75) 0.006
AUC
30
(μg/ml × min) 494.5 (309–860) 318.5 (230–601) 0.015
AUC
180
(μg/ml × min) 1968 (1054–3005) 1755 (980–2464) 0.311
GLP-1
Baseline (pmol/l) 14 (1–27) 11 (4–25) 0.80
Peak (pmol/l) 133 (49–438) 79 (22–165) 0.020
AUC
30
(pmol/l × min) 2880 (920–9205) 1740 (340–3215) 0.016
AUC
180
(pmol/l × min) 9680 (4880–37055) 6860 (2495–12015) 0.020
Insulin
Baseline (mU/l) 0 (0–7.3) 0 (0–13.9) 0.711
Peak (mU/l) 54.9 (12.8– 490) 53.3 (4.2–243) 0.174
AUC
30
(mU/l × min) 446 (57–4593) 366 (0–1265) 0.427
AUC
180
(mU/l × min) 4615 (1363–33961) 5802 (502–16161) 0.818
Glucose
Baseline (mg/dl) 91 (75– 123) 108 (83–170) 0.022
Peak (mg/dl) 225 (139–317) 300 (153–391) 0.473
AUC
30
(mg/dl × min) 4830 (3600–6015) 4775 (3845–6870) 0.837
AUC
180
(mg/dl × min) 29205 (19610–37555) 33800 (17570–58750) 0.273
Prevalence of fasting glucose ≥126 mg/dl 0/13 (0 %) 4/13 (31 %) 0.0484
Postload (120 min) glucose (mg/dl) 136 (51–209) 242 (55–391) 0.174
Prevalence of postload (120 min) glucose ≥200 mg/dl 2/13 (15 %) 7/13 (54 %) 0.0478
Insulin resistance (HOMA IR) 0.6 (0.22–1.75) 0.8 (0.6–5.8) 0.020
Insulin sensitivity (OGIS
180
; ml . min
−1
.m
−2
).
21
488 (310–568) 406 (265–500) 0.009
J Gastrointest Surg
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attenuated hepatic glucose production.
34
Moreover, GLP-1
induced differentiation of beta cells and inhibition of beta cell
apoptosis may play a role in the observed glycemic control.
14
In addition, GLP-1, which is known to induce postprandial
satiety, might result in lowered BMI and % body fat and as
such contributes to the diminished insulin resistance in pa-
tients after Whipple procedure.
35
Similar changes as can be
observed after bariatric procedures might play a role in the
improved insulin resistance after Whipple procedure, yet the
underlying mechanisms remain incompletely understood.
27,36
The inverse relationship between % body fat and OGIS was
independent from the mode of operation, gastric emptying and
postprandial GLP-1 concentrations, as revealed by the multi-
ple regression model. The accelerated gastric emptying may
therefore improve insulin sensitivity in several ways: by stim-
ulating GLP-1-induced insulin release, resulting in diminished
hepatic glucose production, and by the inhibition of appetite
and ensuing reduced % body fat. It is not completely clear
what causes the inverse relation of BMI and GLP-1 release.
Weight loss might be the consequence of the known GLP-1-
induced reduced appetite, but conversely, attenuated postpran-
dial release of GLP-1 has been reported in obese subjects.
37,38
Considering the presently dismal prognosis of pancreatic
cancer,
1–5
the question of glucose metabolism after pancre-
aticoduodenectomy may seem to be of minor importance,
but impaired insulin sensitivity is known to encourage the
development of pancreatic cancer and impair the survival of
affected subjects.
6,39– 42
Pr o sp e c t i v e rand omized trials
comparing Whipple procedure and PPPD have been scarce,
inconsistent in study design and unclear with regard to the
mode of randomization.
5
They seem underpowered when
pancreatic cancer and periampullary neoplasms are looked at
separately , and modest but significant differences in survival
after Whipple procedure and PPPD may have been missed due
Fig. 1 Time course (mean±SD) of paracetamol (a), glucose (b ), insulin (c), and GLP-1 (d) concentrations during the OGTT in patients after
Whipple’ procedure (.) and after PPPD (o)
J Gastrointest Surg
Author's personal copy
to the small number of patients in the subgroups.
5
Larger and
well-designed trials are needed to shed light on the possible
effect of the mode of operation and ensuing insulin sensitivity
on disease-free and overall survival in pancreatic adenocarci-
noma. It remains to be studied whether glycemic control is an
independent factor for the survival of cancer patients treated by
surgery with curative intent.
The observation that metformin, an antidiabetic drug act-
ing similarly to GLP-1, i.e. attenuating hepatic glucose pro-
duction, reduces the risk of pancreatic cancer in diabetic
patients puts emphasis on the probable relationship between
glycemic control and pancreatic cancer survival.
42
The role of GLP-1 analogs such as exenatide, which are
widely used in diabetes therapy, has recently been questioned
by safety concerns.
42–46
Caveats were articulated whether
these therapies might increase the risk of pancreatitis and
pancreatic cancer—in diabetic patients—by stimulating the
proliferation of pancreatic ductal cells. The role and impact
of GLP-1-based therapy in established pancreatic cancer re-
mains unclear among the current controversies. Whether these
concerns apply also to operations that cause exaggerated
postprandial GLP-1 release such as Whipple procedure, total
gastrectomy or gastric bypass remains to be investigated. It is
presently an open question whether survival in pancreatic
cancer treated with PD is improved by GLP-1-induced aug-
mentation of insulin sensitivity or is impaired by some—so far
hypothetical—proliferation-boosting capacity of GLP-1.
Conclusion
In summary, Whipple patients exhibited rapid gastric emp-
tying and tended to have lower fasting glucose levels and
Fig. 3 Fasting glucose (a) and HOMA-IR (b) in Whipple and PPPD
patients (median, interquartile range and 5th and 95th percentile
Fig. 4 Regression diagram: the relationship between % body fat, type
of operation and insulin sensitivity (OGIS
180
) in patients having under-
gone Whipple procedure ( .) and PPPD ( o; r =0.68; p<0.02)
Fig. 2 Relationship between paracetamol (AUC
30
) and early integrated
GLP-1 (AUC
30
; r=0.44; p=0.0254) in patients after Whipple ’ proce-
dure (.) and after PPPD (o)
J Gastrointest Surg
Author's personal copy
less insulin resistance than patients with PPPD. Accelerated
gastric emptying is a strong independent predictor of GLP-1
release, insulin sensitivity and various other measures of
glycemia, indicating that it is a crucial factor accounting for
these findings. As the exact mechanism that reduces insulin
resistance with accelerated gastric emptying is not complete-
ly understood, the preliminary results of this pilot study
warrant further research. In the connotation of pancrea-
ticoduodenectomy, the consequences of pylorus preservation
should be reconsidered, and prospective randomized trials
may shed more light on the consequences of the type of
operation on glucose metabolism.
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Discussant
Dr. David McFadden (Farmington, Connecticut): Thank
you for that excellent presentation, Dr. Miholic, and for the
opportunity of reading your manuscript in advance. Your
study introduced me to two unknown concepts; one is that
patients undergoing pancreaticoduodenectomy have in-
creased gastric emptying, and the second is that glucose
tolerance is improved and diabetes may be cured by this
operation. You attribute this to increased GLP-1 secretion,
and demonstrate here that it is much more pronounced post-
prandially in patients undergoing antrectomy with their
Whipple versus the pylorus preserving variant. I have two
questions and one criticism.
First, given their rapid gastric emptying, and their
low body mass index, were any of your study patients
symptomatic?
Second, although statistically insignificant, the length of
time postoperatively in your antrectomy group was much
longer (31 vs. 19 months) and may have contributed to your
findings. Could this be a Type II error?
Finally, I believe this study would be strengthened by the
addition of a control group, i.e. unoperated normal volun-
teers, to eliminate inter-assay variations. Your fasting GLP-1
levels seem low to me from the values I am familiar with,
and I would expect them to be higher given your findings.
Again, thank you and congratulations on an excellent
contribution to the scientific literature.
Closing Discussant
Dr. Johannes Miholic: Dr. McFadden, although in patients
with accelerated gastric emptying after pancreaticoduo-
denectomy dumping may be expected, we did not look at
postprandial symptoms during our tests. Dumping symp-
toms had not been reported spontaneously by the subjects
during the screening visi t at the outpatient clinic. Rea ctive
hypoglycemia (late dumping) may be a concern in some
subjects, particularly after rapid gastric emptying, and be
considered in future trials.
Recruitment of patients who have undergone Whipple
procedure was a demanding task since the operat ion has
become sort of antiquity. The somewhat longer intervals
since operation in Whipple subjects may thus be explained.
The interval since operation was of no statistical association
with the insulin sensitivity in simple and in multivariate
statistics.
I agree that a control group of healthy volunteers would
have helped to elucidate the results, and controls shall be
included in future studies.
J Gastrointest Surg
Author's personal copy
