(CANCER RESEARCH 52. 3845-3850. July 15. 1992]
Effect of Systemic Hyperinsulinemia in Cancer Patients1
Martin J. Heslin, Elliot Newman, Ronald F. Wolf, Peter W. T. Pisters, and Murray F. Brennan2
Department of Surgery, Surgical Metabolism Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
However, nutritional support to improve the clinical outcome
in this group of patients has not been associated with a survival
Data defining the isolated effect of insulin on whole body protein and
benefit (4, 14). Part of the explanation for the lack of success
glucose metabolism in cancer patients are limited. Ten normal volun
with standard nutritional support may lie in the failure of the
teers (controls), age 55 ±3 years (mean ±SEM); 8 cancer patients, age
61 ±3years, weight loss 2 ±1% (CANWL); and 8 cancer patients, age current nutritional regimens to completely reverse the abnor
malities of intermediary metabolism.
55 ±2 years, weight loss 18 ±2% (CAWL), were studied in the postA well documented abnormality of metabolism in cancer pa
absorptive state. Whole body leucine kinetics were determined during a
baseline and then a study period during which insulin was infused at 1.0 tients is resistance to insulin with respect to carbohydrate me
milliunits/kg/min to achieve a high physiological level of 71 ±6, 83 ± tabolism (15, 16). These studies documented decreased uptake
5, and 64 ±5 microunits/ml in controls, CANWL, and CAWL, respec
of glucose in peripheral tissues and in the whole body under the
tively. Whole body net balance equals protein synthesis minus protein
influence of insulin. However, data examining the response of
breakdown. Glucose disposal (mg/kg/min) is the rate of D30 infusion at
cancer patients to insulin with respect to protein metabolism
steady state.
are limited. This is potentially important for 2 reasons, (a)
Glucose disposal of CANWL and CAWL during the study period was
significantly (P < 0.05, analysis of variance) less than controls (3.91 ± Resistance to the well described anticatabolic actions of insulin
0.6 in CANWL, 3.66 ±1.0 in CAWL, and 5.87 ±0.6 mg/kg/min in (17, 18) could be a partial etiology for the increased catabolism
of protein stores, which has been previously documented in
controls), suggesting resistance to insulin with respect to carbohydrate
cancer patients (8, 9). (b) Resistance to insulin with regard to
metabolism. Hyperinsulinemia, under euglycemic and near basal amino
acid conditions, significantly reversed the negative postabsorptive leu- protein metabolism could be responsible for lack of demonstra
cine net balance (P < 0.05, analysis of variance) by decreasing protein
ble survival benefit in patients supported by TPN. The present
breakdown in controls as well as weight-stable and weight-losing cancer
study was undertaken to examine the isolated effects of hyperpatients, suggesting that cancer patients are not resistant to the antiinsulinemia under euglycemic conditions with near basal amino
catabolic effect of insulin with respect to whole body protein metabo
acid levels on protein and glucose metabolism in weight-stable
lism.
and weight-losing cancer patients.
ABSTRACT
INTRODUCTION
MATERIALS
The syndrome of cancer cachexia is characterized by severe
weakness, debilitation, and generalized host wasting (1). This
malnourished state is associated with decreased survival (2),
and in up to one-half of cancer patients cancer cachexia has
been implicated as the sole cause of death (3). The etiology of
this syndrome is multifactorial in nature, and while decreased
nutrient intake is partly responsible, a major contribution
comes from the well described abnormalities in host interme
diary metabolism of carbohydrate, protein, and fat (4).
Reports documenting abnormal peripheral glucose disposal
(5), gluconeogenesis (6), and whole body glucose turnover (7)
confirm alterations in carbohydrate metabolism in these pa
tients. Abnormalities of protein metabolism have been reported
at the whole body level (8, 9) as well as in skeletal muscle (9)
and liver proteins (9). Fat metabolism is also modified as evi
denced by abnormal host lipid stores (10), and free fatty acid
and glycerol turnover rates (11, 12). The cachectic cancer pa
tient ineffectively utilizes nutrients and furthermore seems to be
unable to adapt to the malnourished state as normal humans do
by conserving lean body mass (13).
With the advent of TPN,1 the ability to provide adequate
nutrient intake in debilitated cancer patients was made possible.
Received 12/16/91; accepted 5/1/92.
The costs of publication of this article »eredefrayed in part by the payment of
page charges. This article must therefore be hereby marked advertisement in accor
dance with 18 U.S.C. Section 1734 solely to indicate this fact.
1This work was supported by USPHS Grant CA09501. the Surgical Metabo
lism Fund, and the Wells Foundation.
~To whom requests for reprints should be addressed, at Department of Surgery.
Memorial Sloan-Kcttering Cancer Center. 1275 York Avenue. New York. NY
10021.
'The abbreviations used are: TPN. total parenteral nutrition; CANWL. cancer
patients with weight loss <10% of premorbid weight; CAWL, cancer patients with
weight loss >10% of premorbid weight: C, control group; RA, rate of disappear
ance; R,, rate of appearance; KIC, a-ketoisocaproic acid.
AND METHODS
Subjects. Cancer patients were selected based on a histológica! di
agnosis of cancer, with or without the presence of weight loss at the
time of presentation. These patients were selected from the Surgical
Sen ice of the Memorial Sloan-Kettering Cancer Center. All were pre
operative surgical patients studied before any surgical, radio-, or nutri
tional therapy except one patient who was studied 6 months after the
last dose of a chemotherapy regimen. Cancer patients were divided into
2 groups based on weight loss greater or less than 10% of premorbid
weight during the 6 months before diagnosis.
The control group consisted of 10 normal, healthy, weight-stable
volunteers within 15% of their ideal body weight (19).
Both cancer patients and controls were studied in the postabsorptive
state after a 10-12-h overnight fast. Informed written consent was
obtained before any testing, and all studies were carried out in the Adult
Day Hospital of the Memorial Sloan-Kettering Cancer Center at rest in
the supine position under an Institutional Review Board-approved pro
tocol. These subjects had no history of systemic illness, hypertension,
ischemie heart disease, or diabetes mellitus. None was taking medica
tion known to alter protein or glucose metabolism. Subjects consumed
their usual diet for the 3 days before study. A 24-h urine collection was
completed before study that was analyzed for total creatinine. Demo
graphic and nutritional indices of the cancer patients and volunteers are
listed in Tables 1 and 2.
Isotopes and Infusâtes. i-[l-l4C]Leucine (50 nCi/mmol) and [MC]HCO.i (250 iiCi/mmol) were obtained from Dupont (Boston, MA).
L-[l-'4C)Leucine was diluted in normal saline to a final concentration of
0.56 nCi/ml. [I4C]HCO3 was also diluted in normal saline to a final
concentration of 0.9 nCi/ml. All tracers were filtered through a 0.2-^m
sterilizing filter (Acrodisc; GelmanSciences, Ann Arbor, MI) before
infusion. The insulin infúsatewas composed of 100 ml of sterile normal
saline, 2 ml of the subject's plasma, and 31 units of regular Humulin
insulin (Lily and Co., Indianapolis. IN) for a final concentration of 300
milliunits/ml. The amino acid infúsatewas 10% Travasol without elec
trolytes (Travenol Laboratories, Deerfield, IL), which contains (in mg/
100 ml) 730 leucine, 600 isoleucine, 580 lysine, 580 valine, 560
3845
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CANCER, INSULIN. AND PROTEIN
METABOLISM
infusion. The arterial glucose was measured at the bedside at 5- to
10-min intervals, and the dextrose infusion rate was adjusted accord
Age (yrs) Gender (M:F)
Diagnosis
ingly. Endogenous glucose production under the influence of insulin at
53 ±3*
Control"
5:5
this level has been demonstrated to be completely suppressed in similar
CANWL'
Lung (n = 5), gastric (n = 3)
61 ±3
6:2
Esophagus (n = 3), pancreas (n = 2),
control and cancer patients (25) during the equilibration period, there
CAWl/
55 ±2
5:3
gastric (n = 1), S. bowel (n = 1),
fore the rate of exogenous glucose infusion to maintain euglycemia at
colon (n = 1)
steady state was used to determine the rate of whole body glucose
°n= 10.
uptake.
* Mean ±SE.
After a 2-h euglycemic, hyperinsulinemic, euleucinemic equilibration
c CANWL is the weight loss <10°/o(n = 8).
period, arterial and expired gas samples were collected at 15-min in
dCAWL is the weight loss a 10% (n = 8).
tervals for 45 min for determination of the same parameters as in the
baseline period. At the termination of the study period, the isotope,
Table 2 Nutritional indices
amino acid, and insulin infusions were discontinued, and the glucose
Significance defined as P < 0.05.
infusion was maintained for 30-45 min to avoid rebound hypoglycemia.
IBW(%)106
loss(%)2±
fat(%)29
Analytical Methods. Arterial blood samples were obtained and al
(mg/dl)4.4
located into appropriate tubes (Becton Dickinson, Rutherford, NJ) and
Control*
±3C
±0.1
±0.4
±2
immediately placed on ice. Arterial blood for immunoreactive insulin
CANWL''
4.3 ±0.1
9.4 ±1.1
29 ±1
103 ±2
1
18±2/"Albumin
CAWL'%
3.9 ±0.2Cr/Hf(mg/cm)6.8
6.2 ±0.7%
26 ±3 determination was collected in plain tubes, centrifuged, and immedi
100 ±5Wt
ately frozen for subsequent analysis by radioimmunoassay (Autopak,
" Cr/Ht, urinary creatinine excretion divided by the height.
Micromedics, Horsham, PA). Arterial blood for immunoreactive glu
*n= 10.
' Mean ±SE.
cagon determination was collected into Na-EDTA tubes with 1000
dCANWL is the weight loss <10% (n = 8).
kallikrein inhibitor units of aprotinin (Trasylol; FBA Pharmaceutical,
' CAWL is the weight loss a 10% (n = 8).
New York, NY), centrifuged, and frozen for later analysis by standard
^Significance versus that of control.
radioimmunoassay (26) (Diabetic Core Center, Philadelphia, PA). A
subaliquot of arterial blood was used for determination of glucose con
phenylalanine, 480 histidine. 420 threonine, 400 methionine, 180 trypcentrations at the bedside (Glucose Analyzer 2; Beckman Instruments,
tophan, 2070 alanine, 1150 arginine, 1030 glycine, 680 proline, 500
Fulierton, CA). The rest of the blood was collected into tubes contain
serine, and 40 tyrosine. The exogenous glucose infúsatewas 30% dex
ing sodium heparin. After centrifugation, an aliquot of plasma was
trose (Abbott Laboratories, North Chicago, IL).
immediately deproteinized using 50 ul of 50% sulfosalicylic acid/ml of
plasma and then frozen at -80°C until extraction of KIC (27) and
Experimental Protocol. The experiment was divided into 2 parts: the
basal postabsorptive state, which consisted of a 120-min equilibration
subsequent determination of the plasma concentration and specific ac
period (-165 to -45 min) and a subsequent sampling period of 45 min
tivity. The KIC was separated from 3 ml of plasma and the plasma
(-45 to O min) immediately followed by a euglycemic, hyperinsulineconcentration determined by high performance liquid chromatography
mic, near basal amino acid period consisting of another 120-min equil
using an internal standard (Series 4; Perkin-Elmer, Stamford, CT) with
ibration period (0-120 min) followed by a second sampling period of 45
fraction collection. Immediately after collection of the KIC peak, 500 M'
min ( 120-165 min) (Fig. 1) During the study period, a 10% amino acid
were used to determine radioactivity using a liquid scintillation counter
solution was administered to achieve near basal amino acid levels with
(Minaxi Tricarb; Packard Instrument Co., Chicago, IL), and 200 ß\
of
maintenance of basal leucine levels (euleucinemia) because of the pu
the remaining collected peak were reinjected for determination of the
tative regulatory effect of leucine on protein turnover (20).
concentration used in the calculation of the specific activities. The
On the morning of study, 2 18-gauge catheters (Deseret, Sandy, UT)
remaining plasma was used for determination of amino acid profiles
were inserted into peripheral forearm veins in one arm for infusion of using ion exchange chromatography and post column ninhydrin derivatracers, glucose, insulin, and amino acids. After documentation of ad
tization (Pickering Laboratories, Mountainview, CA). The average per
equate collateral hand blood flow, the radial artery of the same arm was cent recovery of KIC was 85% in known standards made in the labo
cannulated with a 20-gauge catheter (Deseret) under local anesthesia
ratory.
for sampling of arterial blood. In the opposite arm, a 2-in 18-gauge
The percent CO2 in expired air was determined by gas analysis (Med
polyethylene catheter was inserted retrograde in a deep antecubital vein
ical Gas Analyzer 1100; Perkin-Elmer, Stamford, CT). The volume of
to sample the venous effluent of the forearm muscle bed. Reasonable
expired air in the Douglas bag was determined by the evacuation time
assurance that a deep vein was cannulated was obtained by the inability
with a calibrated pump. Hydroxide of lOx Hyamine (1 ml) in absolute
to palpate the tip of the catheter after placement.
ethanol (2 ml) with phenolphthalein indicator was used to collect 1
At —¿165
min, a primed continuous infusion of l-L-[l-'4C]leucine
mmol of CO2 for liquid scintillation counting (22).
(bolus 16 jiCi, continuous infusion 0.16 ^Ci/min) was started. In addi
Procedures. Skinfolds were measured at 4 classic sites (biceps, tri
tion, l4C-labeled sodium bicarbonate was given as a bolus of 3.6 /iCi to ceps, subscapular, and iliac crest) using skinfold calipers (Lange Cali
prime the bicarbonate pool (21). After the 2-h equilibration period,
pers, Cambridge, MD). By using regression equations that relate skinarterial blood was drawn at I(I nun intervals for glucose, physiological
fold measurements to underwater weight (28), the percent total body fat
amino acid, insulin, and glucagon concentrations, as well as for the
was estimated. Skinfold measurements were performed by a single in
determination of L-[l-14C)leucine and l4C-labeled KIC specific activi
vestigator to minimize variability.
ties. Expired gas was collected in Douglas bags using a Rudolph mask
Calculations. In all calculations, the values from each period were
for 5 min twice during the sampling period for determination of total
averaged to provide one value per period per subject.
CO; production. The specific activity of expired [14C]CO2 was deter
Whole Body Leucine Kinetics. Whole body leucine flux was calcu
mined 4 times during the sampling period by the amount of radioac
lated using a stochastic model for protein metabolism. This analysis
tivity collected in a hyamine solution designed to trap 1 mmol of carbon
dioxide (22).
10 % Amino Acids
Upon completion of the baseline measurements, a primed continu
ous infusion of insulin (bolus = 400 milliunits/m-, continuous infusion
30K> Dextrose
Insulin (1 mU/kg/min)
of 1 milliunit/kg/min) and a continuous infusion of 10% Travaso!
L-1-(14C)-Leucine
amino acid solution without electrolytes were started. The rate of amino
-45
acid infusion was 0.011 ml/kg/min (the rate of leucine infusion was 0.65 Time -165
120
165
0
(min)
Mmol/kg/min). These infusion rates were selected to achieve and main
Study
Baseline
tain a high physiological insulin concentration of approximately 80
microunits/ml and euleucinemia based upon our own data (23) and the
Fig. I. Experimental design. Large arrow, sampling of blood for amino acid
work of others (24). Euglycemia was maintained with a 30% dextrose
and glucose concentrations, KIC specific activities, and expired air.
3846
Table 1 Demographics
ÃŽÃŽÃŽÃŽ
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tm
CANCER, INSULIN, AND PROTEIN
assumes near steady state conditions (29). Using this model, total leucine turnover or flux (ß)equals
METABOLISM
Table 4 Arterial leucine,total arterial amino acid concentration,and KIC
specificactivity
Significancedefined as P < 0.05.
ß= Rd + Ox = Ra + I
SA(dpm/Minol)2638
(¿imol/liter)116
(>imol/liter)1521
±6<"
Control*
±155
2084±218rf 2386
Study
111±7
CANWl/
130±7
Baseline
1722±105
2446
2276 ±143''
Study
131±8
2245
CAWI/PeriodBaseline
123±13
1693±112
Baseline
2573
2221
±
137''KIC
StudyLeucine 118±11TAA"
2327
" TAA, total arterialamino acids;SA, specificactivity.
*«=10.
where Ra equals the rate of leucine incorporation into protein, Ox
equals the rate of leucine oxidation, /?„
(endogenous leucine rate of
appearance) equals the rate of leucine released from protein, and /
equals the rate of exogenous leucine input (^mol/kg/min). The exoge
nous leucine infusion was determined from the rate of infusion of amino
acids. The rate of leucine turnover (ß)is calculated as: ß= F/KIC SA,
where Fis the infusion rate of L-[l-14C]leucine (dpm/kg/min), and KIC
SA (dpm/Ã-imol) is the specific activity of KIC in the plasma compart
ment under equilibrium conditions. KIC is the transaminated ketoacid
of leucine, and measurement of its plasma specific activity is believed to
be a more accurate assessment of the specific activity of leucine in the
precursor pool for protein flux and oxidation (30, 31). By using
L-[l-14C]-labeled KIC "reciprocal pool" kinetics, one accounts for the
total body leucine flux (31).
The leucine oxidation rate (Ox) was calculated as: Ox = E/(K x KIC
SA), where E equals the rate of appearance of 14CO2 in the expired air
(dpm/min), and K represents a correction factor (0.81) that corrects for
the incomplete recovery of labeled 14C carbon dioxide from the bicar
bonate pool (21).
An estimate of the rate of leucine incorporation into protein (Rd) was
calculated as: Rd = Q - Ox. The rate of leucine release into plasma
space from protein degradation (Ra) was calculated as: R, = Q - I. The
net balance of leucine into or out of protein was calculated as the
difference between the Ra and the /?„.
Statistics. All data are presented as mean ±SEM. Statistical anal
ysis was performed by using an analysis of variance or a Student's / test
where appropriate. Statistical significance was defined as P < 0.05.
RESULTS
Demographics and Nutritional Indices. Cancer patients in
both groups had a greater prevalence of males than females
compared to control subjects. Those with weight loss <10% of
premorbid weight were slightly but significantly older than con
trols, and tended to have localized disease. This group was
comprised of lung and gastrointestinal diagnosis, whereas the
group with weight loss greater than 10% of premorbid weight
was solely comprised of gastrointestinal tumors (Table 1).
Neither group of cancer patients had statistically significant
differences in any of the nutritional indices measured including
serum albumin, creatinine/height ratio, or percent of ideal body
weight (Table 2) when compared to controls or each other.
Hormonal Profile and Glucose Disposal. Baseline postabsorptive insulin concentrations in both cancer groups were
within the normal range and were not statistically different
from control (Table 3). All groups were raised to a high phys
iological level during the study period. Neither cancer group
differed significantly from control insulin levels, however
Table 3 Insulin and glucoseconcentrationand glucosedisposal
Significancedefined as P < 0.05.
Insulin
Period
(microunits/ml)
Control"CANWLrfCAWL/BaselineStudy
1*71
±5C
183
4±
BaselineStudyBaselineStudy7±
5C8±
±
164±5C84
Glucose
(mg/dl)
Glucose disposal
(mg/kg/min)
±387
±2
0.63.91
±
90
292±
±0.6'3.66
190±
±393
±0.1'
±35.87
"n = 10.
* Mean ±SE.
c Significanceversusbaseline.
''CANWL is weight loss <10% (n = 8).
" Significance versus control by analysis of variance.
/CAWL is weight loss > 10% (n = 8).
±134
±148
±234
±191
±277
±143
' Mean ±SE.
ü
Significanceversusbaseline.
' CANWL is weight loss<10%(n = 8).
/CAWL is weightloss >10% (n = 8).
CAWL achieved significantly lower levels when compared to
CANWL. Baseline glucagon concentrations were not signifi
cantly different between the controls and either cancer group,
and there was no significant change during the study period in
any of the groups (data not shown).
Baseline postabsorptive glucose concentrations in CANWL
and CAWL were also within the normal range, and were not
significantly different from control levels. Euglycemia was
maintained during the study period in each group with a coef
ficient of variation of the glucose clamps of 8 ±1% in each
group.
During the study period, both groups of cancer patients had
significantly decreased whole body glucose disposal when com
pared to controls, and there was no difference between
CANWL and CAWL.
Arterial Amino Acid Concentrations, i.-[l-'4C]Leucine Infu
sion, and KIC Specific Activities. The baseline leucine levels in
both groups of cancer patients were not significantly different
from control levels, and euleucinemia with near basal amino
acid levels was maintained during the study period in all groups
(Table 4). Total arterial amino acids were not different during
the baseline period in either of the cancer groups from the
control group, and each groups' total arterial amino acids in
creased by approximately 30% during the study period, mostly
due to the large concentration of glycine and alanine in the
amino acid solution (Table 4). Isotopie steady state was
achieved for KIC during both the baseline and study period in
all groups as depicted in Fig. 2. The average L-[l-l4C]leucine
infusion during the experiment was 13.3 ±0.2, 13.7 ±0.2, and
13.8 ±0.2 dpmVml in controls, CANWL, and CAWL, respec
tively (P = NS).
Baseline Leucine K.,, Oxidation and K,,. and Response to
Euglycemic, Euleucinemic, Systemic Hyperinsulinemia. Base
line leucine Ra was 2.18 ±0.06, 2.29 ±0.17, and 2.41 ±0.14
lumol/kg/min in C, CANWL, and CAWL, respectively, which
were not significantly different from each other and in response
to systemic hyperinsulinemia each significantly decreased (P <
0.05 analysis of variance) to 1.87 ±0.10, 1.88 ±0.15, and 2.05
±0.13 /imol/kg/min, respectively (Fig. 3a). Baseline oxidation
of leucine was 0.34 ±0.03, 0.31 ±0.03, and 0.31 ±0.04
/¿mol/kg/min in C, CANWL, and CAWL respectively, which
were also not different from each other and in response to
systemic hyperinsulinemia significantly increased (P < 0.05) to
0.51 ±0.04, 0.54 ±0.03, and 0.51 ±0.05 /xmol/kg/min, re
spectively (Fig. 3A). Baseline leucine Rd was 1.84 ±0.06, 1.98
±0.16, and 2.11 ±0.15 ¿unol/kg/min in C, CANWL, and
CAWL, respectively, and in response to systemic hyperin
sulinemia did not significantly change 1.95 ±0.08, 1.93 ±0.14,
and 2.13 ±0.15 ^mol/kg/min, respectively (Fig. 3c). The whole
3847
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CANCER. INSULIN. AND PROTEIN
KIC SA (dpm/uMol)
4500
Control
4000
•¿"•
CA.NWL
O CAWL
3500
3000
2500
2000
1500
1000
500
-45
-30
-15
120
135
150
166
TIME (min)
Fig. 2. Arterial KIC specific activities. Control group, n = 10; CANWL. n = 8;
CAWL, n = 8. SA, specific activity.
METABOLISM
increased rate of whole body protein turnover, increased liver
protein synthesis, and decreased muscle protein synthesis (37).
Exogenous insulin in the same model has also been shown to
decrease carcass weight loss in cachectic animals (38).
In patients with cancer, the existence of abnormal rates of
whole body protein synthesis and degradation are not as well
established. Most have reported these rates to be elevated com
pared to postabsorptive normal humans (39), starved normal
humans (8), and malnourished benign disease patients (8).
However, others have reported no difference compared to postabsorptive humans (40).
The rates of catabolism and synthesis in the present study
were approximately 10% elevated in the weight-losing group
compared to controls. Prior work has shown that a normal
adaptation to a chronically starved state would be to decrease
protein turnover and conserve nitrogen (8, 41), therefore no
decrease in the rate of catabolism and synthesis in the face of
weight loss probably represents a maladaptation in itself. Our
body net balance of leucine reversed from a net negative value to
positive during euglycemic, euleucinemic, hyperinsulinemia
primarily by the Ra decreasing below the Rd in both cancer
groups, as was also seen in controls (Fig. 4).
a.
Leucine Ra (uMol/kg/mm)
-B-
Control
-A-
CANWL
-O-
CMKL
DISCUSSION
It is widely accepted that cancer patients have abnormalities
of intermediary metabolism. This study has documented that
preoperative cancer patients who display insulin resistance with
respect to glucose metabolism are not resistant to the anticatabolic effect of insulin with respect to whole body protein me
tabolism.
In normal humans, insulin causes a decrease in hepatic en
dogenous glucose production and a stimulation of glucose up
take and storage (32). Resistance to insulin, with respect to both
hepatic and peripheral glucose metabolism, can be seen in pa
tients with adult onset diabetes mellitus (33), and this results in
hepatic overproduction in the fasting state and decreased up
take of glucose in the fed state. Exogenous insulin administra
tion has been shown to reverse these alterations and restore
glucose processing in insulin-dependent and non-insulin-depen
dent diabetes (34). Although there are reports of glucose intol
erance (5) and variable insulin sensitivity in cancer patients,
there are little data on the nature and mechanism of this tissue
insensitivity to insulin. Prior work from our laboratory in
weight-losing cancer patients have documented that the endog
enous glucose production is reduced to zero at the levels of
serum insulin achieved in this study (25), therefore the rate of
glucose infusion is probably a good measure of whole body
glucose disposal in these controls and cancer patients. A state of
insulin resistance with respect to glucose metabolism was dem
onstrated by the decreased rate of glucose infusion in both
cancer groups under similar plasma insulin concentrations.
Clinically, the abnormalities of protein metabolism in cancer
patients include decreased plasma proteins, and visceral organ
and skeletal muscle atrophy (35). In the tumor-bearing rat,
chronic protein malnutrition causes accelerated loss of carcass
weight without effect on the growth of the tumor (36), whereas
the normal non-tumor-bearing animal put under similar condi
tions of malnutrition would adapt and conserve nitrogen. This
suggests that the tumor will continue to grow at the expense of
the host, and is not under the same nutritional constraints as
the host. Further investigations using this model with the ad
dition of protein kinetic measurements found that there was an
Leucin«Oxidation (uMol/kg/mm)
c.
L«ucineRd (uMol/kg/mln)
-B-
Control
-A-
Baseline
CANWL
"€»CWVL
Hyperinsulinemia
Fig. 3. Baseline rates and the response to euglycemic, euleucinemic hyperin
sulinemia. o. leucine Aa. b, leucine rate of oxidation (Ox), c, leucine Ra. Control
group, n = 10. CANWL, n = 8; CAWL, n = 8. Significance defined as
P < 0.05 'versus baseline by analysis of variance.
3848
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CANCER, INSULIN. AND PROTEIN
Leucine Net Balance (uMol/kg/min)
0.5
Baseline
Hyperinsulinemia
Fig. 4. Net balance ofleucine. Control group, n = 10. CANWL. n = 8; CAWL.
n = 8. Significance defined as P < 0.05 'versus baseline by analysis of variance.
laboratory has previously demonstrated increased rates of syn
thesis and degradation in cachectic cancer patients (8) as well as
work by others (9). Most of the patients in the present study
who had significant weight loss were not cachectic subjectively
or by the nutritional indices measured (Table 2), and this may
explain the lack of difference observed between controls and
cancer patients in the baseline state.
Insulin is a potent regulator of protein turnover. In vitro,
insulin decreases protein breakdown and increases muscle pro
tein synthesis (42). In normal humans, the in vivo study of
insulin is more complicated. Systemic euglycemic insulin infu
sion invariably induces a dose-dependent reduction in plasma
amino acid levels, with the branched chain amino acids being
the most significantly affected (43). This decrease in plasma
amino acid concentrations may cause intracellular depletion of
substrate for protein synthesis, and therefore the full effect of
insulin cannot be determined under these conditions. Prior
studies using leucine kinetics (18, 24) maintained euleucinemia,
near basal amino acid levels, and normal glucose concentrations
and demonstrated that high physiological insulin markedly de
creased whole body protein degradation without significantly
affecting synthesis in normal humans, thus confirming that
euleucinemia and near basal amino acids allow insulin to act
fully as an anticatabolite without affecting ongoing protein syn
thesis. The present study has documented that cancer patients
who were resistant to the effect of insulin with respect to whole
body glucose disposal were not resistant to the anticatabolic
effect of insulin with respect to whole body protein metabolism.
Even the cancer patients who had marked premorbid weight
loss were able to significantly reverse the catabolic negative net
protein balance to a positive balance under high physiological
insulin levels with euglycemia, euleucinemia, and near basal
amino acid levels. Maintenance of sufficient amino acids and
glucose is important in order to see the rate of protein degra
dation decrease below the level of synthesis, thus creating a
positive protein balance in controls and cancer patients.
Based on this work, it is unlikely that the loss of protein
stores in the preoperative cancer patient is due to insulin resis
tance with respect to protein metabolism. Also, the preopera
tive patient being supplemented with TPN should respond to
endogenous insulin with respect to protein metabolism, al
though preoperative TPN in the cancer patient has shown min
imal benefit in prior trials (4). One possibility is that the levels
of endogenous insulin that are achieved with standard TPN in
METABOLISM
cancer patients are approximately one-half the value that was
achieved in the present study.4 Since the abnormalities in in
termediary metabolism are still present with the addition of
standard nutritional support, hormonal manipulation using an
abolic agents such as insulin may play a role in the management
of these patients. Finally, this work sets up the opportunity to
study hyperinsulinemia as an anabolic adjunct in clinical trials
with the most catabolic cancer patients: those who would re
quire TPN because they were unable to take in adequate nutri
ents in the postoperative period. The use of TPN would be able
to maintain adequate levels of amino acids and the glucose
present would be able to prevent any insulin-associated hypoglycemia. Perhaps the use of insulin as an anticatabolic agent
in TPN would be able to reverse the degradation of body protein
stores and allow ongoing synthesis to replete the body.
In summary, we have documented that cancer patients who
were resistant to insulin with respect to glucose metabolism
were not resistant to the anticatabolic effects of insulin on
whole body protein turnover. This work defines a possible av
enue of treatment that needs study in controlled trials to deter
mine possible benefit for the pre- and/or postoperative catabolic
cancer patient.
ACKNOWLEDGMENTS
The authors wish to acknowledge the expert technical support of
Bruce Ng and Charles Ahrens and the direction of Nada Vydelingum,
Ph.D. We would also like to thank Warren Heston, Ph.D.; Michael
Burt, M.D., Ph.D.; and the members of the Surgical Metabolism Lab
oratory, from this country and abroad, whose advice and help made this
study possible.
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Effect of Systemic Hyperinsulinemia in Cancer Patients
Martin J. Heslin, Elliot Newman, Ronald F. Wolf, et al.
Cancer Res 1992;52:3845-3850.
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