3 2 ~
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(3-7f 0-5 pU/ml before starvation, 3.7 f 0-5 pU/ml
after 72 h starvation) and gastrin (43k7 pg/ml before
starvation, 39&6 pg/ml after 72 h starvation) did not
change. As previously reported (Henry et al., 1975,
Lancet, ii, 202) plasma secretin levels rose markedly
during the starvation (51 k 7 pg/ml before starvation,
175k51 pg/ml after 72 h starvation; P<O.Ol).
Glucagon like immunoreactivity (GLI) was assayed
using two antibodies. GLI measured with an antiserum reacting with C-terminal fragments (CGLI) rose
from 60210 pg/ml before starvation to 107+19 pg/ml
after 72 h (PeO.01). GLI measured with an antiserum
reacting with N-terminal fragments (N-GLI) did not
Change.
Plasma triglyceride levels did not change after 24 h fast
but at 72 h were higher than the pre-fast levels (649k
6-7 mg/dl before starvation, 100.1 f 6-6 mg/dl after 72 h
starvation; P<0.05). Plasma free fatty acids (FFA)
(951 f 137 pmol/l before starvation, 2598 2 198 pEq/l
after 72 h starvation; P<0.0005) and glycerol (1.4k0.1
mg/dl before starvation, 3.250.3 mg/dl after 72 h
starvation; P < 0005) levels rose steadily during the fast,
while cholesterol levels did not change. Lipids and
hormones which had risen during the fast returned to
normal after 24 h refding.
Glycerol and FFA levels correlated with each other
after 24 and 48 h fasting. After 24 h fasting, significant
correlations were found between both FFA and glycerol
levels, and secretin, G G L I and N-GLI. Partial correlation
coefficients showed a correlation between FFA and
secretin independent of the effects of GLI, but no
correlation between FFA and GLI independent of
secretin.
It is suggested that in acute starvation the rise in
triglycerides results from increased availability of free
fatty acids. Both glucagon and secretin promote lipolysis
in adipose tissue while insulin has anti-lipolytic properties.
The present study suggests that in acute starvation the
elevated secretin and glucagon levels have a role in
enhancing lipolysis and hence providing substrates for
triglyceride synthesis.
During the bypass there was a rise in blood glucose
(P=O-OOl) which was not accounted for by transfusion.
This was associated with a fall in insulin (P=002)and a
rise in growth hormone levels (P=0-05).
These changes
were reversed promptly on cessation of perfusion but
before chest closure. Overnight the glucose level fell
slowly but remained above fasting level and the insulin
and growth hormone levels were also both raised. During
this time isoprenaline 1 pglmin was infused in four patients in whom plasma insulin rose without appreciable
change in plasma glucose. Intravenous glucose tolerance
was impaired postoperatively and this was associated with
an increased insulin response, a markedly increased
growth hormone response and an increased fasting plasma
cortisol level. Somewhat surprisingly the glucose distribution space was diminished postoperatively in
contrast to the expected increase in extracellular fluid
space.
These results show that patients do not become hypoglycaemic during open heart surgery in the absence of
large amounts of added g l u c o e u t that there is impairment of glucose tolerance dcpite the presence of increased
insulin, growth hormone and cortisol levels.
86. INSULIN BINDING TO HUMAN ADIPOCYTES
J. R. W. KEATES,P. H. SBNKSENand M. V.
BRAIMBRIDGB
K. STANTON
and H.KEEN
Department of Medicine, Guy’s Hospital, London
Variation in insulin binding to target organs has been
proposed as a possible mechanism of insulin resistance.
Indeed this has been substantiated in animal models
(e.g. the obese hyperglycaemic mouse); however, its
significance in man is unknown. Does insulin binding
change with alteration in glucose tolerance? If so is it the
cause or result of the change in end-organ resistance.
In an attempt to answer these questions the binding of
mono-iodinated 1a51-insulin to human fat cells was
examined before and after changes in glucose tolerance.
Fat cells were obtained by subcutaneous biopsy from the
anterior abdominal wall of obese human volunteers before
and after starvation, 3 months of hypocaloric diet and 2
days of dexamethasome therapy. Simultaneously 2# h
oral GTT were performed with serial glucose and insulin
estimations. Insulin binding to adipocytes was not related
to serum insulin levels and it did not appear to be r e
sponsible for the observed changes in glucose tolerance.
Departments of Cardiothoracic Surgery and Medicine,
87. EFFECTS OF AGE AND FASTING ON GLUCO-
85. DISTURBANCES OF GLUCOSE HOMEOSTASIS
DURING OPEN HEART OPERATIONS
London
Previous investigations into glucose metabolism in man
during open heart surgery have been complicated by the
use of large quantities of glucose in the ‘pump-prime’.
We have been able to study these procedures in patients
having no glucose in the prime. Mild hypothermic bypass
was used (32OC)in thirteen patients who gave informed
consent to these studies.
Intravenous glucose tolerance tests (IVGTT) were
performed on the morning of operation, 2 h following
return to the ward and on the following day. Insulin
growth hormone and plasma cortisol were also estimated
at these times and at intervals during the operation and
postoperative periods.
NEOGENESIS FROM GLYCEROL IN DOGS
S. E. M. HALL,
M. BERMAN,M. VRANIC and G.
HETENYI,
JR
Departments of Physiology, University of Ottawa,
University of Toronto, CaMda, and National Cancer
Institute, Bethesada, Maryland, U.S.A.
The extent of gluconeogenesis from glycerol was examined in pups and adult dogs both in the postabsorptive state
and during fasting. After a simultaneous injection of
[2-3H]glucose and [U-14C]glycerol,the tracer response
data were analysed with the aid of the SAAM-26 computer modelling program. A four compartmental model
was formulated to calculate the kinetics of the glycerol :
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glucose system. In the postabsorptive state glycerol
concentration and gluconeogenesis declined with age;
13.8% of glucoseC= originated from glycerol in W d a y old pups. 6% in older pups and adults. Approximately
50% of glycerol-C was converted to glucose independent
of age. Glucagon concentration in the youngest pups was
3 times that m e a s u r e d in the adults and it also declined
with age.
During fasting adult dogs maintained normoglycaemia,
the rate of glycerol-(: production increased and the
percentage of a glucose<: derived from glycerol rose to
13*3%.Pups5-19 days old becameslightly hypoglycaemic
after a 2 day fast. They maintained similar glycerol turnover rates and 10.3% of glucose4 arose from glycerol.
After only a 1 day fast, pups less than 4 days old became
hypoglycaemic. Glycerol concentration and turnover rate
decreased and the percentage of glucose-<=derived from
glycerol fell to 3.4%. Plasma glucagon concentration
was maintained in fasting adults whereas in the youngest
pups glucagon concentration declined despite hypoglycaemia. Thus on fasting neonates reduced lipolysis,
and gluconeogenesis from glycerol and did not maintain
glucose homeostasis.
88. PHENFORMIN-INDUCED LACTIC ACIDOSIS:
PREVENTION BY DICHLOROACETATE
P. A. H. HOLLOWAY
and K. G. M. M. ALBERTI
Faculty of Medicine, Chemical Pathology and Human
Metabolism, General Hospital, Southampton
Lactic acidosis remains an acknowledged risk of phenformin therapy, To date no specific treatment has been
discovered. Recently dichloroacetate (DCA) has been
shown to decreaseblood lactate and pyruvate concentrationsthroughthe activation of pyruvatedehydrogenase in
many tissues (Whitehouse, Cooper & Randle, Biochemical Journal, 1974,141,761). The present study was
designed to show whether DCA could prevent phenformin-induced lactic acidosis in rats.
After insertion of indwelling femoral cannulae rats
were fasted overnight then treated with the microsomal
hydroxylase inhibitor, SKF525A. This was necessary
to prevent the rapid hepatic degradation of phenformin.
Three hours later phenformin was infused for 2 i h
(50 mg kg-I h-l) with or without DCA (300 mg kg-'
h-l). In animals given phenformin alone blood lactate
rose to 144t1.7 and blood pyruvate to 0.31+0.04
mmol/l. Glucose concentration fell to 2.0+0.3 mmol/l.
In contrast when DCA was present as well as phenformin blood lactate concentrations rose to only 2.2 0.8
mmol/l while blood pyruvate decreased to 0*04+0.01
mmol/l and the hypoglycaemic effect of phenformin was
e n h a n d with blood glucose. concentrations falling to
1-8kO5 mmol/l. Thus DCA was able to prevent the
development of lactic acidosis.
Other experiments in hepakctomized rats have shown
that in the starved rat phenfordn acts primarily on the
33P
liver while we have also shown that DCA acts mainly in
extrahepatic tissues, decreasing the release of lactate,
pyruvate and alanine into the circulation (Blackshear,
Holloway & Alberti, 1974, BiochemicalJournal,142,279).
It thus appears that DCA prevents lactic acidosis by
decreasing gluconmgenic substrate flow to the liver
rather than by directlycounteractingthe hepatic action of
phenformin. Nonethelea the success of this therapy in
the experimental animal suggests that further trials in
man and animals are indicated.
89. CHANGESIN THE CEREBRALCIRCULATORY
AND METABOLIC RESPONSES TO HYPOXIA
DURING LIVER FAILURE IN GOATS
N. N. STANLEY
and N. S. CHERMACK
Cardiovascular-Pulmonary Division, Department of
Medicine, University of Pennsylvania School of Medicine,
Philadelghia, U.S.A.
Severe arterial hypoxaemia due to pulmonary arteriovenous shunts or interstitial oedema m a y complicate
liver disease. Cerebral blood flow (CBF) and cerebral
metabolic rate for oxygen (CMROS) are often reduced.
Normally hypoxia stimulates CBF to maintain cerebral
oxygen delivery and, unless very severe, does not alter
CMRo,. The present study describes the effect of liver
failure in four unanaesthetized goats on the CBF response and stability of CMRoa in isocapnic hypoxia
produced by inhaling various CO,-emiched hypoxic gas
mixtures.
Each goat was equipped with a chronically implanted
flow probe around an internal maxillary artery, and
catheters in the aorta and sagittal sinus for easy measurement of CBF and CMRO,. Baseline studies showed a
linear relationship in plots of CBF against arterial 0 2
saturation (Sa.0,) and the slope of the CBF/&,Oa
response line was used to quantify each goat's CBF
response to hypoxia. CMRO, was not depressed by hypoxia until the 0 2 tensions in artaid and cerebrai venous
blood (Pa,o, and Pcv,~,) fell velow critical threshold
values of 3.2 and 2.2 kPa respectively. During carbon
tetrachloride induced liver failure (serum bilirubin
> 6 mg/lOO ml) CBF fell by 30% from 68.0 (t2.6) to
47.8 (+2-8) ml 100 g-' min-I, CMROa by 22% from
3-46 (k0.10) to 2.69 (f014) ml 100 g-I min-I and the
CBF response to hypoxia by 61% from 0.81 (t0.08)
to 0.31 (t0.04)ml 100 g-I min-I %Sa,oa-'. There
was also a disproportionate reduction of cerebral
oxygen delivery in hypoxia, and CMROz was further
reduced at Pa,oa and PCV,Oa values much higher than the
critical thresholds for hypoxic CMROa depressions in
health.
The findings suggest a detrimental effect of moderate
hypoxia on cerebral function in liver disease. This may
be of practical importance in the management of patients
with arterial hypoxaemia or other complications (e.g.
anaemia or shock)which impair cerebral oxygen delivery.