Review Article
www.ljm.org.ly
The Role of Nitric Oxide Synthase in
Post-Operative Hyperglycaemia
Qader SS
Department of Surgery, Hawler Medical University, Erbil, Iraq
and Department of Clinical Science, , Lund University, Malmö, Sweden
Abstract: Post-operative hyperglycaemia is important with regard to outcomes of surgical operations. It affects postoperative morbidity, length of hospital stay, and mortality. Poor peri-operative blood glucose control leads to a higher risk of
post-operative complication. Insulin resistance as a cause of post-operative hyperglycaemia has been blamed for some time.
Nitric Oxide (NO) is produced by nitric oxide synthase (NOS) isoenzymes. Inducible nitric oxide synthase (iNOS) is not a
normal cellular constitute. It is expressed by cytokines and non-cytokines e.g. fasting, trauma, intravenous glucose, and lipid
infusion, which are encountered in surgical operations. Review of current published data on postoperative hyperglycaemia
was completed. Our studies and others were explored for the possible role of NO in this scenario. Induction and expression of
iNOS enzyme in pancreatic islet cells is included in the chaotic postoperative blood glucose control. The high concentrations of
iNOS derived NO are toxic to pancreatic -cells and may inhibit insulin secretion postoperatively. Hence, current peri-operative
management is questionable regarding post-operative hyperglycaemia and necessitates development of a new strategy.
Key words: NO, glucotoxicity, lipotoxicity, post-operative hyperglycaemia, pancreatic islets.
Post-operative hyperglycaemia: A real problem
Post-traumatic
hyperglycaemia
is
commonly
encountered after surgery and in patients treated in
intensive care units (ICU). It carries a higher risk for postoperative complications, prolonged recovery periods, and
increased length of stay (LOS) [1,2].
Poor post-operative blood glucose control in diabetic [1]
and non-diabetic patients [2] leads to a higher risk of
complications. Many studies (3, 4) blame insulin resistance
as a cause for post-operative hyperglycaemia. Cytokines
[5,6], fasting [7,8], peri-operative feeding [9,10] and
immobilization were reported to lead to insulin resistance.
Different regimens postulated to overcome the outcome of
elective operations [11,12]. Emergency traumatic surgery
in conditions e.g. high velocity missile injury and traffic
accidents carry an additional risk for post-operative
hyperglycaemia because of double trauma.
To decrease post-operative morbidity and mortality, it is
essential to explore the molecular mechanism of postoperative hyperglycaemia and its relation to trauma.
Pancreatic function during trauma has not been
thoroughly studied. It is very important to comprehend
post-operative hyperglycaemia and evaluate peri-operative
management to improve surgical outcomes.
Review of currently published data on post-operative
hyperglycaemia was conducted and the role of nitric oxide
in this scenario was investigated.
Nitric oxide and nitric oxide synthase system
Nitric oxide (NO) was described in 1989. NO is the
smallest synthetic molecule. It is produced by a family of
enzymes known as nitric oxide synthase (NOS) in almost
all mammalian cells e.g. vascular endothelium, neurons of
the central and enteric nervous system, and cells of the
immune system [13,14]. NO is a free radical and an
extremely reactive gas [15]. It has a short half life of
about 10 seconds. It acts as a signalling molecule,
neurotransmitter, and macrophage mediated immunity
that can heal or kill. Under conditions of high NO
Page 144
production, a number of enzymes can be inhibited by NOenzyme interaction [16-18].
According to their expression, activity, and dependence
on calcium, NOS isoenzymes are divided into 2 major
functional classes:
• Constitutive nitric oxide synthase (cNOS); ncNOS,
ecNOS
• Inducible nitric oxide synthase (iNOS).
Nitric oxide and insulin secretion
cNOS and iNOS can be expressed and/or induced by
different stimuli in various tissue including pancreatic cell [17,19-24]. ncNOS derived NO is recognized as an
important signalling molecule in a variety of cellular
processes e.g. insulin secretion [19,21,22,24].
Our laboratory [23,27,29-30] and others [25,31-33]
presented biochemical and immuno-cytochemical evidence
for occurrence of ncNOS in mouse and rat pancreatic cells. When cNOS is activated, it produces a pulsatile low
amount of NO for a short period of time [29,31,34].
Although the effect of ncNOS derived NO on insulin
secretion is highly controversial, the results from rat and
mouse pancreatic islets suggests that it acts as a negative
modulator for glucose-stimulated insulin secretion (GSIS)
[27,29].
iNOS is not a normal cellular constituent and can only
be expressed in
pathophysiological conditions in a
response to inflammatory cytokines e.g. IL-1, TNF-, and
lipopolysaccharide. Under such conditions, pancreatic cells produce huge amounts of NO in a more sustained
manner [27,34-36] through induction of iNOS, comparing
to the cNOS isoforms [15,37-38]. Non-cytokine induction
of iNOS in pancreatic islets has also been reported. One
hour in vitro incubation of healthy rat and mouse islets
with high glucose concentrations [10-20 mmol/L) induced
iNOS and ncNOS [27,30,34]. However, the activation of
ncNOS was rapid, within minutes. It is at least in part,
associated with the glucose-stimulated influx of
extracellular Ca2+ into -cells [27,33]. Glucose activation
Libyan J Med, AOP: 080416
Review Article
of iNOS was slower and detectable after approximately 60
minutes [27]. The mechanism behind glucose-stimulated
iNOS expression and activity is poorly understood. It has
been suggested that glucose metabolism generates
NADPH through the pentose shunt, which is an important
stimulus in IL-1 induction of iNOS [39,40]. NADPH is an
obligatory substrate for iNOS synthesis of NO [20-21].
This is of great interest since high amounts of iNOS
derived NO is detrimental to -cells [38-39]. Moreover, we
showed that 24 hour intravenous (IV) glucose
administration induced marked expression and activity of
islets iNOS [41].
www.ljm.org.ly
by IV glucose administration, or hyperlipidemia by IV
intralipid infusion, caused marked induction and
expression of iNOS in rat -cells [41]. This is consistent
with previous reports, that plasma insulin response was
much greater following glucose ingestion than IV glucose
administration despite an equivalent increase in plasma
glucose concentration. This is explained by the release of
incretin hormones from endocrine cells in the
gastrointestinal tract e.g. glucagon-like peptide-1 (GLP-1)
[52-53]. The expression of iNOS after IV infusion of
glucose could be explained by suppression of release of
GLP-1 and glucose-dependent insulinotropic polypeptide
(GIP) whose secretion is dependant upon ingestion of
carbohydrates (for GLP-1) or FFA (for GIP).
The relative importance of glucotoxicity versus
lipotoxicity in inducing -cell dysfunction and apoptosis
remains controversial. Although it has been reported that
lipotoxicity alone will not affect -cell function without
signs of glucotoxicity [54], we showed that glucose or
intralipid infusion for 24h induced marked expression and
activity of iNOS [41]. This is in line with results of cultured
cell lines exposed to high glucose or FFA for 24-48 hours
[55-56]. In this context, it is conceivable that iNOS derived
NO might be a contributing factor in this process [55].
Figure1 Simple scheme illustrating the possible mechanisms for
the toxic effects of NOS-derived NO on -cell function
The inhibitory effect of increased NO production on
insulin secretion, due to either enhanced activity of cNOS
(physiological) or induction of iNOS (inflammatory
condition) [29,38,42]. NO is widely accepted as a mediator
of -cell dysfunction and apoptosis [29,30,34,43-45]. A
clear role of iNOS in the pathogenethesis of type 1
diabetes mellitus has been reported [38-39].
Furthermore, IV infusion of nutrients is commonly
prescribed as an important treatment model both pre- and
post-operatively [6,57], in burn patients, and in some
patients as a life long treatment when they can not take
oral food. If IV nutrients induce NO-production in human
-cells, this may explains post-operative hyperglycaemia
to some degree.
Initial inhibition of insulin release is exerted by ncNOSderived NO, when the islets are exposed to high glucose
concentration [26-27].
Lipotoxicity
Long term Total Parenteral Nutrition (TPN) in rats for 10
days resulted in increased iNOS and decreased ncNOS
activity in pancreatic islets [30,34]. Infusion of lipids for 24
hours induced suppression of insulin secretion [41]. This is
in agreement with previous studies [30,34,58]. Although
the induction of iNOS could not account entirely for
alteration in -cell survival, it might negatively modulate
the secretory function of -cells. In addition, long term
exposure of -cells to FFA resulted in a marked production
of reactive oxygen species e.g. superoxide anion (O-2)
[59]. Combination of NO and O-2 resulted in the formation
of peroxynitrite, which is a powerful oxidant and cytotoxic
molecule. The increase in NO, O-2 and peroxinitrite
concentrations
were
positively
correlated
with
mitochondrial and DNA damage in -cells [44]. It has been
reported that an increased plasma FFA obtained by IV
infusion of lipids resulted in decreased plasma levels of
glucagon in humans [60]. The suppression of insulin
secretion during TPN could partly be due to the absence of
incretin hormone which may be normalized by injection of
GLP-1 [61].
Glucotoxicity
Chronic hyperglycaemia is detrimental to pancreatic cells. It could be implicated in the pathogenesis of type 2
diabetes mellitus (DM) in a process called glucotoxicity
[50-51].
We showed that the route of nutrient administration is
important in pancreatic function by both biochemical and
immuno-cytochemical evidences. Hyperglycaemia induced
Fasting and pancreatic function
Cyclic AMP is a potent inhibitor of islet’s NOS activity
[24,26,30,34]. It is markedly suppressed in islets isolated
from fasting mice and rats. Besides, GSIS was markedly
impaired in islets isolated from fasting mice, and
associated with a decreased production of CO and HO-2
expression. Hence two potent inhibitors of islet NO
production; CO and cyclic AMP, were markedly suppressed
In addition, the extremely low level of NO metabolizing
enzymes, e.g. catalase and glutathione peroxidase, makes
pancreatic -cells extremely susceptible to high levels of
intracellular NO (46). High concentration of NO may
interact with vital sites in the -cell such as Kreb’s cycle
enzyme aconitase [47], ion channels [48], or other
enzymes of importance for -cell function [30,34,43,48]
(Figure 1). Indeed, several studies demonstrated that
inhibition of NOS isoenzymes activity by specific inhibitors
was accompanied by enhanced GSIS, both in vitro and in
vivo [27,29,30,34].
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Libyan J Med, AOP: 080416
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in islets isolated from fasting mice and rats. This may
explain the increased iNOS activity in -cells and
suppression of insulin secretion in these animals.
Taken together, decreased CO production and increased
iNOS-derived NO production is associated with a diabetic
condition in islets -cells [62].
Preoperative fasting or IV glucose infusion for 24 hours
induced strong expression and activity of iNOS in rat
pancreatic islets post-operatively (data not published),
which was stronger than those seen in rats that received
preoperative oral glucose or were freely fed. This is of
significant clinical importance if the same thing happens in
human pancreatic islets. Since, preoperative fasting and/or
post-operative IV glucose infusions are applied in surgical
patients, especially in abdominal operations. Hence both
fasting and IV glucose administration play a role, at least
partly, in suppression of insulin secretion and induction of
post-operative hyperglycaemia. Although post-operative
insulin resistance is still blamed, fasting and IV glucose
may act as contributors to insulin suppression by inducing
post-operative hyperglycaemia, which needs further study
in humans.
Trauma and ǃ-cell function
Trauma-induced iNOS expression and activity has been
noted in rat pancreatic islets [63]. During trauma, the
body responds with a series of reactions e.g. a change in
metabolism, to a catabolic state, and an expression of
insulin resistance [64]. The consequence of post-operative
insulin resistance is that patients in the post-operative
period are in a metabolic state similar to T2DM [13].
Insulin resistance persists for about 2-3 weeks after
uncomplicated elective upper abdominal surgery [65]. It
negatively
affects
the
post-operative
recovery,
convalescent period, and LOS.
Surprisingly, in spite of insulin resistance and its role in
post-operative hyperglycaemia, iNOS isoenzyme may be
involved very early in the impairment of the insulin
secretion. Hence, -cells seem to be unable to respond
adequately to a glucose challenge. It seems reasonable to
assume that an improvement in the insulin secretory
capacity of the pancreas may positively affect the postoperative glycemic state and ultimately the outcome of
surgery.
The present findings may stir more debate in the
explanation of post-operative hyperglycaemia.
Conclusions
1. Trauma, fasting, hyperglycaemia, hyperlipidemia and
route of nutrient administration possibly are other factors
contribute to post-operative hyperglycaemia.
2. It is recommended to investigate the molecular
mechanism behind the pathophysiology of post-traumatic
hyperglycaemia in human beings. The role of nitric oxide
in this scenario should be appreciated.
3. New strategy should be developed regarding perioperative management and postoperative hyperglycaemia.
4. A possible pharmacological target is to suppress iNOS
activity in pancreatic islets with agents stimulating cyclic
AMP/PKA pathway e.g. PACAP. This may be a hope to
restore adequate insulin secretion post-operatively.
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