The Journal for Endocrinology and Metabolism.

Photon 105 (2015) 177-212

https://sites.google.com/site/photonfoundationorganization/home/the-journal-for-endocrinology-and-metabolism
Original Research Article. ISJN: 5743-8481: Impact Index: 5.13

The Journal for Endocrinology and Metabolism

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Pain, hyperglycemia, cytokines and insulin resistance in scorpion (Buthidae

family) envenoming syndrome -Insulin-Glucose administration reverses all
clinical manifestations
Dr. Radha Krishna Murthy K.a*, Mr. Z. Naveen Kumarb, Dr. Lavanya M.b, Dr. Ravuri Prabhakar
Raoc, Dr. K. Saraswathid, Dr. Vivek Shridhar Natue
a

Department of Physiology, Santhiram Medical College and General Hospital, Nandyal, AP, India
Department of Physiology, Santhiram Medical College and General Hospital, Nandyal, AP, India
c
Department of Medicine, Santhiram Medical College and General Hospital, Nandyal, AP, India
d
Department of Microbiology, Santhiram Medical College and General Hospital, Nandyal, AP, India
e
Vijayshree Hospital, ghonasare, Chiplun, Ratnagiri, Maharashtra, India
b

Article history:
Received: 16 October, 2015
Accepted: 19 October, 2015
Available online: 04 December, 2015
Keywords:
Glycogenolysis,
hyperglycemia,
counter-regulatory
hormones, suppressed insulin secretion, pro-inflammatory
cytokines, insulin resistance, insulin-glucose infusion, and
glycogenesis
Abbreviations:
ARDS: Acute Respiratory Distress Syndrome, MSOF:
Multi-System-Organ-Failure,
DIC:
Disseminated
Intravascular Coagulation, Na+-K+ATPase activity:
Sodium Potassium stimulated ATPase activity, ROS:
Reactive Oxygen Species,
A-V: Arterio-Venous
anastomoses, COX-2:Cyclo-Oxygenase-2, sP: Substance
P, CCK: Cholecystokinin,
CGRP: Calcitonin geneRelated Peptide, WDR: Wide Dynamic Range, PAG:
Periaqueductal grey, RVM: Rostro Ventro Medial, BK:
Bradykinin,
TRP:
Transient
Receptor
Potential,
ECF=Extra Cellular Fluid Compartment ICF: Intracellular
Fluid Compartment, ADH: Anti Diuretic Hormone , NO:
Nitric Oxide,
FFA: Free Fatty Acids, Indian red
scorpion=Mesobuthus tamulus concanesis, Pocock, Ts:
Tityus serrulatus, PGI2: Prostacyclin, TGF-: Transforming
Growth Factor TGF-, TNF-: Tumor Necrosis Factor-,
IGT: impaired glucose tolerance, MIF=Macrophage
Migration Inhibitory Factor, PAI-1: Plasminogen Activator
Inhibitor-1,
IGF:Insulin-like
Growth
Factor,
MIF:Macrophage Migration Inhibitory Factor, HGP:Hepatic
glucose production
Corresponding Author:
Dr. Radha Krishna Murthy K.*
Professor of Physiology
Email: radhakrishnamurthy48 ( at ) gmail ( dot ) com
Mr. Naveen Kumar Z.
Assistant Professor
Dr. Lavanya M.
Assistant Professor

Saraswathi K.
Professor of Microbiology
Natu V.S.
Director

Abstract
Scorpion sting causes excruciating pain at the site
of
sting,
autonomic
storm,
release
of
catecholamines,
renin,
angiotensin

II,
aldosterone, glucagon, glucocorticoids, either
suppressed insulin secretion or hyper-insulinemia,
hyperglycemia, sudden increase in free fatty acids,
secretion of pro-inflammatory cytokines IL-1, IL-1,
IL- 4, IL- 6, IL- 10, TNF-, IFN-, NO; acute
myocarditis, initial hypertension, cardiovascular
disturbances, peripheral circulatory failure, cardiac
pulmonary edema, ARDS, hyper-aggregation of
+
+
platelets; failure of Na - K ATPase activity,
2
stimulation of Ca + ATPase activity, pulmonary
edema and many other clinical manifestations
causing insulin resistance in scorpion envenoming
syndrome. Scorpion envenoming is a syndrome of
fuel energy deficits, MSOF and death.
Administration of insulin has a primary metabolic
role in preventing, reversing ARDS, MSOF,
metabolic, cardiovascular, haemodynamic, ECG
changes; all the clinical manifestations, suppresses
secretion and actions of pro-inflammatory cytokines
and insulin resistance developed for the
endogenously secreted insulin when that has
become a determinant to survival in scorpion
envenoming syndrome. Treatment: Continuous
infusion of regular crystalline insulin should be given
at the rate of 0.3 U/g glucose and glucose at the
rate of 0.1 g/kg body weight/hour, for 48 - 72 hours,
with supplementation of potassium as needed and
maintenance of fluid, electrolytes and acid-base
balance.

Dr. Prabhakara Rao R.

Professor of Medicine

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177

Citation:
Radha Krishna Murthy K., Naveen Kumar Z., Lavanya M.,
Prabhakara Rao R., Saraswathi K., Natu VS., 2015. Pain,
hyperglycemia, cytokines and insulin Resistance in
scorpion (Buthidae family) envenoming Syndrome - InsulinGlucose administration reverses all clinical manifestations.

The Journal for Endocrinology and Metabolism. Photon

105, 177-212

1. Introduction

Buthotus, Tityus, Leiurus, Androctonus and

Centruroides (Radha Krishna Murthy, 2014 a; b; c;
d; f; 2013; 2002; 2000; 1982; Kankonkar et al.,
1992; Ahmed et al., 2015; Elatrous et al., 2015;
Sahin et al., 2015; Cordeiro et al., 2006; Bouaziz et
al., 2008; Gajanan and Dammas, 1999; Mirakabadi
et al., 2006; Meki et al., 2002; Praveen Kumar and
Vasudeva Murthy, 2013; Freire-Maia and Campos,
1991; 1994; Freire-Maia and De Matos, 1993;
Gueron and Weizman, 1968; Gueron and
Ovsyshcher, 1987; Gueron et al., 1992; 1993;
Ismail, 1993; Ismail, et al., 1992; Cologna et al.,
2009; Ravi Babu and Radha Krishna Murthy, 2014;
Radha Krishna Murthy and Prabhakara Rao, 2014;
Amucheazi and Umeh, 2012; Tarasiuk et al., 1994;
1997; Yugandhar et al., 1999; Sofer, 1995).

Death due to scorpion envenoming syndrome is a

common event all over the world
Scorpion stings are responsible for a number of
deaths in infants, children, and adults in the tropical
and sub-tropical countries all over the world (Radha
Krishna Murthy, 2014 a; b; c; d; e; 2013; 2002;
2000; Ahmed et al., 2015; Elatrous et al., 2015;
Sahin et al., 2015; Bahloul 2005; Cordeiro et al.,
2006; Benvenuti et al., 2002; Bouaziz et al., 2008;
Deshpande and Aparna, 2012; Deshpande 1998;
Deshpande 1993; Deshpande 1993; Deshpande et
al., 2005; Deshpande and Alex, 2000; Gajanan and
Dammas, 1999; Mirakabadi et al., 2006; Meki et al.,
2002; Abdel-Haleem 2005; Praveen Kumar and
Vasudeva Murthy, 2013; Freire-Maia and Campos,
1991; 1994; Aparna et al., 2015; 2013; Amaral
1997; Freire-Maia and De Matos, 1993; Gueron and
Weizman, 1968; Gueron and Ovsyshcher, 1987;
Gueron et al., 1992; 1993; Ismail 1993; Ismail et al.,
1992; Cologna et al., 2009; Ravi Babu and Radha
Krishna Murthy, 2014; Radha Krishna Murthy and
Prabhakara Rao, 2014; Kankonkar et al., 1992;
Amucheazi and Umeh, 2012; Tarasiuk et al., 1994;
1997; Yugandhar et al., 1999; Sofer, 1995). The
annual number of scorpion stings is more than five
hundred thousand and hundreds of thousands of
these victims die every year. For every person killed
by a poisonous snake, 10 persons are killed by
poisonous scorpions. The treatment of scorpion
envenoming syndrome is a difficult problem. Most
of the Textbooks of Medicine (Oxford Textbook of
Medicine 2003; Davidson 2010; Current Medical
Diagnosis & treatment 2012; Boyds Textbook of
Pathology, Robbins & Cotran Pathological basis of
Disease
2010;
Goodman
&
Gilmans
Pharmacological Basis of Therapeutics 2006; and
Physiology (Ganong 1987; Keele, Neil, Joel
Samson Wrights Applied Physiology 2004;
Sabyasachi Sircar 2014) dismiss the problem of
scorpion envenoming syndrome in few words. The
treatment requires extensive knowledge of the
clinical manifestations and an understanding of the
patho-physiological mechanisms behind the clinical
symptomatology.
1.1 Distribution of killer scorpions of
Buthidae family
All the different species and genera of poisonous
scorpions of the world belong to Buthidae family.
The lethal members of the Buthidae family include
the genera of Buthus, Parabuthus, Mesobuthus,

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The following are the different genera of poisonous

scorpions of the world that belong to Buthidae
family.
Buthus- Mediterranean area from Spain to the
Middle East Parabuthus- Western and Southern
Africa, Africa
Buthotus Across Southern Africa to Southeast
Asia Mesobuthus- Throughout Asia
Tityus - Central America, South America, and the
Carribbean Leiurus - Northern Africa and the
Middle East
Androctonus Northern Africa to Southeast Asia
Centruroides - Southern United States, Mexico,
Central America, Carribbean
1.2 Cause of death in scorpion envenoming
syndrome
Scorpion stings result in an excruciating pain,
produce an autonomic storm (Ahmed et al., 2015;
Freire-Maia and Campos, 1991; 1994; Freire-Maia
and De Matos, 1993; Gueron and Weizman, 1968;
Gueron et al., 1992; Natu et al., 2006), severe
ascending pain at the site of sting (Amucheazi, and
Umeh, 2012; Natu et al., 2006), acute myocarditis
(Radha Krishna Murthy, 1982; Radha Krishna
Murthy and Anita, 1986; Radha Krishna Murthy
and Yeolekar, 1986; Radha Krishna Murthy and
Vakil, 1988; Radha Krishna Murthy and
Haghnazari, 1999; Radha Krishna Murthy et al.,
1986 a; b; c;
1988 a; b; 1990; 2003;
Balasubramaniam and Radha Krishna Murthy,
1981; 1984); initial transient hypertension (Radha
Krishna Murthy, 2014 a; b; c; d; e; Radha Krishna
Murthy et al., 1988 a; b); hypotension (Radha

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Krishna Murthy, 2014 a; b; c; d; e; Radha Krishna

Murthy et al., 1988 a; b) , cardiovascular
disturbances (Radha Krishna Murthy, 2014 a; b;, c;
d; e; Radha Krishna Murthy et al., 1988 a; b);
arrhythmias, conduction defects, ischemia &
infarction (Radha Krishna Murthy and Yeolekar,
1986; Radha Krishna Murthy et al., 1988 a; b;
Radha Krishna Murthy, 2014 a; b; c; d; e); acute
pancreatitis (Radha Krishna Murthy et al., 1989;
Radha Krishna Murthy and Prabhakara Rao, 2014);
disseminated intravascular coagulation (DIC)
(Radha Krishna Murthy et al., 1988 a);
hematological changes (Radha Krishna Murthy,
2014 a); acute respiratory distress syndrome (Radha
Krishna Murthy et al., 1992) and many other
clinical manifestations. All these manifestations
could be due to alterations in the hormonal milieu
massive release of catecholamines (Ahmed et al.,
2015; Elatrous et al., 2015; Freire-Maia and
Campos, 1991, Freire-Maia and Campos, 1994;
Gueron and Weizman, 1968; Ismail, 1993);
angiotensin II (Radha Krishna Murthy and Vakil,
1988); renin, aldosterone (Gueron et al., 1992);
glucagon, Cortisol (Radha Krishna Murthy et al.,
2003; Radha Krishna Murthy, 1999; Johnson and
Ensinc, 1976); and either suppressed insulin
secretion (Radha Krishna Murthy and Anita, 1986;
Radha Krishna Murthy et al., 1986 a; b; c; d; 1988
a; b; c) or hyper-insulinemia hyperglycemia
(Radha Krishna Murthy et al., (1986 a; b; c; 1988 a;
b; c; 1989; 1990), osmotic fragility changes of
erythrocytes (Radha Krishna Murthy et al., 1986 e;
f); cytotoxic, apoptotic effects (Omran, 2003);
increased production of pro-inflammatory cytokines
IL-1, IL-1, IL- 4, IL- 6, IL- 10, TNF-, IFN- and
NO; implantation loss, elevated levels of
proinflammatory cytokines generated by the
maternal or fetal immune system associated with
abnormal fetal brain development and increased risk
for neuro developmental disorders in scorpion stung
pregnant women (Ana Dorce et al., 2015); insulin
resistance (Magalhaes et al., 1999; Petricevich,
2010; Ait-Lounis and Laraba-Djeban, 2012) and
death (Fig. 1 9).
1.3 Insulin: New roles for an ancient
hormone
The classical action of insulin is the control of
glucose metabolism through the dual feedback loop
linking plasma insulin with plasma glucose
concentration (Ferrannini et al., 1999).
1.3 (a) Insulin inhibits lipolysis, and platelet
aggregation
Insulin inhibits lipolysis, and platelet aggregation.
In the presence of insulin resistance, hyperaggregation and anti-fibrinolysis create a
prothrombotic milieu. Hyperinsulinemia may be
pro-oxidant, both in vivo and in vitro, and in
scorpion envenoming syndrome.
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1.3 (b) Insulin plays an important role in

thermogenesis
Insulin plays an important role in thermogenesis
and insulin resistance may therefore be implicated
in the defective thermogenesis and severe hyperhydrosis in scorpion envenoming syndrome.
1.3 Insulin lack high blood pressure
Insulin spares sodium and uric acid from excretion,
and in hyperinsulinemia insulin resistance, these
effects may contribute to transient high blood
pressure in scorpion envenoming syndrome.
1.3 (d) Insulin hyperpolarizes the plasma
membranes
Insulin hyperpolarizes the plasma membranes of
both excitable and non-excitable tissues, with
consequences
ranging
from
Baro-receptor
desensitization to Cardiac refractoriness
Prolongation of QT interval, arrhythmias and
various conduction defects in scorpion envenoming
syndrome (Ferrannini et al., 1999).
1.3 (e) Insulin is vaso-dilatory agent
Insulin is a vaso-dilatory agent by regulating the
Sodium Potassium pump (Na + - K+ ATPase
activity) and intra-cellular calcium transients (Ca2+
ATPase activity) (Radha Krishna Murthy, 1982).
1.3 (f) Insulin exerts a host of central effects
(a) All the above mentioned clinical manifestations
are reversed by administration of insulin in the
experimental scorpion envenoming syndrome
(Radha Krishna Murthy et al., 1988 b; 1990) and in
the scorpion sting victims (Yugandhar et al., 1999,
Radha Krishna Murthy et al., 1991) demonstrated
by us in the years 1988-1999!
(b) Insulin is the physiological antagonist to the
actions of catecholamines and all the other counterregulatory hormones.
(c)
The
catecholamines
bring
out
the
cardiovascular, respiratory & ECG changes,
metabolic disturbances through their action on
stimulation of Alpha receptors and suppressed
insulin secretion. Alpha blockers are essentially
acting indirectly through insulin secretion (Radha
Krishna Murthy and Anita, 1986 a; Radha Krishna
Murthy et al., 2003; 1988 a; b; c; Radha Krishna
Murthy and Haghnazari, 1999).
(d) Scorpion envenoming is a serious medical
emergency due to over-stimulated secretions and
stimulation of counter-regulatory hormonal actions.
e)Therefore, it is logical to use insulin as insulin
infusion in the critically ill scorpion sting victims
with focus on the cytokines, Reactive Oxygen
Species (ROS), myocardial damage, and many other

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clinical manifestations.
f) Ahmed and his co-investigators from Egypt
(Ahmed et al., 2015) demonstrated insulin
deficiency in their scorpion sting children which
confirmed our experimental work carried out in
1986 (Radha Krishna Murthy et al., 1986 a; Radha
Krishna Murthy et al., 1988 a; b; 1989; 1990 a;
1992; 1999; 2003)!
g) We also advocate the use of either insulin alone
or combination of insulin and anti-scorpion serum
to treat the scorpion sting victims (Radha Krishna
Murthy, 2002; Natu et al., 2006).
h) We recommend continuous infusion of regular
crystalline insulin should be given at the rate of 0.3
U/g glucose and glucose at the rate of 0.1 g/kg body
weight/hour, for 48 - 72 hours, with
supplementation of potassium as needed and
maintenance of fluid, electrolytes and acid-base
balance in scorpion sting victims.
The experimental basis of the various pathophysiological mechanisms involved in the genesis
of glycogenolysis - hyperglycemia in scorpion
envenoming syndrome and its reversal (in the
experimental animals and scorpion sting victims) by
administration of insulin, role of hyperglycemia as a
toxic agent, role of pro-inflammatory interleukins
insulin resistance, insulin an anti-inflammatory
agent are reviewed.
Insulin crosses the blood brain barrier, and exerts a
host of central effects such as sympatho- excitation,
vagal withdrawl, stimulation of corticotrophin
releasing factor, collectively resembling a stress
reaction in scorpion envenoming syndrome
(Ferrannini et al., 1999).
1.4 Administration of Insulin as treatment
for scorpion sting victim
2.0
Pain
in
Scorpion
Envenoming
Syndrome
Poisonous scorpion stings result in excruciating
pain at the site of sting and the pain reappears
despite repeated local infiltration of xylocaine and
other drugs.
Therefore an account of Physiology of pain, pain
pathways role of Hypothalamus activation of
neuro-endocrine axis, adverse physiological effects
of acute pain and the injury response, metabolic and
endocrine responses to injury, is given to
understand various mechanisms in acute pain in
scorpion envenoming syndrome. (Fig. 1, 2)
2.1 Apical skin - high basal sympathetic
tone - cortico-hypothalamic control
Apical skin is found in those areas of the body that
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are exposed but are poorly insulated by

subcutaneous fat, like hands and feet, web spaces of
the fingers and toes. The arterioles in apical skin
have a high basal sympathetic tone, and also contain
arteriovenous (A-V) anastomoses, which are under
cortico-hypothalamic control (Sabyasachi Sircar,
2014).
2.2 Scorpion stings at apical skin
Majority of the scorpion stings take place on the
finger tips and web spaces of the fingers with apical
skin (Yugandhar et al., 1999; Radha Krishna
Murthy et al., 1991; Radha Krishna Murthy, 2014 a;
b; c; d; e; 2013; 2002; Ahmed et al., 2015; Elatrous
et al., 2015; Sahin et al., 2015; Bouaziz et al., 2008;
Gajanan and Dammas, 1999; Meki et al., 2002;
Praveen Kumar and Vasudeva Murthy, 2013;
Freire-Maia et al., 1994). This could be the reason
for the rapid disappearance/ absence of scorpion
venom from the site of sting (Murugesan et al.,
1999).
2.3 Acute pain
Acute pain is defined as pain of recent onset
related to injury such as scorpion sting. The ability
of the somatosensory system to detect noxious and
potentially tissue-damaging stimuli involves
multiple interacting peripheral and central
mechanisms.
2.4 Nociceptors
Nociceptors have membrane proteins that convert
chemical energy into depolarizing potential.
Secondary hyperalgesia occurs due to the
sensitization of the Spinothalamic neurons. The
pain producing substances are called algogenic
substances.
2.5 Algogenic substances
Potassium ions, histamine, serotonin, bradykinin
(formed from dying cells) and prostaglandin E2 are
few of the algogenic substances released from
injured tissues.
2.6 Signalling molecules in pain pathways
Tissue damage associated with infection,
inflammation or ischaemia; produces disruption of
cells, degranulation of mast cells, secretion by
inflammatory cells, and induction of enzymes such
as cyclo-oxygenase-2 (COX-2). Ranges of chemical
mediators act either directly via ligand-gated ion
channels or via metabotropic receptors to activate
and/or
sensitise
nociceptors.
Endogenous
modulators of nociception, including proteinases,
pro-inflammatory cytokines (IL-1, IL-1, IL- 4, IL6, TNF-, IFN- and NO), anti-inflammatory
cytokines (IL-10) and chemokines (CCL3, CCL2,
CX3CL1) can also act as signalling molecules in
pain pathways (McGillicuddy et al., 2011;
Macintyre, 2010; Nalini et al., 2009; Greisen et al.,

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2001). Many of these signalling molecules (IL-1,

IL-1, IL- 4, IL-6, TNF-, IFN-, NO, IL-10, CCL3,
CCL2, CX3CL1) participating in pathways are
increased either in experimental scorpion
envenoming or in scorpion sting victims.
2.7 Nociception- tissue damage
Nociception is processing of noxious stimuli.
Noxious stimuli activate Nociceptors (peripheral
sensory organs), generate action potentials and
transmit the information through pain pathways to
central nervous system.
2.8 Noxious soup of chemicals
Pain is detected by nociceptors the unmyelinated
nerve endings. Nociceptor activation leads to
generator potential. Generator potentials depolarize
the distal axonal segment and initiate self
propagating action potential.
Tissue injury causes release of cellular mediators
like potassium ions (K+), hydrogen ions (H+),
prostaglandins, bradykinin, substance P (sP),
cholecystokinin (CCK), calcitonin gene-related
peptide (CGRP) and activate the terminal nerve
endings of sensitized nociceptor sensory afferent
fibers. Substance P (sP) is responsible for further
release of bradykinin and histamine from mast cells
and 5HT from platelets. These cellular mediators
increase vascular permeability, neurogenic edema
and nociceptor irritability. The noxious soup of
chemicals exacerbates the inflammatory response,
and recruits adjacent nociceptors.
2.9 Pain sensations
The pain sensations are carried to spinal cord in
spinal nerve. The dorsal root ganglion contains the
soma of sensory neuron. The Primary sensory
neuron carries sensory information from the sensory
receptor to the spinal cord or brain stem. The lateral
division of the dorsal root consists of thinly
myelinated group III (A delta) fibers and
unmyelinated group-IV fibers (McGillicuddy et al.,
2011; Macintyre, 2010; Nalini et al., 2009; Greisen
et al., 2001).
2.10 Secondary sensory neurons
The secondary sensory neuron carries the sensations
from the spinal cord or brain stem to the specific
relay nuclei of the Thalamus. The nociceptive
specific neurons respond only to nociceptive
stimuli, and the wide dynamic range (WDR)
neurons respond to noxious and non- noxious
stimuli. After crossing, the fibers for pain ascend in
the lateral Spinothalamic tract (spinal lemniscus).
2.11 Spinothalamic tract
The Spinothalamic tract conveys pain sensation to
the intra-laminar nuclei of the thalamus after
passing and relaying in the medullary and pontine
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reticular formation. This pathway provides

information on the sensory- discriminative aspects
of pain.
2.12 Spino-mesencephalic tract
The spino-mesencephalic tract conveys pain
sensation to the reticular formation and
periaqueductal gray matter to the amygdale through
parabrachial nucleus.
2.13 Spino-parabrachial pathway
The spino-parabrachial pathway originates from
superficial dorsal horn lamina I neurons and
projects to the ventromedial hypothalamus and
central nucleus of the amygdala. Multiple further
connections include those with cortical areas
involved in the affective and motivational
components of pain, projections back to the
periaqueductal grey (PAG) region of the midbrain
and rostroventromedial medulla (RVM), which is
crucial for fight or flight responses and stressinduced analgesia, and projections to the reticular
formation.
2.14 Hypothalamus - activation of neuroendocrine axis
The Spinothalamic tract conveys pain fibers to the
hypothalamus, which activates neuro-endocrine axis
(McGillicuddy et al., 2011; Macintyre et al., 2010;
Nalini et al., 2009; Greisen et al., 2001).
2.15 Reflex sympathetic efferent response
Reflex sympathetic efferent responses sensitize
nociceptors by releasing norepinephrine which
produces peripheral vasoconstriction at the site of
injury. Norepinephrine stimulates the release of
bradykinin (BK) and substance P (sP) leading to
peripheral vasoconstriction and trophic changes.
2.16 Tertiary sensory neuron
The tertiary sensory neuron carries the sensations
from spinal & medial lemniscus and terminates in
the specific thalamic nuclei to the sensory cortex.
2.17 Increased synthesis and extravasation
of humoral proinflammatory cytokines
Acute tissue injury results in an increased synthesis
and extravasation of humoral proinflammatory
cytokines (IL-1, IL-1, IL- 4, IL- 6, IL- 10, TNF-,
IFN- and NO). These
cytokines are responsible for exacerbating
edematous
and
irritative
components
of
inflammatory pain.
2.18 Persistent pain
Elevated levels of IL-1 result in the development
of persistent pain. The inflammatory mediators and
proinflammatory cytokines activate transducer
molecules such as transient receptor potential (TRP)
ion channel.

181

2.19 Central projections of pain pathways

Different qualities of the overall pain experience are
subserved by projections of multiple parallel
ascending pathways from the spinal cord to the
midbrain, forebrain and cortex.
The
spinoreticular
(spinoparabrachial)
and
spinomesencephalic tracts project to the medulla
and brainstem and are important for integrating
nociceptive information with arousal, homeostatic
and autonomic responses as well as projecting to
central areas mediating the emotional or affective
component of pain.
The spinoparabrachial pathway originates from
superficial dorsal horn lamina I neurons that express
the NK1 receptor and projects to hypothalamus and
central nucleus of the amygdala (McGillicuddy et
al., 2011; Macintyre et al., 2010; Nalini et al., 2009;
Greisen et al., 2001).
2.20 Adverse physiological effects of acute
pain and the injury response
Acute pain is one of the activators of the complex
neurohumoral and immune response to injury. Thus
acute pain and injury of various types are inevitably
interrelated and if severe, the injury response
becomes counterproductive and can have adverse
effects on outcome. Combination of surgery or
trauma and the associated acute pain result in a
painful
experience
and
an
associated
hormonal/metabolic response. This includes
increased cortisol, catecholamines and glucagon,
and a decrease in insulin sensitivity. (Fig. 1, 2)
2.21 Adverse physiological effects of
painful experience
Clinically significant injury responses can be
broadly classified as
Inflammation,
Hyperalgesia,
Hyperglycemia,
Protein catabolism,
Increased free fatty acid levels (lipolysis) and
Changes in water and electrolyte flux.
In addition, there are cardiovascular effects of
increased sympathetic activity and diverse effects
on respiration, coagulation and immune function.
2.22 Metabolic and endocrine responses
to
injury
in
scorpion
envenoming
syndrome
(McGillicuddy et al., 2011; Macintyre et al., 2010;
Nalini et al., 2009; Greisen 2001)
2.23 Endocrine Secretions - responses to
injury (Fig. 1, 2, 3)
Increased Catecholamines Adrenaline & Noradrenaline
Increased secretions of Glucocorticoids
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Increased Glucagon secretions

Altered thyroid hormone secretions
Increased Angiotensin II
Suppressed Insulin secretions or
Increased insulin secretions (Hyperinsulinemia)
Insulin resistance
Increased IL-1, TNF-, IL-6
2.24 Metabolic responses to injury
2.24 [I] Carbohydrate Metabolism
Hyperglycemia,
Glucose intolerance,
Insulin resistance
Increased Glycogenolysis,
Increased gluconeogenesis,
Suppressed Insulin secretions or
Increased insulin secretions (Hyperinsulinemia)
Insulin resistance
2.25 [II] Protein catabolism
Muscle protein catabolism,
Increased synthesis of acute phase proteins
Increased secretions of Glucocorticoids
Increased Catecholamines Adrenaline & Noradrenaline
Increased Glucagon secretions
Increased IL-1, TNF-, IL-6
2.23
[III] Lipid Metabolism
Increased lipolysis and oxidation due to
Increased Catecholamines Adrenaline & Noradrenaline
Increased secretions of Glucocorticoids
Increased Glucagon secretions
Increased growth hormone
2.24
[IV] Water and electrolyte flux
Retention of water and sodium
Increased excretion of potassium,
Reduced functional ECF with shifts to ICF
Increased Catecholamines Adrenaline & Noradrenal ine
Increased aldosterone,
Increased ADH,
Increased secretions of Glucocorticoids
Increased angiotensin II,
Increased prostaglandins
2.25 Hyperglycemia due to pain
Hyperglycemia is proportional to the extent of the
injury response. Injury response mediators stimulate
insulin-independent membrane glucose transporters
glut-1, 2 and 3, which are located diversely in brain,
vascular endothelium, liver and some blood cells.
Circulating glucose enters cells that do not require
insulin for uptake, resulting in cellular glucose
overload and diverse toxic effects. Excess

182

intracellular
glucose
non-enzymatically
glycosylates proteins such as immunoglobulins, and
render them dysfunctional.
Excess glucose enters glycolysis and oxidative
phosphorylation pathways, leading to excess
superoxide molecules that bind to nitric oxide (NO),
with formation of peroxynitrate, result in
mitochondrial dysfunction and death of cells served
by glut-1, 2 and 3. (Macintyre et al., 2010; Nalini et
al., 2009; Greisen et al., 2001) (Fig. 3, 4, 5, 6, 7, 8)
2.26 Increased Free Fatty Acid levels
associated with pain
Free fatty acid (FFA) levels are increased due to
several factors associated with the injury response
and can have detrimental effects on cardiac
function. High levels of FFA can depress
myocardial contractility, increase myocardial
oxygen consumption (without increased work), and
impair calcium homeostasis and increase free
radical production leading to electrical instability
and ventricular arrhythmias (Macintyre et al., 2010;
Nalini et al., 2009; Greisen et al., 2001). We have
demonstrated elevated levels of free fatty acid
levels in our experimental animals injected with
scorpion venom (Radha Krishna Murthy and Medh,
1986 (d); Radha Krishna Murthy et al., 1988 (d);
1988 (a); 1990; 1992 (b); 1999; 2003; Radha
Krishna Murthy and Zare, 2002) (Fig. 3, 4, 5, 6, 7,
8, 9).
2.27 Protein catabolism
The injury response is associated with an
accelerated protein breakdown and amino acid
oxidation, in the face of insufficient increase in
protein synthesis (Greisen et al., 2001).
2.28 Painful trauma - disturbed metabolic
state with impaired insulin sensitivity
Painful trauma results in a disturbed metabolic state
with impaired insulin sensitivity, which is related to
the magnitude of the trauma. Pain reduced wholebody insulin-stimulated glucose uptake because of a
decrease in non-oxidative glucose disposal. The
suppression of endogenous glucose output during
hyperinsulinemia tended to be decreased after pain.
Pain elicited a twofold to threefold increase in
serum cortisol, plasma epinephrine, and serum free
fatty acids. Similarly, circulating concentrations of
glucagon and growth hormone tended to increase
during pain.
2.29 Acute severe pain decreases insulin
sensitivity
Acute severe pain decreases insulin sensitivity,
primarily by affecting non-oxidative glucose
metabolism. Counter regulatory hormonal response
plays an important role. This may indicate that pain
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relief in stress states is important for maintenance of

normal glucose metabolism (Greisen et al., 2001).
2.30 Impaired insulin action resides in
skeletal muscle
The impaired insulin action after pain probably
resides in skeletal muscle. Defects in both skeletal
muscle GLUT-4 translocation and glycogen
synthase activity could be the intracellular
mechanisms of the impairment of insulin action
immediately after surgery.
2.31 Noncardiogenic pulmonary edema
after scorpion envenoming
Pulmonary edema, an important finding and
commonly the cause of death, has two components:
a cardiogenic (left ventricular dysfunction) and a
non-cardiogenic component. The latter appears to
be related to an increase of pulmonary vascular
permeability that accompanies activation of the
inflammatory cascade. Complement system
activation, release of substance P, activation of mast
cells and subsequent release of other mediators
(PAF, leukotrienes and prostaglandins) can
contribute to triggering of the inflammatory cascade
(Cologna et al., 2009; Amaral and Rezende, 1997;
Aparna et al., 2015; 2013; Deshpande and Aparna,
2012; Deshpande, 1998; 1993; Deshpande et al.,
2005).
2.32 Scorpion venom causes release of
mediators
that
affect
inflammatory
processes
Scorpion stings result in a massive release of
neurotransmitters, mainly from the autonomic
nervous system; however, the central nervous
system is also affected. The injection of scorpion
venom also causes damages to the tissue, which
induces a systemic release of mediators that affect
inflammatory
processes,
including
kinins,
eicosanoids, and platelet activating factor, nitric
oxide, and cytokines (Ana Dorce et al., 2015).
2.33 Pregnant women are among the
possible scorpion sting victims
Due to the high incidence of scorpion stings,
pregnant women are among the possible victims.
During pregnancy, the immune system plays an
important role ensuring the normal development of
the pregnancy, also preventing the development of
complications. Cytokines also play a fundamental
role in the development of neurons, including the
proliferation, survival, differentiation and axodendritic growth, and regulation of neuronal
synapses (Ana Dorce et al., 2015).
2.34 Cytokines - key role for a successful
pregnancy
Cytokines are important mediators playing a key
role for a successful pregnancy, where they are

183

involved in the implantation of the blastocyst and

formation and development of the embryo,
particularly in the development of the central
nervous
system.
The
uterus
promotes
immunological adaptations during pregnancy to
prevent rejection of the fetus by the mother.
IL-10 appears to be the key cytokine for protective
effect on the fetal-placental unit for the maintenance
of pregnancy since it inhibits the secretion of Th1
and cytokines such as IL-6, TNF-, and IFN-g.
Decreased levels of IL-10 - implantation
loss
Decreased levels of IL-10 in the fetuses were
reported after scorpion venom injection. This
alteration would explain the implantation loss. (Fig.
2). Elevated levels of proinflammatory cytokines
generated by the maternal or fetal immune system
have been associated with abnormal fetal brain
development and increased risk for neuro
developmental disorders (Ana Dorce et al., 2015).
2.35 Behavioral alterations in scorpion
envenoming
We have reported behavioral alterations in our
experimental animals. Changes in the levels of
TNF-, and IL-1a after the venom injection were
reported. These alterations could be related to
behavioral alterations, in which adult males had a
decrease in the locomotor activity and females had
enhanced anxiety and depression. Furthermore,
TNF-, can play an integral part in modulating
anxiety-like behavior as well as in fear conditioning
(Ana Dorce et al., 2015).
2.36 IL-1 system associated with an
increased risk of placental and perinatal
brain damage
The IL-1 system is associated with an increased risk
of placental and perinatal brain damage. It is
possible that the alterations on IL-1 levels are
responsible for the increase in weight of the
placenta. IFN-g along with other components of the
immune system is involved in the process of
neurogenesis. Under normal conditions, the
microglia is activated by IFN-g, a cytokine
produced by T cells, which induces cell
differentiation. Scorpion venom decreased the level
of IFN-g which would explain the reduction in the
number of hippocampal cells in the offspring of
dams envenomed during pregnancy (Ana Dorce et
al., 2015). (Fig. 2)
2.37 Scorpion envenoming causes release
of proinflammatory cytokines
The signs and symptoms of Tityus serrulatus (Ts)
envenoming involve intense activation of the
immune system with the release of mainly
proinflammatory cytokines such as TNF-,, IL-6,
INF-alpha and other mediators such as leukotriene
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B4 and prostaglandin E2. The uncontrolled release

of pro-inflammatory mediators by macrophages can
induce a generalized inflammation that can lead to
multi-organ failure. Tityus serrulatus alpha-like
toxin, (Ts5) is a proinflammatory toxin inducing the
cytokine production of TNF-alpha and IL-6 (Pucca
et al., 2015).
3. Scorpion venom increase the membrane
permeability to Na+
Scorpion venom increase the
membrane
permeability to Na+ by opening the voltage
sensitive Na+ channels, and this effect is associated
with Ca2+ entry blockade of Ca2+ - activated K+
channels. This will result in a disturbance of
transmembrane K+ gradient resulting in either
absolute or relative hyperkalemia (Radha Krishna
Murthy, 2014 a; b; c; Ismail, 1993).
3.1 Factors contributing and aggravating
hyperkalemia
a) The deficiency of some of the normal body
mechanisms causing K+ influx arising primarily
from the pronounced prolonged hyperglycemia
(Radha Krishna Murthy, 2014 a; b; c; e; Ismail,
1993; Radha Krishna Murthy and Zare, 2002;
Radha Krishna Murthy et al., 2003; 1999; 1992;
1990; 1988 a; b; d),
b) Enhanced glycogenolysis (Balasubramaniam and
Radha Krishna Murthy, 1981; 1984; Radha Krishna
Murthy, 2014 a; b; c; e; Radha Krishna Murthy and
Zare, 2002; Radha Krishna Murthy et al., 2003;
1999; 1992; 1990; 1988 a; b; c; d) and
c) Inhibited glycogenesis from decreased insulin
secretion (Balasubramaniam and Radha Krishna
Murthy, 1981; 1984; Radha Krishna Murthy, 2014
a; b; c; e; Ismail, 1993; Radha Krishna Murthy and
Zare, 2002; Radha Krishna Murthy et al., 2003;
1999; 1992; 1990; 1988 a; b; c; d)
d) Venom induced release of catecholamines which
in turn cause K+ efflux from the liver (Ismail, 1993;
Ismail et al., 1991)
e) Decreased serum Ca2+ secondary to disseminated
intravascular coagulation (DIC) (Radha Krishna
Murthy et al., 1988 d), increased deposition in the
heart and /or decreased intestinal absorption and
increased urinary excretion (Ismail, 1993, Ismail et
al., 1991)
f) Decreased serum magnesium (Ismail, 1993;
Ismail et al., 1991)
g) Changes in [K+] may shift the balance between
glycogen synthesis and glycogen breakdown
(Ganong, 1987; Keele, Neil, and Joels 2000).

184

We have demonstrated hyperkalemia (Radha

Krishna Murthy, 1988 a); hyperglycemia,
hypocalcaemia - decreased serum Ca2+ levels
(Radha Krishna Murthy, 1988 a); suppression of
insulin secretion (Radha Krishna Murthy and
Anita, 1986; Radha Krishna Murthy and Zare,
2002; Radha Krishna Murthy et al., 2003; 1999;
1992; 1990; 1988 a; b; c; d ) and depletion of
glycogen content (enhanced glycogenolysis) and
inhibited glycogenesis in the liver, atria, ventricle
and skeletal muscles in the experimental animals in
acute
myocarditis
produced
by
scorpion
(Mesobuthus tumulus Concanesis, Pocock) venom
(Balasubramaniam and Radha Krishna Murthy,
1981; 1984; Ismail, 1993; Radha Krishna Murthy
and Zare, 2002; Radha Krishna Murthy et al., 2003;
1999; 1990; 1988 a; b; d)
There is sufficient experimental and clinical
evidence that venoms from different scorpion
species
release
catecholamines
from the
sympathetic nervous system and stimulate the
cardiac adrenergic nerve endings causing sinus
tachycardia, arrhythmias, conduction defects and
arterial hypertension. Sinus tachycardia is due to an
effect of catecholamines released by toxin on beta
adrenergic receptors. Arterial hypertension is due to
an effect of catecholamines released by toxin from
adrenal glands and postganglionic nerve endings on
alpha adrenergic receptors (Ahmed et al., 2015;
Radha Krishna Murthy, 2000; Meki et al., 2002;
Praveen Kumar and Vasudeva Murthy, 2013;
Freire-Maia and Campos, 1991; Freire-Maia et al.,
1994; Gueron and Weizman, 1968; Gueron et al.,
1992; Ismail, 1993; Tarasiuk et al., 1994; 1997).
3.2 Scorpion envenoming - Autonomic
storm - Angiotensin II
Scorpion envenoming results in an autonomic storm
which leads to a massive release of catecholamines,
suppressed insulin secretions (Mirakabadi et al.,
2006; Gueron and Weizman, 1968; Gueron et al.,
1992; Ismail, 1993; Ismail et al., 1992; Radha
Krishna Murthy and Prabhakara Rao, 2014; Radha
Krishna Murthy and Haghnazari, 1999) and an
increase in angiotensin II levels (Radha Krishna
Murthy and Vakil, 1988). Angiotensin II stimulates
the release of catecholamines, thereby synergizing
and amplifying each others actions, and these may
act at least in part, at similar sites (Gueron et al.,
1992; Edwin Jackson, 2006; Ganong, 1987; Keele,
Neil and Joels 2000) (Fig. 1).
3.3 Severe Scorpion Envenoming causes an
increase in Blood Sugar, Insulin, Glucagon,
and Cortisol
Severe scorpion envenoming causes an increase in
the circulating levels of blood sugar (Radha Krishna
Murthy, 2014; Ahmed, 2015; Aparna et al., 2014;
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Elatrous et al., 2015; Cordeiro et al., 2006; Bouaziz

et al., 2008; Gajanan and Dammas, 1999; Meki,
2002; Praveen Kumar and Vasudeva Murthy, 2013;
Freire-Maia et al., 1994; Gueron et al., 1992; Ismail,
1993; Radha Krishna Murthy, 2015; 2014 b; 1992;
1990; Radha Krishna Murthy and Prabhakara Rao,
2014 a; Radha Krishna Murthy et al., 1999; 1988 a;
b; c; d; 1986 b;) insulin, glucagon (Radha Krishna
Murthy and Anita, 1986; Johnson and Ensinck,
1976; Johnson et al., 1976; Radha Krishna Murthy
et al., 2003; 1988 a; d; 1992; Radha Krishna Murthy
and Zare, 2002) and Cortisol (Radha Krishna
Murthy et al., 2003; Radha Krishna Murthy and
Zare, 2002). Subcutaneous or intravenous injection
of scorpion venom (Mesobuthus Concanesis,
Pocock) in the dogs caused hypo-insulin secretion
30 min after venom injection, and elevated insulin
levels 60 min after venom injection. Insulin and
blood glucose were higher at 60 and 120 min after
venom injection in our experimental animals.
3.4 Mechanism of increased glucagon
secretion
Nor-epinephrine released from the adrenergic nerve
terminals of the pancreas may be more effective
stimulus to glucagon secretion.
3.5 Mechanism of release of glucocorticoid
and insulin secretion
Glucocorticoids could be released following stress
or injury. The sympatho-adrenal axis primarily
serves to maintain the pressure necessary for organ
perfusion. Thus, during the ebb phase, the insulin
levels are reduced and
With the onset of hyper-metabolism, characteristic
of the flow phase, the hormonal environment is
changed and the insulin levels are increased
(Douglas, 1986).
3.6 Effects of the hormonal actions are
synergistic in the presence of increased
circulating levels of all the catabolic
counter-regulatory hormones
In the presence of increased circulating levels of all
the catabolic counter-regulatory hormones, the
effects of these hormonal actions are synergistic and
produce hyperglycemia (Douglas, 1986). Thus, the
counter-regulatory hormones and a simultaneous
suppressed insulin secretion or insulin resistance is
responsible for glycogenolysis in the atria,
ventricles,
liver;
and
skeletal
muscles
(Balasubramaniam and Radha Krishna Murthy,
1981; 1984; Radha Krishna Murthy et al., 2003;
1988 a; b; c; d; Radha Krishna Murthy and
Haghnazari, 1999); hyperglycemia (Radha Krishna
Murthy et al., 1988 a; b; c; d;); lipolysis and
elevated free fatty acid levels (Radha Krishna
Murthy et al., 1986 a; b; c; d; 1988 a; b; c; d) and
increased protein breakdown products (Ismail,
1993).

185

3.7 Hormonal disturbances cause metabolic

changes
Suppressed insulin secretion or hyper-secretion of
insulin (insulin resistance) would result in
glycogenolysis hyperglycemia, sudden increase in
Free Fatty Acids and increased protein breakdown
products (Fig. 1, 2).
3.8 Hyperinsulinemia - insulin resistance
Hyperinsulinemia observed in our studies could be
equated with insulin resistance. Insulin resistance
could be caused by a change in the receptor
membrane, a change in hormone-receptor binding
characteristics, or a change in the post receptor
events (Izzo, 1991) (Fig. 3).
3.9 Severe scorpion envenoming is a
syndrome of fuel-energy deficits & Result in
Multi-System-Organ-Failure (MSOF)
Severe scorpion envenoming is a syndrome of fuelenergy deficits and an inability of the vital organs to
utilize the existing metabolic substrates. This
ultimately may result in Multi-System-OrganFailure (MSOF) and death. These changes are
brought about by a massive release of
catecholamines,
angiotensin
II,
glucagon,
glucocorticoids, and either insulin deficiency or
insulin resistance (Fig. 3, 4, 5, 6, 7, 8, 9).
4.0
Mechanisms
of
production
of
Hyperglycemia due to scorpion venom (Fig.
3, 4, 5, 6, 7, 8)
a) Epinephrine elevates blood glucose and lactate
concentration by a series of enzyme activities. In
addition, insulin secretion is predominantly
inhibited via alpha receptors (Edwin Jackson 2006).
b) Epinephrine also can cause glycogenolysis in
muscle (Edwin Jackson 2006) thus providing
substrate in the form of lactate for hepatic
gluconeogenesis.
c) In addition to circulating catecholamines, Norepinephrine released from nerve endings in the liver
might influence glucose production (Defronzo,
1987; Naomi Karau-Friedmann, 1984).
d) The liver is richly innervated by Sympathetic
nerves; Stimulation of Sympathetic system can lead
to increased glucose production, an effect mediated
mostly through activation of alpha adrenergic
receptors. This indicates a possible role of Norepinephrine released by the nerve terminals in the
glucose production (Naomi Karau-Friedmann,
1984).
4.1
Physiological
Basis
of
Glycogenolysis
-Hyperglycemia
scorpion envenoming

the
in

4.2 Role of Glucagon (Fig. 3, 4, 5, 6, 7, 8)

a) Glucagon acts mostly on the liver and adipose
tissue where it antagonizes the action of insulin.
Glucagon raises blood glucose concentration by
enhancing the breakdown of liver glycogen to
glucose (glycogenolysis) and by promoting
gluconeogenesis from lactate, pyruvate, glycerol
and amino acids.
b) Glycogenolysis produces a rapid rise in blood
glucose within a few minutes; gluconeogenesis
produces a slower, more sustained rise in blood
glucose lasting for hours or days (Keele, Neil and
Joels 2000).
c) Glycogenolysis is mediated by activation of
adenyl cyclase in the hepatic cell membrane and
subsequent increase in intracellular c AMP and
activation of protein kinases which in turn activate
the Phosphorylase responsible for converting
glycogen to glucose-6-phosphate, and inactivates
glycogen synthatase. Phosphatase in the liver then
acts on glucose 6 phosphate to release glucose into
the hepatic venous blood (Ganong 1987, Keele,
Neil and Joels 2000).
4.3 Glucagon is potent stimulant of glucose
output from the liver
Glucagon as a stimulant of glucose output from the
liver is more potent than insulin as a promoter of
glucose retention (Edwin Jackson, 2006; Ganong,
1987; Keele, Neil and Joels 2000).
Role of catecholamines (Fig. 3, 4, 5, 6, 7, 8)
a) Catecholamines act similarly (like glucagon) to
enhance glycogenolysis but on molar basis,
Adrenaline and Nor-adrenaline, are weaker than
glucagon; however, Nor-adrenaline released
locally at sympathetic nerve terminals might have
powerful effects.
b) Catecholamines antagonize insulin by
increasing c AMP formation in the liver, fat and
muscle; in the liver this activates Phosphorylase,
promotes
glycogenolysis,
and
leads
to
hyperglycemia.
c) Catecholamines promote glycogenolysis in
muscle and enhance lactate formation.
4.4 Adrenalin inhibits glucose-induced
secretion of insulin
Adrenalin enhances gluconeogenesis from lactate.
Adrenalin inhibits glucose-induced secretion of
insulin from the beta cells of islets in endocrine
pancreas. Sudden stoppage of insulin secretion
leads rapidly to hyperglycemia (Edwin Jackson,
2006; Ganong, 1987; Keele, Neil and Joels 2000).
4.5 The acute hyperglycemia seen in acute

Ph ton

186

myocarditis induced by injection of scorpion venom

(Mesobuthustamulus Concanesis, Pocock) could be
because of suppression of insulin release from beta
cells of the pancreas as well as the capacity for
adrenal catecholamines to provoke glycogen
breakdown and peripheral inhibition of glucose
uptake.
4.6
Reduction in glycogen content (Fig.
3, 4, 5, 6, 7)
Epinephrine stimulates inhibition of insulin
secretion which in turn stimulates glycogenolysis in
the muscle, thus providing a substrate in the form of
lactate for hepatic gluconeogenesis (Keele, Neil and
Joels 2000). This might explain the reduction in
glycogen content of atria, ventricle, and liver and
skeletal muscle in rabbits, hyperglycemia in the
dogs within 30 min after venom injection
(Balasubramaniam and Radha Krishna Murthy,
1981; 1984; Radha Krishna Murthy and
Haghnazari, 1999; Radha Krishna Murthy, 2003;
1986 a; b; c; 1988 a; b; c).
4.7 Effects of acute ischemia on myocardial
metabolism (Fig.4)
a) The immediate metabolic changes in the
myocardium during acute ischemia are largely
determined by the rates of glycolysis and
glycogenolysis and to a lesser extent, of fatty acid
availability in relation to the demand for
phosphorylation (Oliver, 1975; Oliver and Opie,
1994).
b) Glycolysis increases with mild hypoxia, and in
areas
of
profound
hypoxia,
decreased
glycogenolysis occurs. Hydrolysis of stored
triglycerides results from the activation of
myocardial lipase with increases in Free Fatty
Acids (FFA). Greater glycogenolysis was observed
in atria and ventricular tissue in response to a
smaller dose of scorpion venom compared to lower
rate of glycogenolysis with a higher dose of
scorpion venom (Balasubramaniam and Radha
Krishna Murthy, 1981; 1984; Hannele, 1992; Izzo,
1991).
c) Important early systemic changes have been
recorded in man in the first few hours of the onset
of acute myocardial ischemia.
d) Feeling of impending death: This is due to an
increase in catecholamines. These changes probably
result from the anxiety and pain associated with
ischemia, including a sustained rise in plasma
catecholamines, FFA, cortisol concentrations, a
transient elevation in blood glucose, and decreased
plasma insulin levels (Bondy and Rosenberg, 1980;
Goldstein et al., 1995; Serrano, 1992; Susan, 1996).
e) Plasma FFA is absorbed by tissues in an
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exponential relationship to their molar binding with

plasma albumin, while glucose uptake depends on
adequate concentrations of plasma insulin, which is
reduced in acute myocardial infarction. In many
patients, the increase in plasma FFA concentrations
is such that the two main binding sites of albumin
are saturated, and the ischemic myocardium extracts
proportionately more FFA than at lower plasma
concentrations. The ischemic myocardium is
presented, therefore, with a considerable excess of
FFA relative to glucose and, in a severely ischemic
zone, the available oxygen may be insufficient for
oxidation (Oliver, 1975; Oliver and Opie, 1994).
4.8 Renin-angiotensin system
Increased sympathetic activity causes elevated renin
release by direct stimulation of juxtaglomerular
cells. A subsequent increase in angiotensin II
secretion enhances the ongoing sympathetic nerve
output by a direct action on the brainstem and by a
blunting of Baroreceptor mechanisms. Thus, the
renin-angiotensin system is an important facilitator
of ongoing Sympathoadrenal traffic (Radha Krishna
Murthy and Vakil, 1988; Edwin Jackson 2006;
Ganong, 1987; Keele, Neil and Joels 2000; La
Grange, 1977; Bondy and Rosenberg, 1980).
4.9 Hyperglycemia in scorpion envenoming
Hyperglycemia (Cordeiro et al., 2006; Bouaziz et
al., 2008; Gajanan and Dammas, 1999; Radha
Krishna Murthy, 2002; Mirakabadi et al., 2006;
Meki et al., 2002; Praveen Kumar and Vasudeva
Murthy, 2013; Cologna et al., 2009; Radha Krishna
Murthy, 2014 a; b; c; d; e; Radha Krishna Murthy,
2013; 2000; Radha Krishna Murthy and
Haghnazari, 1999; Radha Krishna Murthy et al.,
2003; 1986 a; b; c; 1988 a; b; c; d) was found after
envenoming. This could be due to a massive release
of catecholamines (Ahmed et al., 2015, Aparna et
al., 2015; Elatrous et al., 2015; Gueron and
Weizman, 1968; Gueron et al., 1992; Ismail, 1993),
increased glucagon,
Cortisol (Radha Krishna
Murthy and Haghnazari, 1999; Radha Krishna
Murthy et al., 2003) and changes in insulin
secretion (Radha Krishna Murthy and Anita, 1986;
Johnson and Ensinck, 1976; Johnson et al., 1976;
Radha Krishna Murthy et al., 1988 a; b; c; d). (Fig.
3, 4, 5, 6, 7, 8)
4.10 Effects of an acute increase in
epinephrine and Cortisol on carbohydrate
metabolism during insulin deficiency
Elevations in plasma epinephrine (Ahmed et al.,
2015; Elatrous et al., 2015; Gueron and Weizman,
1968; Gueron et al., 1992; Ismail., 1993) and
Cortisol levels (Johnson and Ensinck, 1976;
Johnson et al., 1976; Radha Krishna Murthy and
Haghnazari, 1999; Radha Krishna Murthy et al.,
2003) are associated with scorpion envenoming. In
diabetic patients, plasma epinephrine and Cortisol

187

levels increase during diabetic keto-acidosis.

Goldstein et al. demonstrated an acute physiological
rise in the plasma epinephrine level was associated
with a transient increase in hepatic glucose
production and a sustained fall in glucose clearance
and persistent hyperglycemia (Goldstein et al.,
1995). The initial increase in glucose production
was primarily due to an increase in hepatic
glycogenolysis, whereas the later elevation in
glucose production was due to a stimulation of
gluconeogenesis (Izzo, 1991).
4.11 Cortisol may be synergistic with other
stress hormones
Cortisol may be synergistic with other stress
hormones. Glucose production was reported to be
synergistically
enhanced
by
a
combined
epinephrine, glucagon, and Cortisol infusion, while
glucose production was increased in an additive
manner by epinephrine and glucagon infusions.
Glucagon
and
Cortisol
modify
lactate
gluconeogenesis in an additive rather than a
synergistic manner (Goldstein et al., 1995).
4.12 Small increases in epinephrine level
during
insulin
deficiency
worsen
hyperglycemia
Small increases in the plasma epinephrine level
during insulin deficiency can significantly worsen
the resulting hyperglycemia. This occurs as a result
of what is probably an additive effect on hepatic
glucose production, without any additional change
in glucose clearance. The small increase in
epinephrine significantly increases the importance
of gluconeogenesis, as the period of insulin
deficiency becomes prolonged.

Hyperglycemia increases the risk of myocardial

infarction, peripheral vascular disease, stroke etc.
Hyperglycemia is harmful.
All the above mentioned clinical manifestations are
reversed after administration of insulin in our
scorpion envenomed experimental animals (Radha
Krishna Murthy et al., 1988 (a); Radha Krishna
Murthy et al., 1990) and in scorpion sting victims
(Radha Krishna Murthy et al., 1991; Radha Krishna
Murthy et al., 1992 (a); Yugandhar et al., 1999).
5.2 Hyperglycemia - Reactive Oxygen
Species (ROS) (Fig. 3, 4, 5, 6, 7, 8)
a) Hyperglycemia is known to increase the
production of O2 and other reactive oxygen species
(ROS). Prostacyclin (PGI2) and nitric oxide (NO)
are secreted by endothelial cells, are potent
vasodilators and platelet anti-aggregators. ROS
inactivate prostacyclin (PGI2) and nitric oxide (NO)
(Das, 2007).
b) Hyperglycemia increase leukocyte rolling,
leukocyte adherence and leukocyte transmigration
through mesenteric venules (Booth et al., 2001). It
is due to decreased release of endothelial NO
(eNO), and result in inflammation. Local
application of insulin completely attenuated the proinflammatory events, inhibited free radical
generation, and NF-K activation in mononuclear
cells and reduced soluble intercellular adhesion
molecule-1, monocytes chemo attractant protein-1
and plasminogen activator-1 production by
enhancing NO synthesis (Aljada et al., 2000).
5.3 Hyperglycemia - suppressed insulin
secretion IL-6, TNF-, IL-18 (Fig.9)
Hyperglycemia and suppressed insulin secretion
cause an increase in plasma IL-6, TNF- and IL-18
levels within 2 hours (Das, 2007).

5.0 Glucose toxicity

In virtually all tissues except the brain, glucose, at a
fixed insulin concentration, promotes its own
utilization in a concentration-dependent manner.
The superiority of insulin in stimulating glucose
oxidation seems to be explained by its anti-lipolytic
effect. Even a small increment in serum insulin
concentration promptly suppresses lipolysis, and
consequently, the use of FFA for energy production,
which in turn, enhances glucose oxidation. In
contrast, glucose per se is unable to suppress
lipolysis in man. Glucose per se (i.e.
hyperglycemia) is a cellular toxin.
Hyperglycemia may cause a generalized
desensitization of all cells in the body through the
down-regulation of the glucose receptors in the
glucose transport system (Hannele, 1992).

5.5 What is hyperglycemia?

Presence of hyperglycemia (hyperglycemia is
defined as plasma glucose >110 mg %) is an
indication that insufficient insulin (either qualitative
or quantitative) is present in the circulation or more
precisely there is peripheral insulin resistance.

5.1 Hyperglycemia is toxic

Hyperglycemia per se is toxic. Insulin is an antiinflammatory agent, and is cardio-protective.
Insulin can improve endothelial function, cardiac
function, lipid profile and can lower blood pressure.

5.6 Counter-regulatory hormones-Insulin

resistance-pro-inflammatory cytokines (Fig.
4)
Peripheral insulin resistance is due to increased
production of stress hormones such as

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5.4 Impaired glucose tolerance (IGT) Increased pro-inflammatory cytokines

Hyperglycemia acutely increases pro-inflammatory
cytokine concentrations by an oxidative mechanism
and this effect is more pronounced in subjects with
impaired glucose tolerance (IGT) (Das, 2007).

188

corticosteroids,
adrenaline,
nor-adrenaline,
enhanced production of pro-inflammatory cytokines
such as IL-6, IL-8, IL-18, TNF-, and or decreased
production of anti-inflammatory molecules IL-4, IL10 and transforming growth factor (TGF-)
(Das, 2007) (Fig. 4).
5.7 Insufficient insulin - Increased Free
Fatty Acids
Insufficient insulin causes a decrease in glycolytic
substrate and an increase in free fatty acids that
reduces myocardial contractility and promotes
cardiac failure and arrhythmias (Oliver and Opie,
1994).
6.0 Increased TNF-, IL-1beta, IL-6 and IL-8
levels in moderate and severe cases of
Tityus serrulatus scorpion sting victims
TNF-, IL-1beta, IL-6, IL-8 and IL-10 levels were
significantly increased in moderate and severe cases
of scorpion sting victims and the levels of these
cytokines were positively correlated with the
severity of envenomation, as evaluated by clinical
profile and plasma venom concentration (Fukuhara
et al., 2003).
6.1 Source of cytokines
a) The source of cytokines could be from the
myocardium and/or from leukocytes, lymphocytes,
monocytes, and macrophages.
b) Ischemia stimulates the production of proinflammatory cytokines from the myocardium.
c) Increased mesenteric venous pressure due to
myocardial dysfunction causes increased endotoxin
absorption from the gut.
d) Endotoxin is a potent stimulant of synthesis and
release of pro-inflammatory cytokines from various
cells/ tissues especially macrophages (Das, 2007).
6.2 TNF- (Fig. 9)
TNF- is secreted by a variety of cells/ tissues
including adipose tissue, macrophages and heart.
6.3 TNF- - insulin resistance, hypertension
and inflammation
TNF- plays a major role in insulin resistance,
hypertension and inflammation. TNF- is released
by myocardium, and directly decreases myocardial
contractility. TNF- causes dysfunction and
apoptosis of endothelial cells, decrease the
production of eNO and enhance procoagulant
activity and fibrin deposition. TNF- stimulates
endothelial cells and leukocytes to produce
increased amounts of ROS that in turn inactivate
eNO (Aljada et al., 2002; Meldrum and Donnahoo,
1999). (Fig. 9)

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6.4 TNF- and other pro-inflammatory

cytokines depress myocardial function
Ischemic myocardium produces TNF-. TNF- in
turn suppresses myocardial contractility, which
results in increased mesenteric venous pressure and
absorption of endotoxin from the gut. The absorbed
endotoxin stimulates the production of TNF-.
TNF- induces further myocardial depression and
exacerbates cardiac failure. Thus, a vicious cycle is
initiated that may prove fatal (Das, 2007).
6.5 Insulin suppressed pro-inflammatory
cytokines
Insulin suppresses circulating concentrations of
FFA and production of pro-inflammatory cytokines
TNF-, IL-6, and ROS and enhances the production
of IL-4, IL-10, eNO and PGI2 (Das, 2007).
6.6 TNF- - Apoptosis
TNF- is secreted by a variety of cells/tissues
adipose tissue, macrophages and cardiac tissue.
TNF- plays a major role in insulin resistance,
hypertension, inflammation and septic shock. TNF causes dysfunction and apoptosis of endothelial
cells, decreases the production of eNO and enhances
procoagulant activity and fibrin deposition (Levine
et al., 1990).
6.7 Pregnant women are among the
possible scorpion sting victims
Due to the high incidence of scorpion stings,
pregnant women are among the possible victims.
During pregnancy, the immune system plays an
important role ensuring the normal development of
the pregnancy, also preventing the development of
complications. Cytokines also play a fundamental
role in the development of neurons, including the
proliferation, survival, differentiation and axodendritic growth, and regulation of neuronal
synapses (Ana Dorce et al., 2015).
6.8 Cytokines - key role for a successful
pregnancy
Cytokines are important mediators playing a key
role for a successful pregnancy, where they are
involved in the implantation of the blastocyst and
formation and development of the embryo,
particularly in the development of the central
nervous
system.
The
uterus
promotes
immunological adaptations during pregnancy to
prevent rejection of the fetus by the mother.
IL-10 appears to be the key cytokine for the
maintenance of pregnancy due to its protective
effect on the fetal-placental unit, since it inhibits the
secretion of Th1 inflammatory cytokines such as IL6, TNF- and IFN-g.
Decreased levels of IL-10 in the fetuses were
reported after scorpion venom injection. This
alteration would explain the implantation loss (Fig.

189

8).
Elevated levels of proinflammatory cytokines
generated by the maternal or fetal immune system
have been associated with abnormal fetal brain
development and increased risk for neuro
developmental disorders (Ana Dorce et al 2015).
6.9 Behavioral alterations in scorpion
envenoming
We have reported behavioral alterations in our
experimental animals (Radha Krishna Murthy et al.,
1984 a; b; c; 1986 a; b; c;, d; Radha Krishna
Murthy, 1990). Changes in the levels of TNF- and
IL-1 after the venom injection were reported.
These alterations could be related to behavioural
alterations, in which adult males had a decrease in
the locomotor activity and females had enhanced
anxiety and depression. Furthermore, TNF- can
play an integral part in modulating anxiety-like
behavior as well as in fear conditioning (Ana Dorce
et al., 2015).
6.10 IL-1 system associated with an
increased risk of placental and perinatal
brain damage
The IL-1 system is associated with an increased risk
of placental and perinatal brain damage. It is
possible that the alterations on IL-1 levels are
responsible for the increase in weight of the
placenta. IFN-g along with other components of the
immune system, it is involved in the process of
neurogenesis. Under normal conditions, the
microglia is activated by IFN-g, a cytokine
produced by T cells, which induces cell
differentiation. Scorpion venom decreased IFN-g
levels which would explain the reduction in the
number of hippocampal cells in the offspring of
dams envenomed during pregnancy (Ana Dorce et
al., 2015) (Fig. 8).
6.11 Scorpion envenoming causes release
of proinflammatory cytokines & multi-organ
failure
The signs and symptoms of Tityus serrulatus (Ts)
envenoming involve intense activation of the
immune system with the release of mainly
proinflammatory cytokines such as TNF-, IL-6,
INF- and other mediators such as leukotriene B4
and prostaglandin E2. The uncontrolled release of
pro-inflammatory mediators by macrophages can
induce a generalized inflammation that can lead to
multi-organ failure. Tityus serrulatus alpha-like
toxin, (Ts5) is a proinflammatory toxin inducing the
cytokine production of TNF- and IL-6 (Pucca et
al., 2015) (Fig. 8).
6.12 Insulin administration decreased
serum IL-1, IL- 6, Macrophage Migration
Inhibitory Factor and TNF- concentration
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Insulin administration acts via the Insulin-like

Growth Factor (IGF), enhances tissue perfusion
and glucose uptake, suppresses lactate, FFA,
glycerol production and lipolysis; improves
survival. Insulin also suppresses excess production
of IL-1, IL- 6, TNF- and Macrophage Migration
Inhibitory Factor (MIF), enhances the synthesis of
eNO and anti-inflammatory cytokines IL-4 and IL10, facilitates improvement in myocardial function
and recovery (Das, 2001).
7.0 Free Fatty Acids (FFA) Insulin myocardial carbohydrate metabolism
At physiologic concentrations, plasma insulin is a
major regulator of myocardial substrate exchange.
Insulin
promotes
myocardial
carbohydrate
metabolism directly by stimulating carbohydrate
uptake and indirectly through inhibition of lipolysis.
The lowered plasma concentration of FFA mediates
the indirect action of insulin, and infusion of FFA
significantly blunts insulin stimulation of
myocardial carbohydrate removal (Barrent et al.,
1984).
Apart from controlling hyperglycemia, insulin also
intervenes with many other metabolic and
inflammatory pathways. Plasma free fatty acids,
which are increased due to enhanced catabolism,
would induce inflammation and also worsen the
clinical outcome. Normalizing free fatty acids by
exogenous insulin could yield significant results
(Dandona et al., 2003).
7.1 Insulin clot dissolution
Suppression of Plasminogen Activator Inhibitor-1
(PAI-1) production by insulin is of benefit as this
would increase clot dissolution. There are many
other potential benefits of insulin, mainly inhibition
of pro-inflammatory Early Growth Response Gene1(Egr-1) and tissue factor indicating its antiinflammatory properties. The basic mechanism by
which insulin acts as an anti-inflammatory factor is
by enhancing nitric oxide production.
7.2 Insulin Vasodilatory effect
The vasodilatory effect of insulin could also be one
of the reasons for its favorable effects (Aljada et al.,
2002).
7. 3 Triggering of apoptosis
Apoptosis could be induced by extracellular
inducers like toxins, hormones, growth factors,
cytokines and nitric oxide. The process of direct
initiation of apoptosis could be induced by tumor
necrosis factor (TNF ), elevated levels of
cytokine IL-1, IL-1, IL- 4, IL- 6, IL- 10, TNF-
IFN- and NO (Omran, 2003; Robbins and Cotran,
2010).

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7.4
Increased
production
of
proinflammatory cytokines in experimental
scorpion envenoming
Scorpion envenoming causes increased production
of pro-inflammatory cytokines. IL-1, IL-1, IL- 4,
IL- 6, IL- 10, TNF-, IFN- and NO are produced
and released in the experimental animals after
injection of either crude scorpion venom or purified
fractions of the Buthidae scorpion venoms (Omran,
2003) (Fig. 4).
7.4
Increased
production
of
proinflammatory cytokines in scorpion sting
victims (Fig. 4)
1. Scorpion envenoming by Leiurus quinquestriatus
and B. judaicus resulted in increments of IL- 6 in
the serum of 8 of 10 children one to three hours
after the sting. Increased plasma levels of IL-1, IL6, IL-8, IL- 10, TNF-, IFN- and NO were reported
in scorpion sting patients (Omran, 2003; Robbins
and Cotran 2010; Magalhaes et al., 1999;
Petricevich, 2010; Ait-Lounis et al., 2012).
2. Cytokine IL-1 is produced by the venom from
the scorpions Androctonus australis hector (Aah),
Centruroides noxius and Tityus serrulatus.
3. Cytokine IL- 4 is produced by the venom from
the scorpion Aah.
4. Cytokine IL- 6 is produced by the venom from
the scorpions Androctonus australis hector,
Centruroides noxius, Tityus serrulatus and Leiurus
quinquestriatus (Magalhaes et al., 1999;
Petricevich, 2010; Ait-Lounis et al., 2012).
Cytokine IL- 10 is produced by the venom from the
scorpions
Androctonus
australis
hector,
Centruroides noxius and Tityus serrulatus (Sofer,
1995).
Cytokine TNF- is produced by the venom from the
scorpions, Centruroides noxius and Tityus
serrulatus.
Cytokine IFN- is produced by the venom from the
scorpions
Androctonus
australis
hector,
Centruroides noxius and Tityus serrulatus
(Magalhaes et al., 1999; Petricevich, 2010; AitLounis et al., 2012).
Nitric Oxide (NO) is a free radical and is produced
by the venom from the scorpion Buthus martensi
Karch. Nitric Oxide (NO) is a free radical and the
key endothelium derived releasing factor in the
regulation of vascular tone and vasomotor function
(Magalhaes et al., 1999).
NO is also produced by Macrophages and some
neurons in the brain.
Ph ton

Nitric Oxide is also considered as a second

messenger for a number of physiological
mechanisms such as neurotransmission, vascular
tone and arterial blood pressure.
NO is also responsible for penile erection (Boyds
Textbook of Pathology 2013). This could be the
reason for Priapism observed in scorpion sting
victims.
There are three different types of NOS: endothelial
(e NOS), neuronal (n NOS), and inducible (i NOS). i
NOS is induced when macrophages and other cells
are activated by cytokines - TNF-, IFN-. NO
relaxes vascular smooth muscle and promotes vasodilatation. NO reduces platelet aggregation and
adhesion, inhibits mast-cell induced inflammation
and inhibits leukocyte recruitment. High levels of i
NOS induced NO are produced by leukocytes,
mainly neutrophils and macrophages (Magalhaes et
al., 1999; Petricevich, 2010; Ait-Lounis et al.,
2012).
7.5 Nitric Oxide (NO) - insulin resistance
Nitric Oxide (NO) decomposes to nitrite and nitrate.
Several pro-inflammatory cytokines are capable to
cause modifications in the levels of nitrite and
nitrate production has been associated with severe
scorpion envenoming, hypertension, septic shock
and insulin resistance (Magalhaes et al., 1999;
Petricevich, 2010; Ait-Lounis et al., 2012).
7.6 Action of scorpion venom - in vitro Apoptosis
Omran carried out in vitro experiments on 293T and
C2C12 cell lines to find out the mechanism of the
action of the scorpion Leiurus quinquestriatus
venom. The damage induced to 293T and C2C12
cell lines by scorpion Leiurus quinquestriatus
venom is direct and is not secondary to disruption
of the microcirculation. 50 ug/ml of the venom
highly reduced the cell survival. The toxins in the
Leiurus quinquestriatus venom act at the membrane
level. The toxins may cross either sarcolemma or
translocated by a carrier or move through pores or
channels in the membranes. This allows the passage
of ions down their concentration gradient resulting
in osmotic changes followed by several mechanisms
leading to cell death (Omran, 2003).
7.7 Cytotoxic effects due to dose of the
venom
We have demonstrated that the hormonal and
metabolic effects of the venom from scorpions of
Buthidae family are dependent upon the dose of the
venom
(Radha
Krishna
Murthy,
1982;
Balasubramaniam and Radha Krishna Murthy,
1981; 1984; Radha Krishna Murthy et al 1984 b; c;
1988 a; b; c; d; 1989; 1990; 1991; 1992; Radha
Krishna Murthy, 2013; 2014 a; b; c; d; e). The

191

apoptotic effects of the scorpion venom are more

prominent in the early stages of toxicity (Omran,
2003). Less glycogenolysis was observed in atria,
ventricle, skeletal muscle and liver tissue in our
experimental animals injected with higher dose of
the scorpion (Mesobuthus tamulus concanesis
Pocock) venom given compared to severe
glycogenolysis in the animals injected with smaller
dose of the venom given (Balasubramaniam and
Radha Krishna Murthy, 1981; 1984).
8. Defect in insulin action - impairment in
insulin secretion
In muscles and adipocytes, this would be reflected
by a defect in insulin action, whereas at the level of
beta cells of the islets of Langerhans, this would be
manifested by impairment in insulin secretion
(Defronzo, 1987; Goldstein et al., 1995).
8.1 Haemodynamic abnormalities in shortterm insulin deficiency - Magnified lipolysis
and beta oxidation of FFA
In diabetic keto-acidosis, the simultaneous
relative insulin deficiency and excessive secretion
of counter-regulatory hormones lead to magnified
lipolysis and beta oxidation of FFA with a parallel
hepatic
overproduction
and
peripheral
underutilization of ketone bodies. The clinical
characteristics of patients are drowsiness and overbreathing. In addition, signs of circulatory collapse,
such as tachycardia, weak pulse, and low blood
pressure are normally present (Avogaro et al.,
1996). Similar clinical manifestations are usually
observed in scorpion sting victims (Ahmed et al.,
2015; Aparna et al., 2015; Elatrous et al., 2015;
Sahin et al., 2015; Bouaziz et al., 2008; Gajanan
and Dammas, 1999; Meki et al., 2002; Praveen
Kumar and Vasudeva Murthy, 2013; Freire-Maia et
al., 1994; Gueron and Weizman, 1968; Gueron et
al., 1992; Ismail, 1993; Choudhry et al., 2011).
8.2 Insulin levels in scorpion envenoming
Insulin levels, as measured by radioimmunoassay,
were significantly either suppressed or elevated
after Mesobuthus tamulus concanesis, Pocock
scorpion venom injection (Radha Krishna Murthy
and Anita, 1986; Choudhry et al., 2011; Radha
Krishna Murthy et al., 2003; Radha Krishna Murthy
and Zare, 2002; Radha Krishna Murthy, 2002;
2000; Radha Krishna Murthy and Hase, 1994;
Radha Krishna Murthy et al., 1992 a; b; 1990; 1988
a; b; c; d).
8.3 Catabolic state with low Insulin /
glucagon (I/G) ratio
The insulin/glucagon ratio (I/G ratio) may be more
important than the levels of individual hormones. A
high I/G ratio produces an anabolic state with more
nutrient incorporation into peripheral tissues. A
high ratio is associated with low levels of c AMP
Ph ton

and a respiratory quotient close to 1, indicating that

carbohydrates are the predominant energy source.
When I/G ratio are low, a catabolic state is
produced in which nutrients are mobilized.
Scorpion envenoming causes a low I/G ratio (Susan
1996).
8.4 What is "Hyperinsulinemia"?
Hyperinsulinemia is said to exist when plasma
insulin levels are inappropriate for the blood
glucose estimated simultaneously.
8.5 Insulin resistance
When insulin levels are elevated with a normal
glucose level, "true hyperinsulinemia" is the most
appropriate term, while high insulin levels with
elevated blood glucose levels may be referred to as
"insulin resistance". Elevated insulin levels were
observed 30 min following venom injection (Radha
Krishna Murthy and Anita 1986; Choudhry et al
2011; Radha Krishna Murthy and Zare 2002; Radha
Krishna Murthy 2002; 2000; Radha Krishna Murthy
and Hase, 1994; Radha Krishna Murthy et al., 1992
a; b; 1990; 1988 a; b; c; d; 2003).
8.6 Hyper-insulnemia and hyperglycemia in
scorpion envenoming syndrome
We have observed hyperglycemia along with
suppressed/ reduced insulin secretion (hypo-insulin
secretion) and hyperglycemia along with hyperinsulnemia in all our experimental animals. This
was confirmed by Deshpande and his co-workers in
their experimental animals (Choudhry et al., 2011).
8.7 Insulin receptor and the signaling
pathways not defective
Exogenous
insulin
administration
reversed
haemodynamic, cardiovascular, metabolic, electrocardio graphic (ECG) changes, pulmonary edema
and many other clinical manifestations in the
experimental animals (Radha Krishna Murthy et al.,
1988 a; 1990) and in the scorpion sting victims
(Radha Krishna Murthy et al., 1991; Yugandhar et
al., 1999) suggesting that the insulin receptor and
the signaling pathways are not defective.
8.8 Counter-regulatory hormones and
hyperglycemia
Hyper-insulinemia and hyperglycemia are observed
in scorpion envenoming syndrome. The increased
circulating insulin levels and failure to counter the
hyperglycemia may indicate the action of counterregulatory hormones (Radha Krishna Murthy and
Haghnazari, 1999; Radha Krishna Murthy et al.,
2003). We have reported an elevation of glucagon
and Cortisol level in experimental animals along
with changes in insulin secretion. Various
investigators have reported increased Renin
(Gueron and Weizman, 1968; Gueron et al., 1992),
angiotensin II levels, (Radha Krishna Murthy and

192

Vakil, 1988) in the experimental animals and

scorpion sting victims. Epinephrine and norepinephrine levels were also elevated in scorpion
envenoming syndrome.
8.9 Hyperglycemia and hyper insulinemia
- insulin resistance
Hyperglycemia and hyper-insulinemia - insulin
resistance is observed in all our experimental
animals (Radha Krishna Murthy and Haghnazari,
1999; Radha Krishna Murthy et al., 2003; Radha
Krishna Murthy and Yeolekar, 1986; Radha
Krishna Murthy et al., 1986 a; b; c; 1988 a; b; c; d)
and in the studies reported by Choudhry et al 2011.
Thus, development of insulin resistance (for the
endogenously secreted insulin) is a possibility in
scorpion envenoming syndrome.
8.10 Insulin resistant state
The relationship between insulin resistance, plasma
insulin level, and glucose intolerance is mediated to
a significant degree by changes in ambient plasma
FFA concentration [57, 70]. Plasma FFA levels can
be suppressed by relatively small increments in
insulin concentration. Consequently, an elevation of
circulating FFA concentration can be prevented if
large amounts of insulin are secreted. If
hyperinsulinemia cannot be maintained, plasma
FFA concentration will not be suppressed normally,
and the increase in plasma FFA concentration will
result in increased hepatic glucose production.
Short-term hyperglycemia can induce insulin
resistance (Hannele, 1992).
8.11 Causes of insulin resistance
In any insulin-resistant state, the cause of insulin
resistance can be due to an abnormal beta cell
secretion, circulating insulin antagonists, or target
tissue defect in insulin action (Defronzo, 1987;
Douglas, 1986; Edwin Jackson2006; Oliver, 1975;
Serrano et al., 1992).
8.12 Counter-regulatory hormones downregulate insulin receptors
Insulin resistance could be caused by a change in
the receptor number, hormone-receptor binding
characteristics, or post-receptor events. Insulin
receptors are probably down-regulated by high
concentrations of agonist hormone/s (Izzo, 1991).
8.13 Insulin resistance - pre-receptor,
receptor, and post-receptor abnormalities
Insulin resistance may occur because of prereceptor, receptor, and post-receptor abnormalities
(Serrano et al., 1992).
Insulin resistance as a result of pre-receptor
abnormalities involves metabolic (elevated counterregulatory hormonal and non-hormonal) factors.
Circulating insulin antagonists as a cause of insulin
Ph ton

resistance have been clearly demonstrated in a

variety of clinical syndromes.
8.14 Excess endogenous or exogenous
glucocorticoids are often associated with
carbohydrate intolerance
Glucagon and glucocorticoids stimulate hepatic
glucose production through increased activity of
hepatic gluconeogenic enzymes (Serrano et al.,
1992).
8.15 Post-receptor resistance - Hormonal
antagonists
Post-receptor resistance can be caused by other
hormones. Hormonal antagonists consist of all
counter-regulatory hormones, such as growth
hormone, Cortisol, glucagon, and epinephrine.
Increases in circulating levels of glucagon, Cortisol
and catecholamines have been demonstrated in
scorpion envenoming (Izzo, 1991).
8.16 Corticosteroids decrease peripheral
glucose utilization
A rise in corticosteroids decreases peripheral
glucose utilization by diminishing the activity of
glucose transporters and inhibiting insulin-mediated
translocation of these facilitative transporters.
Additionally, glucocorticoids affect insulin receptor
affinity and number, decreasing insulin binding to
its receptor.
8.17
Catecholaminergic
hyperactivity
antagonize insulin effects
States
of
Catecholaminergic
hyperactivity
antagonize insulin effects through several
mechanisms. Catecholamines stimulate hepatic
glucose production by direct stimulation of
glycogenolysis and gluconeogenesis and indirectly
by increasing glucagon secretion. Additionally,
catecholamines decrease peripheral glucose disposal
both in vitro and in vivo.
8.18 Effect of acidic pH to accelerate insulin
dissociation from the receptor
The accelerated receptor degradation has been
found to be responsible for a decreased number of
receptors. The effect of acidic pH to accelerate
insulin dissociation from the receptor is markedly
reduced, leading to an inhibition of receptor
recycling and acceleration of receptor degradation
(Serrano et al., 1992).
We have demonstrated an increase in pH (acidosis)
in the experimental scorpion envenoming (Radha
Krishna Murthy et al., 1988 a).
8.19 Catecholamines induce inhibition of
tyrosine Kinase activity
In addition to animal studies, several in vitro
models of insulin resistance suggest defects in the

193

receptor Kinase activity. Catecholamines induce a

90% inhibition of the tyrosine Kinase activity
(Serrano et al., 1992).
8.20 Tissue insensitivity to insulin
Tissue insensitivity to insulin is an important
pathogenic disturbance that contributes to glucose
intolerance (Bondy and Rosenberg, 1980; Serrano
et al., 1992).
8.21 Tissue insensitivity to insulin in the
basal state
In the basal state, the liver represents a major state
of insulin resistance. This is reflected by an
overproduction of glucose despite the presence of
fasting hyperglycemia and hyperinsulinemia
(Defronzo, 1987).
8.22 Tissue insensitivity to insulin in the
insulin- resistance state
In the insulin-resistance state, muscle is the primary
tissue responsible for insulin resistance (Defronzo,
1987). Severe scorpion envenoming syndrome is
thus a syndrome of fuel-energy deficits and an
inability of the vital organs to utilize the existing
metabolic substrates. This ultimately may result in
Multi-System-Organ-Failure (MSOF) and death.
These changes are brought about by a massive
release of catecholamines, Angiotensin II, glucagon,
Glucagon, Glucocorticoids, and either insulin
deficiency, suppressed insulin secretion, or insulin
resistance.
8.23 Counter-regulatory hormones in
scorpion
envenoming
syndrome

antagonistic to insulin
Knowledge of hormonal interactions have shown
that the disease Diabetes mellitus is not due solely
to insulin deficiency but also to the actions of
hormones, such as glucagon, Growth hormone and
glucocorticoids, which are many ways antagonistic
to insulin (Keele, Neil and Joels 2000).
9.0 Central role of the adipocyte in insulin
resistance
Insulin acts slowly in vivo, but rapidly in vitro,
suggesting that the pathway insulin traverses from
beta cell of the endocrine pancreas to insulin
sensitive tissue may be altered. Insulin resistance
may result from reduced capillary permeability to
insulin. The transport of insulin across the
endothelial barrier not only limits the rate of insulin
to stimulate glucose uptake by skeletal muscle, but
appears to determine the rate at which insulin
suppresses liver glucose output. Because the liver
circulation is fenestrated, it is not possible that
insulin transport into the liver is the rate
determining step for suppression of liver glucose
output. Insulin is transported into an extra-hepatic
tissue (Ramnanan et al., 2012).
Ph ton

9.1 "Second signal" is generated by the

extra-hepatic tissue
A "second signal" is generated by the extra-hepatic
tissue, the signal is released into the blood, and the
signal in turn controls hepatic glucose output.
9.2 Second signal is FFA
The second signal is free fatty acids (FFA). Insulin,
by regulating adipocyte lipolysis, controls liver
glucose production. Thus, the adipocyte is a critical
mediator between insulin and liver glucose output.
Evidence that FFA also suppress skeletal muscle
glucose uptake and insulin secretion from the B-cell
supports the overall central role of the adipocyte in
the regulation of glycemia.
9.3 Insulin resistance at the fat cell
Insulin resistance at the fat cell may be an important
component of the overall regulation of glycemia
because of the relationships between FFA and
glucose production, glucose uptake, and insulin
release. It is possible that insulin resistance at the
adipocyte itself can be a major cause of the
dysregulation
of
carbohydrate
metabolism
(Bergman and Mittelman, 1998).
9.4 Hepatic insulin resistance
Insulin is a primary regulator of hepatic glucose
metabolism in healthy individuals. Failure of the
liver to appropriately respond to insulin (hepatic
insulin resistance) is an underlying cause of the
increased hepatic glucose production (HGP).
Insulin is known to rapidly suppress hepatic glucose
production (HGP) through its direct action at the
liver, as well as through indirect effects thought to
be mediated primarily at adipose tissue and the cell.
Insulin signaling in the central nervous system
(CNS) has the ability to modify neural input to the
liver, and as a result, to suppress hepatic glucose
production (HGP). CNS insulin action has been
suggested to suppress adipose tissue lipolysis and cell glucagon secretion, thereby providing
additional potential mechanisms for central control
of HGP.
9.5 Activation of the insulin-brain-liver
signaling axis
The activation of the insulin-brain-liver signaling
axis is required for the rapid action of insulin on
glucose production. CNS insulin action plays a role
in the suppression of HGP.
The insulin-driven suppression of lipolysis (and not
CNS insulin-driven input to the liver) is responsible
for the acute inhibition of hepatic glucose
production in response to modest non-hepatic
hyperinsulinemia (Ramnanan et al., 2012).

194

9.6 Acute brain insulin action in rodents

In rodents, acute brain insulin action reduces blood
glucose levels by suppressing the expression of
enzymes in the hepatic gluconeogenic pathway,
thereby reducing gluconeogenesis and endogenous
glucose production (EGP).
9.7 Acute brain insulin action in canine
The canine brain senses physiologic elevations in
plasma insulin, and that this in turn regulates
genetic events in the liver. In the context of basal
insulin and glucagon levels at the liver, this input
augments hepatic glucose uptake and glycogen
synthesis, reducing net hepatic glucose output
(NHGO) without altering EGP (Ramnanan et al.,
2011).
9.8 Insulin's central effects are redundant in
acute regulation of hepatic glucose
metabolism
Although the canine brain can sense insulin and,
thereby, regulate hepatic gluco-regulatory enzyme
expression, CNS insulin action is not essential for
the rapid suppression of glucose production caused
by the hormone. Insulin's direct hepatic effects are
dominant, thus it appears that insulin's central
effects are redundant in the acute regulation of
hepatic glucose metabolism (Ramnanan et al.,
2012).
9.9 Sympathetic nervous system regulates
adipo-cytokines
Scorpion venoms induce systemic inflammation
associated with an increase in cytokine release and
chemokine production. Androctonus australis
hector (Aah) venom induces high plasma
concentrations of pro-inflammatory cytokines IL1, IL-6 and TNF-, and increased sympathetic
tone. Sympathetic nervous system regulates the
expression of several adipo-cytokines through
adipocyte beta-adrenergic receptor (Ait-Lounis and
Laraba-Djeban, 2012).
9.10 Adipose tissue secretes various
cytokines
Adipose tissue secretes various cytokines TNF-,
IL-6 and adipokines such as leptin and adiponectin.
These are involved in glucose metabolism and
insulin resistance. Overproduction of TNF- in both
adipose tissue and skeletal muscle contributes to
insulin resistance.
9.11 TNF- can induce insulin resistance
TNF- can stimulate the production of other
cytokines and chemokines, such as IL-6 and
Monocyte Chemoattractant Protein 1 (MCP1),
which can induce insulin resistance. TNF-
selectively stimulates the expression of a key
component of its own signaling pathway, MitogenPh ton

activated protein 4 kinase isoform 4 (Map4k4),

through a TNFR1-dependent mechanism to induce
insulin resistance in adipose tissue (Ait-Lounis and
Laraba-Djeban, 2012).
9.12 Hyperglycemia and hyperinsulinemia
We
have
reported
hyperglycemia
and
hyperinsulinemia in our experimental animals after
scorpion envenoming (Radha Krishna Murthy, 2014
a; b; c; d; e; 2002; 2000; Radha Krishna Murthy and
Haghnazari, 1999; Radha Krishna Murthy et al.,
2003; 1992 a; b; 1991; 1990; 1988 a; b; c; 1986 a;
b; c).
9.13 Glucose intoleranc
We have reported hyperinsulinemia in our
experimental animals (Radha Krishna Murthy, 2014
a; b; c; d; e; 2002; 2000; Radha Krishna Murthy and
Haghnazari, 1999; Radha Krishna Murthy et al.,
2003; 1992 a; b; 1991; 1990; 1988 a; b; c; 1986 a;
b; c). The plasma insulin concentration increased
(hyperinsulinemia) in mice injected with Aah
venom. Aah venom blocks the action of insulin,
resulting in glucose intolerance (Ait-Lounis and
Laraba-Djeban, 2012).
9.14 Adipose tissue inflammation in
scorpion venom
IL-1, IL-6 and TNF- concentration in adipose
tissue were increased 24 hours after envenomation.
These findings demonstrate that there is a local
inflammatory profile in adipose tissue 24 hours
following scorpion envenoming (Ait-Lounis and
Laraba-Djeban, 2012).
9.15 Scorpion venom increase the TNF- in
Quadriceps skeletal muscle
TNF- concentration was higher in animals injected
with venom or its toxic fraction 24 hours postenvenomation (Ait-Lounis and Laraba-Djeban,
2012).
9.16 TNF- and IL-1 work synergistically to
cause insulin resistance
It is likely that several cytokines act collectively to
amplify the inflammatory response of adipose
tissue. The concentrations of TNF-, IL-6 and IL-1
in adipose tissue were increased by venom. IL-1
and TNF- act synergistically in adipose tissue to
enhance secretion of IL-6. TNF- induced IL-6 is in
part mediated by IL-1. TNF- induces IL-6
secretion in adipose tissue and skeletal muscle.
Increased IL-6 expression in adipose tissue after
envenomation may be due to TNF- production.
TNF- and IL-1 work synergistically to cause
insulin resistance.
9.17 Mechanisms of activation of proinflammatory cytokines
Sympathetic nervous system regulates lipolysis, fat

195

cell number, secretion of some adipocytokines. The

following could be the mechanisms of activation of
pro-inflammatory cytokines in adipose tissue
following envenomation.
Adipose tissue is innervated by the sympathetic
nervous system. Sympathetic nervous system can
regulate lipolysis, fat cell number, and the secretion
of some adipocytokines, such as TNF- and MCPI.
The activity of the sympathetic nervous system
increases following envenomation releasing
massive quantities of catecholamines (Ahmed et al.,
2015; Elatrous et al., 2015; Freire-Maia et al., 1994;
Gueron and Weizman, 1968; Gueron et al., 1992;
Ismail, 1993). In addition, the activity of
sympathetic nervous system can contribute to
insulin resistance through effects of catecholamines
on adipocytes. The expression of adipocytokines is
regulated through -adrenergic receptors. The
lipolytic action of venom mainly involves the 2/1
subtype of adrenergic receptors (Ait-Lounis and
Laraba-Djeban, 2012).
9.18 Adipocyte is a critical mediator
between insulin and liver glucose output
Adipocyte is a critical mediator between insulin and
liver glucose output. FFA also suppresses skeletal
muscle glucose uptake and insulin secretion from
the B-cell of the pancreas. This indicates the overall
central role of the adipocyte in the regulation of
glycemia.
9.19 Insulin resistance at the adipocyte
itself can be a major cause of the
dysregulation of carbohydrate metabolism
Insulin resistance at the fat cell may be an important
component of the overall regulation of glycemia
because of the relationships between FFA and
glucose production, glucose uptake, and insulin
release. It is possible that insulin resistance at the
adipocyte itself can be a major cause of the
dysregulation
of
carbohydrate
metabolism
(Bergman and Mittelman, 1998).
9.20 Insulin resistance syndrome
Insulin resistance causes many metabolic
abnormalities. These are collectively known as the
insulin resistance syndrome.
9.21 Insulin-sensitising mechanism
Reduced FFA availability from adipose tissues to
liver and skeletal muscle is a pivotal component of
the insulin-sensitising mechanism in liver and
skeletal muscle. Adipocytes secrete multiple
proteins which regulate insulin signalling and
impact on abnormalities of the insulin resistance
syndrome.

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9.22 Low plasma adiponectin is associated

with insulin resistance
Low plasma adiponectin is associated with insulin
resistance. Like FFA, adiponectin is probably an
important signalling molecule regulating insulin
sensitivity in muscle and liver. Adipocyte
production of Plasminogen Activator Inhibitor-1
(PAI-1), an inhibitor of fibrinolysis, and angiotensin
II secretion are partially corrected by PPAR
activation (Greisen et al., 2001).
9.23
Uncontrolled
release
of
proinflammatory mediators - generalized
inflammation & MSOF
The signs and symptoms of Ts envenoming involve
intense activation of the immune system with the
release of mainly proinflammatory cytokines such
as TNF-, IL-6, INF- and other mediators such as
leukotriene B4 and prostaglandin E2. The
uncontrolled release of pro-inflammatory mediators
by macrophages can induce a generalized
inflammation that can lead to multi organ failure.
Tityus serrulatus alpha-like toxin, Ts5 causes an
increase in vitro of IL-1- , IL-6, and TNF-
production in vitro and in vivo (Pucca et al., 2015).
9.24 Painful trauma - disturbed metabolic
state with impaired insulin sensitivity
Painful trauma results in a disturbed metabolic state
with impaired insulin sensitivity, which is related to
the magnitude of the trauma. Pain reduced wholebody insulin-stimulated glucose uptake because of a
decrease in non-oxidative glucose disposal. The
suppression of isotopically determined endogenous
glucose output during hyperinsulinemia tended to
be decreased after pain.
Pain elicited a twofold to threefold increase in
serum cortisol, plasma epinephrine, and serum free
fatty acids. Similarly, circulating concentrations of
glucagon and growth hormone tended to increase
during pain (Greisen et al., 2001).
9.25 Acute severe pain decreases insulin
sensitivity
Acute severe pain decreases insulin sensitivity,
primarily by affecting non-oxidative glucose
metabolism. Counter regulatory hormonal response
plays an important role. This may indicate that pain
relief in stress states is important for maintenance of
normal glucose metabolism.
9.26 Impaired insulin action resides in
skeletal muscle
The impaired insulin action after pain probably
resides in skeletal muscle. Defects in both skeletal
muscle GLUT-4 translocation and glycogen
synthase activity could be the intracellular
mechanisms of the impairment of insulin action

196

immediately after surgery (Greisen et al., 2001).

9.27 Non-glucose actions of insulin
Insulin has many non-glucose actions. It acts
anabolically on protein and fat metabolism and has
many other actions, such as on water and salt, the
autonomic and central nervous systems, and
vascular and thermogenesis homeostasis (Ferrannini
et al., 1999). It is tempting to suggest that pain may
induce alterations in sensitivity to many of these
insulin actions as well as to the insulin-stimulated
glucose disposal.
The release of hormones and free fatty acids may in
part explain the decrease in insulin sensitivity,
suggested also by the notion of the hormones
working in an additive manner on glucose
metabolism.
Another possible mediator of the response to pain is
neural signaling with nociceptive afferent impulses
to the central nervous system and sympathetic
efferent impulses to the muscles and the liver.
Sympathetic nerve activity in the liver causes
increased glucose release from the hepatocytes.
Cytokines could also be candidates for such
mediation, as they have been shown to increase
after surgery and to induce insulin resistance.
Normally, the development of insulin resistance is
taken to be an unfavorable sign. It invariably
coexists with stressful situations.
10.0 Administration of insulin in scorpion
envenoming syndrome
We were the first to report and demonstrated that
the administration of insulin alone (Radha Krishna
Murthy et al., 1990) or insulin and alpha-blocker
(Radha Krishna Murthy et al., 1988 a) successfully
reversed metabolic and ECG changes in
experimental scorpion envenoming. Insulin
administration along with alpha-blocker (Radha
Krishna Murthy et al., 1988 a) produced more
glycogenesis and lipogenesis and reversed the rise
in plasma angiotensin II levels (Radha Krishna
Murthy et al., 1988 b; c; d) than insulin
administration alone. However, alpha-blockers are
known to stimulate the gastric acid secretion; this
may in turn, aggravate the existing sub-clinical or
clinical acute pancreatitis known to occur in some
patients, in to a fully blown-up fulminating acute
pancreatitis in some scorpion sting victims.
We have demonstrated experimental acute
pancreatitis and acute myocarditis due to scorpion
envenoming. Sofer and his co-workers (Sofer et al.,
1997; Sofer, 1995; Sofer et al., 1996; Sofer and
Gueron, 1992; Sofer et al., 1991; Sofer and Gueron,
1988; Tarasiuk et al., 1994, Tarasiuk et al., 1997)
observed pancreatitis in their scorpion sting
Ph ton

children. Abdominal and mild epi-gastric pain was

the complaint of 36% patients, and a mild elevation
of serum amylase levels was found in 20% of these
victims.
10.1 Actions of Insulin
Insulin acts on several enzymes. Insulin activates
hexokinase to convert glucose to intracellular
glucose 6-phosphate. Insulin activates glycogen
synthatase and simultaneously inhibits enzymatic
breakdown of glycogen. Insulin enhances the
activity of some glycolytic enzymes and inhibits
enzymes favoring glucose synthesis (Keele, Neil
and Joels 2000).
10.2 Myocardial protective action
Insulin has myocardial protective action, which can
be attributed in part, to its ability to control
hyperglycemia. Insulin has anti-inflammatory
actions and prevents apoptosis of myocardial tissue
that facilitates myocardial recovery from ischemic
insults (Das, 2007; 2001).
10.3 Importance of glycogen in the liver
When liver glycogen is high the rate of deamination of amino acids in the liver is depressed
and the amino acids remain available for protein
synthesis.
A high level of liver glycogen depresses the rate of
ketone formation. A glycogen rich liver is protected
against the harmful effects of many poisons (Keele,
Neil and Joels 2000).
10.4 I.V. inj. of glucose + Insulin - quickest
way of building up liver glycogen
The quickest way of building up liver glycogen, is
by raising the blood glucose level + insulin; this
obviously best done by the intravenous injection
(Keele, Neil and Joels 2000).
10.5 About alpha blockers and scorpion
envenoming syndrome
(a) If stimulation of nerves to the pancreas inhibits
insulin secretion via the release of catecholamines
(via alpha adreno-receptor stimulation to the
pancreas), then it is logical to convert the inhibitory
response to an excitatory response by using alpha
blocking drugs.
(b) Scorpion envenoming causes massive release of
catecholamines and the toxicity is mediated by
alpha and beta adrenergic receptor stimulation. The
Alpha adrenergic blocking action of the released
catecholamines due to scorpion envenoming was
demonstrated by us using Tolazoline Hydrochloride
given intravenously (Radha Krishna Murthy et al.,
1988 a).

197

Figure 1: Pain in scorpion stings Neuro-endocrine Metabolic Changes

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198

Figure 2: Mechanism of effects of severe pain cytokine production insulin resistance - implantation loss and increased risk for neuro developmental disorders in scorpion envenoming
syndrome

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199

Figure 3: Physiological Basis of the Glycogenolysis resulting in Hyperglycemia in scorpion envenoming

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200

Figure 4: Mechanism of glycogenolysis and production of Hyperglycemia Adrenaline and glucagon promote hepatic glycogenolysis by stimulating adenyl cyclase
Adrenaline also activates adenyl cyclase in skeletal muscle. Glucose-6-phosphatase is absent in muscle ATP = Adenosine Triphosphate, C AMP = Cyclic AMP, ACTH= Adrenocorticotropic
Hormone

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201

Figure 5: Hyperglycemia Cytokines-Insulin Resistance in Scorpion Envenoming Syndrome

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202

Ph ton

203

Figure 8: Hyperglycemia - myocardial dysfunction

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204

Figure 9: Actions of TNF-

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205

(c) We chose Insulin (given parenterally) +

Tolazoline Hydrochloride (alpha blocker) (given
parenterally) + Sodium bicarbonate (given
parenterally) to demonstrate the reversal of
metabolic & electrocardiographic changes (Radha
Krishna Murthy et al., 1988 a) and plasma
angiotensin II levels (Radha Krishna Murthy et al.,
1988 b; c,) induced by Indian red scorpion (Buthus
tamulus) venom.
10.6
Insulin
administration
reversed
metabolic changes and other abnormalities
due to envenoming
10.7
Insulin stimulates activation of
glycogen synthatase system
Insulin administration reversed metabolic changes
and other abnormalities due to envenoming (Radha
Krishna Murthy et al., 1988 a; 1990). Insulin
stimulates activation of glycogen synthatase
system. This could be the reason for an increase in
glycogen content of cardiac, skeletal muscles and
liver of the insulin, alpha blocker + sodium
bicarbonate treated animals after envenomation.
Moreover, glycogen availability may be an
important independent determinant of cardiac
function. Elevated glycogen in heart partially
protects against mechanical deterioration in anoxia
(Radha Krishna Murthy, 2014 a; b; c; d; e; 2003;
2002; 2000).
10.8 Insulin stimulates glycogen synthesis
Insulin stimulates glycogen synthesis. Insulin may
reduce c AMP formation in adipose cells. This will
reduce the lipolytic response to adrenaline or
glucagon and favor anabolic processes leading to
synthesis of glycogen. Thus insulin counter-acts the
effects of catecholamines favoring glucose uptake
and inhibition of glucose release from liver. This
could be the reason for an increased glycogen
content of atria, ventricle, liver and skeletal muscle
after insulin administration (Ganong, 1987; Keele,
Neil and Joels 2000).
Recommendations
Treatment using Continuous infusion of regular
crystalline insulin
Use of xylocaine:Avoid using local xylocaine, as
patient complains of more pain after half an hour
once the action of xylocaine wears off. Patients
with systemic manifestations do not complain of
pain. Patients without systemic manifestations and
patients improving from systemic manifestations
complain of pain at the site. Use injection
Diclofenac and injection Tramadol for pain and
reassurance. Sometimes Injection Pentazocine and
Injection Mezolam are required.Continuous
infusion of regular crystalline insulin should be
given at the rate of 0.3 U/g glucose and glucose at
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the rate of 0.1 g/kg body weight/hour, for 48 - 72

hours, with supplementation of potassium as
needed and maintenance of fluid, electrolytes and
acid-base balance.
Special Finding
This Review article will revolutionize the treatment
of the scorpion envenoming syndrome caused by
the poisonous scorpion stings of Buthidae family
distributed in more than 45 developing countries.
This review article will revolutionize the
perception about the new roles of life saving
actions of insulin in different diseases.
Research Highlights
Poisonous scorpion stings result in

Excruciating pain at the site of site of sting

Cause Autonomic storm

Produce an increase in Catecholamines,

Angiotensin
II,
Aldosterone,
Glucagon,
Glucocorticoids, Thyroid hormones,

Suppressed insulin secretion initially

followed by Hyperinsulinemia

Hyperglycemia

Sudden increase in Free Fatty Acids

Cardiac arrhythmias, Conduction defects,

ischemia & infarction changes

Cardiogenic
&
Non-cardiogenic
pulmonary oedema

Sudden increase in Pro-inflammatory

cytokines

Insulin Resistance for endogenously

secreted insulin and result in

Death

Insulin
is
Anti-inflammatory,
Cardio-protective,
Reverses
Metabolic
changes
Insulin administration saves Life
Conclusion
Scorpion envenoming results in an autonomic
storm, massive release of catecholamines,
Angiotensin II, Glucagon, Glucocorticoids; either
suppressed insulin secretion or hyperinsulinemia
causing
hyperglycemia,
pro-inflammatory
cytokines IL-1, IL-1, IL- 4, IL- 6, IL- 10, TNF-
IFN- and NO, insulin resistance, and many
metabolic changes. Under these conditions,
scorpion envenoming syndrome results in fuelenergy
deficits,
Multi-System-Organ-Failure
(MSOF) and death. Administration of insulinglucose infusion to scorpion sting victims appears
to be the physiological basis for the control of the
metabolic response when that has become a
determinant to survival.

206

Authors
interests

contribution

and

competing

Dr. K. Radha Krishna Murthy (Corresponding

author) and all the authors declare that they have no
conflict of interests. All the authors contributed
equally in preparation of the manuscript. All the
authors declare that they comply with the
Principles of Ethical Publishing in the Journal for
Endocrinology and Metabolism.
Acknowledgements
Dr. K. Radha Krishna Murthy (Corresponding
author) and all the authors thank Dr. M.
Santhiramudu and Dr. M. Madhavi Latha for their
encouragement.

Ait-Lounis A., Laraba-Djeban F., 2012. TNF-

involvement in insulin resistance induced by
experimental scorpion envenomation. Plos negl Tropical
Disease, 6 No.7; e1740. Published online July 17, 2012.
doi.:10.1371/journal.pntd.0001740 PMCD:PMC3398957
Aljada A., Osende J.I., Mohanty P., Kapur, N., Dandona
P., 2002. Insulin inhibits the pro-inflammatory
transcription factor early growth response gene-1 (Egr-1)
expression in mononuclear cells (MNC) and reduces
plasma tissue factor (TF) and plasminogen activator
inhibitor-1 (PAI-1) concentrations. Journal of Clinical
Endocrinology and Metabolism, 87, 1419-1422.
Aljada A., Saadesh R., Ghanim H., Hamouda W., Assian
E., Ahmad, S., 2000. Insulin inhibits the expression of
intercellular adhesion molecule-1 by human aortic
endothelial cells through stimulation of nitric oxide.
Journal of Clinical Endocrinology and Metabolism, 85,
2572-2575.

Most important
This Review article will revolutionize the treatment
of the Scorpion Envenoming Syndrome caused
by the poisonous scorpion stings of Buthidae
family distributed in more than 45 developing
countries.This review article will revolutionize the
perception about the new roles of life saving
actions of insulin in different diseases.
Poisonous scorpion stings result in Excruciating
pain at the site of site of sting Cause Autonomic
storm Produce an increase in Catecholamines,
Angiotensin
II,
Aldosterone,
Glucagon,
Glucocorticoids, Thyroid hormones, initially
suppressed insulin secretion followed by
Hyperinsulinemia Hyperglycemia Sudden increase
in Free Fatty Acids

Cardiac arrhythmias, Conduction defects,

ischemia & infarction changes

Cardiogenic
&
Non-cardiogenic
pulmonary oedema

Sudden increase in Pro-inflammatory

cytokines
Insulin Resistance for endogenously secreted
insulin and result in
Death
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