Integrative Obesity and Diabetes
Review Article
ISSN: 2056-8827
Extra pancreatic synthesis of insulin
Suman Bhattacharya, Sarbashri Bank, Rajeshwary Ghosh, and Asru K Sinha*
Department of Biochemistry, Sinha Institute of Medical Science and Technology, Kolkata, West Bengal, India
Abstract
It is currently believed that insulin, an essential hormone for carbohydrate metabolism, is produced only in the pancreas. Many investigators on the other hand had
reported that various cells in different organs of the body beside pancreas are also capable of synthesizing insulin. This hormone not only has a critical role in the
carbohydrate metabolism, but the protein is also reported to prevent the atherosclerosis and hypertension. The multifunctional synthesis of the protein in different
cells in various organs is presented in the review. Insulin was reported to be synthesized in the liver, brain, thymus, adipocytes, gastrointestinal tract, bone marrow
and in the leukocytes. Insulin synthesis was confirmed by cDNA analysis, amino acid sequence and by bioassay of the hormone. Liver was found to synthesize insulin,
and glucose was found to stimulate NO synthesis in the liver and NO thus produced stimulated insulin and Glut-4 synthesis in the liver. Insulin synthesis occurs not
only in human but also all animals. The lymphocytes and the leucocytes in the circulation were found to synthesize insulin. It is possible that synthesis of insulin in
leucocytes could be involved for the ready supply of insulin in the prevention of thrombosis in platelets which did not produce any insulin. The synthesis of insulin in
different organs in many different animals has also been reported. It was concluded that the synthesis of insulin in different cells was essential to maintain the cellular
integrity from carbohydrate derived energy for all living organisms.
Introduction
Ever since the discovery of insulin in 1921 by Best and Benting
[1,2], an essential hormone for the systemic carbohydrate homeostasis,
a protein, which was first to be determined for its chemical structure
and molecular weight [3-5], remains in the public mind, in general, as a
pancreatic protein. However there is no binding reason that the protein
hormone could not be synthesized in other organ than pancreas only. It
should be noted here that the gene-make up of all cells in any particular
organism is identical, suggesting that a particular gene responsible for
the expression of a particular protein in any cells would have the same
gene in all other cells as well. The expression of all protein in cells is not
possible due to the fact the gene expression of any protein is not only
a multistep process, but a particular stimulus is needed to initiate the
synthesis of a particular protein. For example, it should be mentioned
here that the amylase produced in the parotid gland is identical to the
amylase produced by pancreas [6,7]. Although insulin production
was first identified in the pancreatic β cells [8,9] the synthesis of this
protein identical to that in the pancreas has been reported to occur in
many other organs and isolated cells beside pancreas in more recent
time. This review summarizes some of these new findings related to the
synthesis of the hormone in different organs.
It should be mentioned that the role of insulin in different
metabolic and pathologic processes is so diverse that the effects of any
other known hormone can be comparable to those of the hypoglycemic
protein. The effect of insulin is not only essential to the carbohydrate
metabolism but the hormone has critically important role ranging
from the control of hypertension to the prevention of atherosclerosis
leading to prothrombotic disorder to neuropathy [10-15]. Almost
all life threatening diseases are further aggravated by the systemic
reduction of insulin level.
Integr Obesity Diabetes, 2015
doi: 10.15761/IOD.1000138
Extra pancreatic synthesis of insulin in different tissues
and organs of human, animals and plant kingdom
Plant kingdom
It should also be mentioned that not a single form of life in the
animal kingdom is known that does not need the hypoglycemic
hormone [16,17], even yeast is also known to possess insulin receptor:
we have found that the garlic (Allium sativum) bulbs has insulin like
molecule (unpublished). As garlic plant is 500 million years old in the
evolutionary tree it may indicate that insulin was a present even in the
earliest period of life in earth.
Human and animal kingdom
In humans, a survey in the literature demonstrated the synthesis of
the hormone in different cells including 1. Pancreas [18-20], 2. Liver
[21-23], 3. Thymus [24], 4. Lymphocytes [23], 5. Brain and neurons
[25-27], 6. Pituitary [25], 7. Hypothalamus [25], 8. Jejunum [28], 9.
Ileum [28], 10. Ceccum [28], 11. Adipocyte [24], 12. Spleen [24], 13.
Bone marrow [24]. This list is not however complete, it is possible that
there are many other cells capable of synthesizing insulin remain to be
identified. The synthetic ability of some of above organs and their cells
are briefly described below.
Pancreas: The pancreas was probably earliest organ identified
Correspondence to: Asru K Sinha, Sinha Institute of Medical Science and
Technology, 288, Kendua main road, Garia, 700 084, India, Tel: +91-9903792100,
Fax: +91-33-24127905; E-mail: [email protected]
Key words: insulin, liver, brain, nitric oxide, glut-4, leucocytes, thymus, adipocyte
Received: December 12, 2015; Accepted: January 02, 2016; Published: January
05, 2016
Volume 2(1): 176-179
Bhattacharya S (2015) Extra pancreatic synthesis of insulin
to synthesize insulin in its β cells. There are extensive literature are
available are available in this area [8,9].
Liver: Indirect evidences are available for many years that liver
disease including liver fibrosis (i,e the replacement of hepatocytes
by fibroblast [29]) infection with hepatic viruses were able to cause
diabetic mellitus indicating that normal liver does synthesize insulin
[29]. The hepatocytes from the adult normal liver have also been
reported to synthesis insulin due to the expression of pro insulin genes
in the presence of glucose [21-23]. The presence of stress induced
protein identified to be dermcidin isoform-2 (Mr. 11Kda) in the liver
has been reported to inhibit insulin synthesis in the presence of glucose
to maintain the systemic glucose homeostasis [30,31].
The liver is unique in its ability to synthesize insulin, in that most
of the pancreatic insulin received by the liver is destroyed, and for the
synthesis of glycogen (an insulin dependent process), the liver is capable
of synthesizing its own insulin [21-23,32-34]. The influx of glucose into
the hepatic cells is facilitated by the synthesis of Glut-4 by glucose itself
through the synthesis of NO [35], similar to the case of adipocytes,
independent of pancreatic insulin [36,37]. Indeed the adult hepatic
stem cells can trans differentiate into pancreatic insulin producing cells
[22]. The rat liver insulin has been reported to be indistinguishable
from the pancreatic insulin as determined by different analytical
methods [23]. However the insulin receptors in adipocytes, and in the
liver membrane has been reported to be different [38,39], the role of
glucose as the initiator of insulin synthesis and release in the pancreatic
β cells are well known [8,9]. In the case of liver cells glucose has an
even more unique role in the synthesis of secretion of insulin in that for
the synthesis of insulin in the liver cells the presence of both NO and
glucose are needed. The glucose was found to activate a constitutive
form of nitric oxide synthase [GANOS, (glucose activated nitric oxide
synthase)] that is essential for the synthesis of insulin through the
synthesis of NO [35].
That NO has an essential role in the glucose induced insulin
synthesis was further supported by the effect of estrogen or
progesterone that was found to stimulate NO level at nM ranges [40].
As such, the treatment of alloxan treated type I diabetic mice model, by
the injection of 3.5 µM estriol or even 3.5 nM progesterone was found
to stimulate insulin synthesis even in these mice when the pancreas
itself failed to synthesis any insulin [40]. These results demonstrated
that in the presence of glucose and NO, the insulin synthesis can be
“switched” over from the pancreas to liver in type I diabetes at least in
the mice model. The reason for the failure of liver to synthesize insulin
in the presence of glucose alone was determined to the presence of
high amount of dermcidin isoform-2, a potent inhibitor of all forms
of NOS. The inhibition of dermcidin by its antibody was found to be
capable of inducing insulin synthesis in liver in the presence of glucose
(unpublished). The involvement of dermcidin isoform-2, NO, glucose
and Glut-4 (glucose transporter-4) is described diagrammatically in
the (Figure 1).
Brain: Experiments using complementary DNA (cDNA) had
demonstrated that adult human brain transcribes insulin mRNA
encoding insulin as determined by PCR [25]. The pathogenesis
of Alzheimer disease has been reported to be related to type II
diabetes mellitus like condition in human brain [41,42]. In animals
the expression of insulin gene was also found. The impaired insulin
synthesis in brain has been related to the development of Alzheimer
disease in brain in human [43]. The treatment of adult mice brain
with glucose was similarly found to synthesize insulin as determined
Integr Obesity Diabetes, 2015
doi: 10.15761/IOD.1000138
Figure 1. Diagrammatical representation of the role of glucose, nitric oxide (NO), dermcidin
isoform-2 and Glut-4 in the synthesis of insulin in hepatocytes.
by in vitro translation of insulin mRNA (unpublished). Insulin gene
is reported to be expressed in pituitary cells in the brain of tilapia fish
in greater quantity than that in hypothalamus [25]. Insulin has also
been reported to be released from neuronal cells in culture by the
depolarization induced by K+ [27] and in the cloned rabbit neuronal
cells through the synthesis of insulin mRNA in post natal rabbit brain
[26].
Insulin synthesis in the cells in lymphocytes and leucocytes in
the circulation of human
The deficiency of insulin either is type I diabetes mellitus or in
type II diabetes mellitus is a well-known to be major risk factor for the
development of atherosclerosis leading to acute coronary syndrome,
a major killer disease of the human race [44-47]. The type II diabetes
mellitus has been equated to atherosclerosis and the risk factor like
dyslipidemia (hypercholesterolemia) has been directly related to the
type II diabetes mellitus [48,49]. Insulin has been reported to be a
global antithrombotic humoral factor due to the ability of the hormone
to inhibit platelet aggregation [50]. As human platelets are anucleated
cells and are incapable of synthesizing any protein, it is conceivable
that the other cells in the circulation might provide the much needed
locally available of insulin to prevent the acute coronary syndrome
particularly when pancreatic production of insulin became impaired.
Indeed, the systemic hypoglycemia has been reported to be a risk factor
for acute coronary syndrome [51,52]. It has been reported that IM-9
lymphocytes in culture was capable of synthesizing insulin efficiently
[23]. We have found that leukocytes in the human circulation were
capable of synthesizing insulin in the presence of glucose as evidenced
by in vitro translation of insulin mRNA (unpublished). This review
indicates that the infusion of glucose in the circulation may avert the
impending ACS (acute coronary syndrome) through the increase
synthesis of insulin in the leukocytes that would inhibit the platelet
aggregation to inhibit the condition.
Volume 2(1): 176-179
Bhattacharya S (2015) Extra pancreatic synthesis of insulin
Discussion
In this article we have tried to present a general overview of the
information regarding the extra pancreatic synthesis of insulin in
human as well as in other forms of life. Insulin is a well-known hormone
appreciated for carbohydrate metabolism in diabetes mellitus only but
that the hormone is also involved in the prevention of thrombosis
[50,53], stroke (both ischemic and hemorrhagic) [54], hypertension
[55], Alzheimer’s disease remains largely unappreciated [56]. Also,
semantically (the meaning of the word) “insulin” became largely
inappropriate in that the word insulin originated from the “insula” in
the islets of langerhans. Hundreds of researchers from different parts
of the world had reported that insulin is also produced by different
organs and cells of the body. And, as such, the word insulin is perhaps
somewhat inappropriate, and perhaps has only “historical value”. In
this context, it should be mentioned here that no other hormone in
the animal kingdom has so many different functions both in the health
and in diseases. The hormone is so essential for the maintenance for
the life that even when insulin is injected in the system. The antibody
against the hormone which is rapidly synthesized in the system does
not interfere with the effect of insulin when the hormone was reinjected in the system. It should also be mentioned that the synthesis of
other hormone and protein are sometimes occurred in the different site
than the classically assigned issue. For example, synthesis of estrogens
not only occurs in ovary but also in the fat cells and, similarly amylase
not only produced in the parotid gland but the same amylase is also
produced in the pancreatic cells. In that sense it would be unusual to
think that a multifunctional insulin should be produced only in the
pancreas.
Obviously, the list of organs that can synthesize insulin is not
complete at present, as many more new discoveries will come to help
our understanding of the fascinating hypoglycemic protein, a major
transducer of energy from the carbohydrates releasing solar energy
trapped in the molecules produced by photosynthesis. However, the
time has come to go beyond the belief that pancreas is the only source
of the protein hormone as the pancreas was found to be only one of
the many organs and tissues werecapable of producing insulin for the
maintenance of life process as a whole. It should be mentioned here
that for the synthesis of the proteins, the information molecules of the
genes, the required energy is derived from the hydrolysis of 4 phosphate
bonds, particularly that from ATP and GTP for the synthesis of a
single peptide bond. The above issue on the essential role of insulin in
living systems however immediately brings forth the question why the
hormone is so important for the survival of all forms of lives? The issue
could be answered, at least partly, that all cells and its components are
spontaneously degrading due to constant wear and tear of the proteins
and the “ordered” cell structure is continuously becoming “disordered”
(i,e the change of “entropy”) and the availability of the energy supply
is essential to change the “disordered” condition to its “ordered” form
obeying the 2nd law of thermodynamics which cannot be violated.
Insulin is perhaps the most important transducer for the production
of energy from the carbohydrates. It could be suggested that for the
maximum efficiency of the energy transduction from the carbohydrate,
insulin synthesis was made available in different tissues and cells in the
evolutionary process for the ready supply of the energy transducer at
demand.
It can be hypothesized that the protein (insulin) has so many diverse
activities that should be produced only in the pancreas only to meet the
multitude of physiologic/metabolic demands as presented in the text
would be very unlikely. This is the only hormone known currently to be
Integr Obesity Diabetes, 2015
doi: 10.15761/IOD.1000138
present in the numerous cells to carry out functions in cells to meet the
immediate need without depending on the pancreatic supply of insulin
for the energy transduction and for maintaining cellular integrity.
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Copyright: ©2015 Bhattacharya S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Integr Obesity Diabetes, 2015
doi: 10.15761/IOD.1000138
Volume 2(1): 176-179