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NUTRIENT INDUCED INSULIN SECRETION: SIGNAL
TRANSDUCTION MECHANISMS
Akhila Gungi
08311a2305
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SREENIDHI INSTITUTE OF SCIENCE AND TECHNOLOGY
YAMNAMPET, GHATKESAR, HYDERABAD-501301.
Department of Biotechnology
CERTIFICATE
This is to certify that Ms Gungi Akhila bearing Roll No. 08311A2305 has submitted
Technical report entitled Nutrient Induced Insulin Secretion: Signal TransductionMechanisms in partial fulfilment for the award of Bachelor of Technology degree in
Biotechnology to Jawaharlal Nehru Technological University Hyderabad.
Seminar Supervisor Senior Faculty Member H.O.D.Biotechnology
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NUTRIENT INDUCED INSULIN SECRETION: SIGNAL
TRANSDUCTION MECHANISMS
Akhila.G, 08311A2305
ABSTRACT
Type 2 diabetes arises from a combination of impaired insulin action and defective pancreatic -cell
function. Classically, the two abnormalities have been viewed as distinct yet mutually detrimental
processes. The combination of impaired insulin-dependent glucose metabolism in skeletal muscle and
impaired -cell function causes an increase of hepatic glucose production, leading to a constellation of
tissue abnormalities that has been referred to as the diabetes "ruling triumvirate." And Type II Diabetes is
one of the leading diseases in todays world filled with unhealthy food habits and stress filled lives.
Therefore it is important to look into this disease and try and reduce its impact and if possible also find a
cure. Till today the only treatment that was available for Diabetes Mellitus was controlling the peripheral
blood glucose levels by various methods. It is hence important to learn about the cell signalling that takes
place in the pancreatic-cells and try and target some specific signals and see if we can rectify the
condition at a molecular level. This report therefore talks about some such signals that are involved in the
Insulin Signaling pathway.
Key Words:
INTRODUCTION
Diabetes mellitus type 2 formerly non-insulin-
dependent diabetes mellitus (NIDDM) or adult-onset diabetes is a metabolic disorder that is
characterized by high blood glucose in the context
of insulin resistance and relative insulin deficiency.
This is in contrast to diabetes mellitus type 1 in
which there is an absolute insulin deficiency due to
destruction of islet cells in the pancreas. (1)
Figure 1: Universal blue circle symbol for diabetes.
It has been classically thought that Type II Diabetes
is the insulin resistance developed by the skeletal
muscle and adipose tissue, be it on a genetic or on
an environmental basis to insulin-dependentglucose uptake and nonoxidative disposal.
However, the onset of hyperglycaemia reflects two
separate events occurring at different sites, namely
a failure of the -cell's compensatory ability with an
attendant rise in hepatic glucose production. In this
context, hyperglycaemia is viewed as a vicarious
mechanism to promote peripheral glucose
utilization by mass action, in the face of insulin
resistance. And paradoxically, even though insulin-
resistance is seen first in the muscle and adipose
tissues, Diabetes is actually a disease of the liverand pancreatic -cells. The hyperglycaemia is seenmore in these areas. (2).
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INSULIN SECRETION
The secretion of insulin by the pancreatic beta cell
is modulated by various nutrients, neurotransmitters
and peptide hormones. And in-vitro it has been seen
that glucose is the only secretagogue that can
induce Insulin from pancreatic -cells. But actuallymany other molecules like fats, peptides, peptide
hormones and neurotransmitters can influence this
process. Therefore the islets of Langerhans are
viewed as a fuel sensor which simultaneously
integrates the signals of many nutrients and
modulators to secrete insulin according to the needs
of the organism. The unique feature of the
pancreatic -cell is that it possesses a transduction
system for calorigenic nutrient signals which is
entirely different from that of neuromodulators or
peptide hormones. Indeed, fuel stimuli must be
metabolised in the beta cell to cause secretion. By
contrast, neuromodulators, such as the potentincretin GLP-I, influence the secretory process
following their interaction with specific cell-surface
receptors. (3)
Figure 2 : Model illustrating the role of glycolytic oscillations and the two arms in beta-cell signalling. Oscillations in the
metabolism of glucose generate oscillatory O2 consumption, cytosolic ATP/ADP ratio, K+
ATP channel opening
probability, membrane potential fluctuations and free Ca2+ in the cytoplasm. On the other hand, glucose-derived
pyruvate is carboxylated to oxaloacetate by pyruvate carboxylase. This anaplerotic reaction favours the formation of
malonyl-CoA by acetyl-CoA carboxylase. Malonyl-CoA in turn inhibits carnitine palmitoyl-transferase I with a
resulting elevation of long chain acyl- CoA esters in the cytoplasm. Elevated free Ca 2+ and fatty acyl-CoA synergize to
cause full induction of insulin release. (3)
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Despite several efforts, the complete cracking of the
code of Signal transduction of Insulin secretion
induced by glucose has not yet been discovered. An
important reason behind this is that glucose is
involved in both metabolism and in signalling, and
the interrelated role of these two actions is difficult
to determine.
Until now the accepted signal transduction that
takes place was as follows.
Figure 3 : Release of Insulin from Pancreatic -cells on glucose input as a signal.
Initially due to glucose intake, and metabolism of
glucose ATP is generated in the cell. Then
metabolically sensitive K+-channels close in
response to physiological variations of ATP and/or
ADP with resulting opening of voltage-gated Ca2+
channels. As a consequence of Ca2+
influx,
cytosolic Ca2+
rises which triggers the exocytotic
release of insulin. However, the recent evidenceindicates that the picture may be more complex and
that what may be named the KATP/Ca2+ pathway
does not fully account for the action of nutrient
stimuli. Indeed, K+-induced insulin secretion, which
elevates Ca2+
maximally, causes transient secretion
of insulin whereas glucose-induced secretion is
sustained.
There are many other signals other than glucose
which influence the release of Insulin from the -
pancreatic cells.
They are molecules like:
Glucagon GLP-1 Gastric Inhibitory Polypeptide Vasoactive Intestinal Polypeptide Cholecystokinin Arginine Vasopressin Acetylcholine Epinephrine Somatostatin Calcitonin gene related Peptide Galanin
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All the above molecules are hormones and
neurotransmitter molecules.
In this report, the Glucagon like peptide has been
highlighted and its pathway of transduction has
been discussed.
GLUCOSE COMPETENCE
The functional consequences of bidirectional
crosstalk in the -cell system are easiest to
understand from the standpoint of the glucose
competence concept. By definition, -cells will
secrete insulin in response to glucose only when
they are glucose-competent. By contrast,
diminished glucose-induced insulin secretion is
typical of single -cells maintained in primary cellculture, and is characteristic of foetal -cells in
which the glucose-signalling system is
incompletely developed. It is also symptomatic of
the metabolic disorder of glucose homeostasis
known as Type II diabetes mellitus in which the -
cell glucose signalling system becomes impaired.
Under these less than optimal conditions -cells can
be viewed as relatively glucose-incompetent. The
induction of glucose competence is proposed to
result from the conditioning influences of
circulating insulinotropic hormones which renderthe -cell glucose-signalling system capable of
responding to glucose. Glucose competence may
therefore be envisioned as a metabolic state in
which the glucose signalling system is fully
primed and ready to go. (4)
INCRETIN EFFECT
The incretin effect is defined as the observation thatintestinally derived factors released in response to
oral glucose or nutrients augment glucose-
stimulated insulin secretion. The not - yet -
identified intestinal factors were termed incretins,
which stimulate the sec ret ions of the endocrine
pancreas. The first incretin to be identified was GIP
(Gastric inhibitory polypeptide) which has a role in
inhibiting gastric motility and acid secretion.
GLUCAGON & GLUCAGON LIKE PEPTIDE
(GLP-1)
The search for intestinal incretins in addition to GIPwas rewarded in 1982, 10 years after the isolation
of GIP from extracts of intestines, by a finding
arising from the experiment al approach of reverse
genetics. The cloning of the complementary DNAs
(cDNAs) encoding the proglucagon of the
anglerfish followed by cloning of the mammalian
proglucagon c DNAs and genes, predicted the
encodement of two new glucagon- related peptides
in addition to glucagon in the proglucagon
prohormone.
Glucagon is a hormone that plays a very important
role both in release of glucose by hepatic cells and
release of insulin in pancreatic cells. Glucagon-like
peptide-1 (GLP-1) is derived from the transcription
product of the proglucagon gene. The major source
of GLP-1 in the body is the intestinal L cell that
secretes GLP-1 as a gut hormone.
Both are a product of tissue-specific alternative
post-translational processing of proglucagon. The
proteolytic cleavage of the GLP- 1s from theproglucagon in the intestine occurs by a
complicated process. At least fur isopeptides result
from the processing: peptides of 37 and 36 amino
acids, GLP-1(137) and GLP- 1(136) amide, as
well as two amino- terminally truncated
isopeptides, GLP-1(737) and GLP-1(736) amide.
Only the two truncated GLP-1s have insulinotropic
activities. Both isopeptides of active GLP-1, GLP-
1(737) and GLP-1(736) amide have
indistinguishable insulinotropic potencies in all
systems in which they have been studied so far,
including humans. In addition to the intracellular
cleavages of proglucagon that take place within the
intestinal L- cells, an extracellular cleavage of the
first two amino acids of GLP- 1(737) and GLP-
1(736) amide take place by an enzyme known as
Dipeptidyl Peptidase IV (DPIV). Cleavage of GLP-
1 by DPIV attenuates its actions on the GLP- 1
receptor. The GLP-1(937) or GLP- 1(936) amide
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so formed by cleavages by DPIV have weak
antagonist activity. Inhibitors of DPIV potentiate
the insulinotropic activities of GLP-1 (41) and may
be useful in the treatment of type 2 diabetes.
Figure 4 : Alternative posttranslational processing of proglucagon in the pancreas and intestines. The basic amino acidsarginine (R) and lysine (K) are sites for enzymatic cleavages by prohormone convertases in the -cells of the pancreatic
islets and the L cells of the intestine. The major recognized bioactive peptides formed by cleavages are shaded and are
glucagon in the pancreas and the two isoforms of glucagon-like peptide-1 (GLP-1) in the intestines. Shown below is the
amino acid sequence of GLP-1(737) with the sequence of GLP-1(736) amide indicated by the C-terminal Arg-NH2.
Amino acids in boldface type are those in GLP-1 that differ from the corresponding amino acids in the sequence of
glucagon. (4)
STIMULATORY ROLE OF GLP-1 IN
INSULIN SECRETION FROM PANCREATICCELLS
The glucagon- like peptide- 1 has proved to be a
potent glucose- dependent insulinotropic peptide,
distinct from GIP.
GLP-1 is a potent direct stimulator of insulin and
somatostatin secretion from - and -cells,
respectively, and suppresses glucagon secretion
from -cells, either directly or indirectly, by the
paracrine suppressive actions of insulin.
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Figure 5 : Role of GLP-1 in Diabetes
The actions of GLP-1 to stimulate insulin secretionfrom -cells are directly dependent on the glucose
concentrations. The effectiveness of GLP-1 as an
insulin secretagogue increases as the glucose levels
rise and is attenuated as glucose levels fall. This
important property of GLP-1 and the other incretins
such as GIP, to auto regulate the potencies of their
actions on augmenting insulin secretion in step with
ambient glucose concentrations provides a means to
protect against hypoglycaemia. A cellularmechanism in -cells to explain this
interdependence between glucose and GLP-1
actions is described below and involves a synergetic
cross-talk between the glycolysis (glucose
metabolism) and cyclic adenosine monophosphate
(cAMP) signaling pathways. This mutual
interdependence between glucose metabolism and
GLP-1 actions on -cells is referred to as the
glucose competence concept, that is, glucose is
required for -cells to respond to GLP-1, and GLP-
1 (or other incretins) is required to render -cells
competent to respond to glucose.
GLP-1 SIGNALLING PATHWAY IN INSULIN
SECRETION
Soon after GLP-1 was discovered to be a potent
glucose-dependent insulin secretagogue, it was
found that the peptide bound to high-affinity sites
on -cells and stimulated the formation of cAMP ininsulinoma cell lines. These findings indicated that
the hormone acts though specific receptors located
on the surface of -cells that are coupled to the
stimulatory G protein (Gs). The receptor is a
member of the seven membranespanning, G
proteincoupled family of receptors. By sequence
similarities, GLP-1 receptor falls into a new
subclass of receptors that include those for
glucagon, VIP, secretin, GIP, pituitary adenylatecyclase activating peptide (PACAP), growth
hormonereleasing hormone, calcitonin, and
parathyroid hormone. The coupling of GLP-1
receptor to cellular signaling appears to be
primarily mediated by G and the cAMP pathway.
Stimulation of phosphoinositol turnover induced by
GLP-1 in COS cells transfected with a GLP-1
receptor expression vector has been reported, but
may be a consequence of artifactual recruitment of
Gq by the greatly overexpressed numbers of
receptors. More recent data suggest that trophic
effects of GLP-1 on pancreatic -cells, through
stimulation of phosphatidylinositol 3-kinase, are
induced by transactivation of epidermal growth
factor (EGF) receptor signaling. The mechanism of
action is proposed to involve c-srcmediated
proteolytic processing of membrane-anchored
betacellulin or other EGF-like ligands that leads to
transactivation of the EGF receptor by GLP-1.
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Activation of Ion Channels
One way by which GLP-1 increases secretion on
insulin by pancreatic -cells is by Activation of Ion
Channels.
Studies of ion channels in -cells have elucidatedmechanisms by which elevated glucose levels result
in the secretion of insulin. Insulin secretion requires
the influx of calcium ions from the extracellular
fluid into the cell, a process that triggers exocytosis,
that is, fusion of secretory granules with the plasma
membrane, lysis of the granules, and release of
insulin into the extracellular fluid (ECF) or
bloodstream. The influx of calcium is largely
dependent on the opening of voltage-sensitive
calcium channels (Ca-VS), whose activation
(opening) is in turn dependent on the voltage
potential between the inside and outside of the cell
controlled by the adenosine triphosphatesensitive
potassium channels (K-ATP). This inwardly
rectifying potassium channel appears to be an
important target for glucose and cAMP signaling,
as determined by electrophysiological studies using
whole-cell patch clamp and excised patch studies,
in which the electrical potential of the cell and
activities of single channels located on the plasma
membrane are recorded. The K-ATP of -cells is
also believed to be the receptor for the actions of
the sulfonylurea drugs. It is now recognized that K-
ATP consists of a complex of two subunits: Kir6.2,
the inward rectifier, and SUR-1, an ATP-binding
cassette. Another ion channel that has important
functions in the regulation of the resting potential of
-cells is the nonselective cation channel (NS-CC).
The NS-CC gates both Ca2+
and Na+, is present on
-cells at a density equivalent to that of K-ATP, and
contributes substantially to the depolarizingbackground conductance that permits changes in
the activity of K-ATP channel to regulate the
resting potential of -cell. (4)
The sequence of events is as shown in the following
figure.
Figure 6 : Model of the proposed ion channels and signal transduction pathways in a pancreatic -cell involved in the
mechanisms of insulin secretion in response to glucose and glucagon-like peptide-1 (GLP-1). The key elements of the
model are the requirement for the dual inputs of the glucose-glycolysis signaling pathway and the GLP-1/receptor-
mediated cyclic adenosine monophosphate protein kinase A (PKA) signaling pathways to effect closure of adenosine
triphosphatesensitive potassium channels (K-ATP). The closure of these channels results in an increase in the resting
potential (depolarization) of the -cell, leading to opening of voltage-sensitive calcium channels (Ca-VS). The influx ofcalcium through the open-end Ca-VS triggers vesicular insulin secretion by the process of exocytosis. Repolarization of
the -cell is achieved by the opening of calcium-sensitive potassium channels (K-Ca). It is believed that the GLP-1receptor is coupled to a stimulatory G protein (Gs) and a calcium-calmodulinsensitive adenylyl cyclase. (5)
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ROLE OF GLP-1 IN TRANSCRIPTIONAL
REGULATION OF INSULIN
In addition to stimulating glucose-dependent insulin
secretion, GLP-1 stimulates transcription of the
insulin gene, proinsulin mRNA levels, insulin
biosynthesis, and accumulation of cellular stores ofinsulin. These unique insulinotropic actions of
GLP-1 contrast markedly with the actions of the
sulfonylurea class of oral hypoglycaemic drugs that
stimulate the secretion, but not the production, of
insulin. The reason for these differences in the
actions of GLP-1 and the sulfonylurea drugs
appears to be that GLP-1, unlike sulfonylureas,
stimulates the formation of cAMP. The cAMP
signaling pathway stimulates transcription of theinsulin gene by activating the DNA-binding
transcription factor CREB, which binds to a key
cAMP response element (CRE) located in the
promoter of the insulin gene and thereby enhances
the efficiency of transcription of the gene Nuclear
activity in response to GLP-1mediated increases in
cAMP includes recruitment of the CREB-binding
protein (CBP) that couples the proteinDNA
complex. This complex consists of CREB bound to
the CRE and CBP bound to CREB, resulting in
enhancement of insulin gene transcription. Discrete
from its effects on insulin gene expression via
cAMP/CREB, GLP-1 also stimulates the
recruitment of PDX-1 from the cytosol to the
nucleus, leading to enhanced DNA binding and
transcriptional activity of the insulin gene. Whereas
translocation of PDX-1 was shown to be dependent
on cAMP/protein kinase A (PKA), the PDX-1 DNAbinding activity was determined to be
phosphatidylinositol (PI) 3-kinase dependent
Figure 7 : Functional responses to glucagon-like peptide-1 (GLP-1) receptor signaling in -cells. The binding of GLP-1
to its receptor activates adenylyl cyclase, resulting in the formation of cyclic adenosine monophosphate (cAMP), which
activates the cAMP-dependent phosphorylase protein kinase A (PKA). PKA phosphorylates and so activates several
targets within the cell, such as ion channels that influence insulin secretion. PKA has also been implicated in PDX-1
mediated insulin gene expression activation. Phosphorylated CREB (in response to cAMP) further amplifies insulin gene
transcription. This cascade of signaling results in a stimulation of the insulin gene and increased insulin biosynthesis to
replenish stores of insulin secreted in response to nutrients (glucose) and incretins (GLP-1). GLP-1 receptor signaling
also imparts stimulatory actions, via phosphatidylinositol-3 kinase, upon PDX-1, mitogen-activated protein kinase
MAPK), and protein kinase B (PKB). These signaling cascades impart functional responses, including gene expression,
proliferation, and anti-apoptosis. (4)
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EXTRAPANCREATIC ACTION OF GLP-1
Glucagon-like peptide-1 exerts physiologic actions
of several extra-pancreatic organs, some of which
appear to be mediated by the known, characterizedGLP-1 receptor and others by an as yet unidentified
receptor type. The GLP-1 receptor gene is highly
expressed in the lung, stomach, hypothalamus, and
pancreatic islets. Notably, the lung GLP-1 receptor
binds GLP-1, VIP, and PMI, resulting in the
stimulation of mucous secretion and relaxation of
the pulmonary artery. In the stomach, GLP-1
inhibits gastric motility and acid secretion by
inhibiting intestinal motor activity in response to
nutrients in the distal gut, thus participating in the
iliac break phenomenon. GLP-1 appears to exert
actions in the hypothalamus to promote satiety.
Two mechanisms have been proposed in these
actions on satiety:
Autonomic nervous system Hormonal.
Activation of the vagus nerve in response to mealsis believed to stimulate the production of GLP-1 in
the nucleus of the tenth nerve (vagus, nucleus
tractus solitarus) located in the rhombencephalon
(hindbrain).
GLP-1 is transported via axons to the ventral
medial hypothalamus, where it acts on receptors in
the appetite control centres. In addition to the
autonomic nervous system pathway, GLP-1
secreted from the L-cells of the ileum and colon,
via splanchnic reflexes and possibly duodenal
hormones such as GIP, is proposed to gain access to
the hypothalamus by uptake from the circulation via
the area postrema and the sub-fornicular organ.
Both of these areas of the brain allow transport of
circulating macromolecules across the blood-brain
barrier. This proposed mechanism of access of
GLP-1 to the hypothalamus is similar to that
proposed for the satiety hormone, leptin, produced
in and secreted from adipose tissue in which
circumstance access to the hypothalamus is viauptake by and transport through the choroid plexus.
Relatively high affinity GLP-1 receptors have been
identified in many organs.
Therefore GLP-1 can be identified as a signal that
not only increases insulin secretion and production
but also works in a way to reduce our intake of food
by promoting satiety during feeding and leads to
cessation of feeding.
The following table shows the various GLP-1
receptors in different organs and the function of
GLP-1 in these different organs.
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Table 1 : Actions of glucagon-like peptide-1(4)
Target tissue GLP-1 receptors Actions
Pancreas -cells Yes Stimulates insulin secretion
-cells Yes Stimulates glucagon secretion (direct)
Suppresses glucagon secretion (indirect via insulin)
-cells Yes Stimulates somatostatin secretion
Stomach Yes Decreases motility and acid secretion
Lung Yes Increases mucous secretion, relaxes pulmonary artery
Hypothalamus Yes Promotes satiety, suppresses energy intake
Heart Yes Elevates blood pressure and heart rate
Kidney, heart, gut Yes Unknown
Liver ? Increases glycogenesis
Muscle ? Increases glycogenesis
Adipose ? Increases lipogenesis
Now we shall see how this signal plays a role in
Diabetes Mellitus type II.
POTENTIAL ROLE OF GLP-1 IN DIABETES
Because a major role of GLP-1 and GIP is to
augment glucose-stimulated insulin release, the
possibility arises that an impairment or alteration in
the production, secretion, or actions of GLP-1 (or
GIP) may contribute to or even be a cause of the
blunted insulin secretory dynamics or the
diminished sensitivity of peripheral tissues to the
actions of insulin. This may be particularly relevant
in the aging population, wherein 19% of the U.S.
population is diagnosed with type 2 diabetes.
Unlike type 1 diabetes, in which the -cells are
destroyed, the -cells of patients with type 2
diabetes are intact and are capable of secreting
insulin, albeit with abnormal secretory dynamics,
resulting in insufficient insulin levels to counteract
the hyperglycaemia characteristic of diabetes. In theearly stages of the development of diabetes before
hyperglycaemia is manifested, the -cells hyper
secrete insulin to maintain normoglycemia (normal
glucose tolerance to an oral glucose load. As the
resistance of peripheral tissues such as skeletal
muscle and fat to the actions of insulin increases,
the production of insulin by the -cells further
increases but eventually can no longer compensate,
and postprandial hyperglycaemia ensues (impaired
glucose tolerance), which then worsens and
progresses to fasting hyperglycaemia (diabetes).
Such a decompensation of the capacity of the -cell
to produce insulin during the development of
diabetes possibly may be aggravated by, or even
due to, a loss of effectiveness of the GLP-1 incretin
hormone. Either decreased secretion of GLP-1,
increased metabolism, or diminished sensitivity of
the -cells to GLP-1 could be responsible for the
loss of effectiveness. Notably, reduced action of
GLP-1 at peripheral target tissues would further
exacerbate the problem. It is known that in patients
with type 2 diabetes the incretin effect to augment
insulin secretion is reduced or lost. This loss of the
incretin effect appears to occur in the face of
enhanced secretion of the incretin hormones GLP-1
and GIP, suggesting that the elevated levels of the
incretins may in some way desensitize their action
on their respective receptors. Perhaps the
hypothetical desensitization occurs by way of a
partial uncoupling of the receptor from thestimulatory G protein that activates adenylyl
cyclase in the cAMP-mediated signaling pathway.
Even a slight impairment in receptor coupling to
cAMP formation may be envisioned to impair
regulation of the K-ATP channel and thereby
reduce the probability of K-ATP closure. The result
of this chain of events would be a lessening of the
incretin effect in augmenting the glucose-stimulated
secretion of insulin. In regard to the anti-apoptotic,
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pro-proliferative, and pro-differentiation effects of
GLP-1 in islet physiology, the reduction in
sensitivity of the -cell to GLP-1 in the type 2
diabetic state would likely make matters worse.
Suppression of GLP-1s regenerative effects, along
with an enhanced rate of -cell death (further
augmented by a glucotoxic environment), wouldundoubtedly play a part in the eventual failure of
the functional pancreatic unit.
With the apparent discoveries of GLP-1 binding
sites on adipocytes and receptor mRNA in skeletal
muscle and adipose tissues of rats, it is possible that
a partial desensitization of the GLP-1 receptor on
these tissues may contribute to the insulin resistance
of diabetes apart from the desensitization of the
receptor on -cells. The concept of GLP-1 receptor
desensitization and its relevance to diabetesrequires that the desensitization be incomplete.
Otherwise, as discussed below, the administration
of GLP-1 to patients with type 2 diabetes would not
be expected to therapeutically enhance insulin
secretion as it appears to do.
Desensitization of the GLP-1 receptor on -cells in
patients with type 2 diabetes may also influence
glucagon secretion. Either the diminished insulin
secretion resulting from reduced insulinotropic
actions of GLP-1 on -cells or the desensitization ofGLP-1 receptors on -cells would reduce
suppressive effects on -cells, resulting in excessive
secretion of glucagon. Clearly, the actions of
excessive glucagon antagonize those of insulin in
the target tissues of the liver, muscle, and fat, thus
worsening the diabetic condition. It is not known
whether or not GLP-1 receptors on the -cells that
secrete somatostatin undergo desensitization. If
they did desensitize, however, the decrease in the
suppressive effect of somatostatin on insulin
secretion predictably would be diminished, thereby
serving to restore insulin secretion. On the other
hand, if the GLP-1 receptor on -cells is not
desensitized, the inhibition of insulin secretion
would be enhanced.
USE OF GLP-1 AS TREATMENT FOR
DIABETES
As seen above, the signalling pathways and the role
of GLP-1 in transcription of Insulin, we can infer
that GLP-1 can be used not only for manipulation
of a signal but also as a direct medicine to treat thecondition of Diabetes. All of todays therapies are
mainly oriented towards lowering peripheral blood
glucose. None of the treatment methods available
today look at the molecular basis of Diabetes.
GLP-1 offers us great potential for developing
treatment methods that have not yet been seen by
todays medical science. Stimulation of endogenous
insulin from the pancreas, which results in the
delivery of insulin directly to the liver and other
insulin responsive organs via the combined portaland system circulation, is much preferred to the
systemic delivery of insulin administered
subcutaneously.
And today many sulfonylurea drugs are being used
which only help secrete Insulin but do not help in
its synthesis. Also there is always the disadvantage
of-cells being completely depleted of the insulin
they have. Furthermore, because the sulfonylurea
drugs are believed to act directly on the K-ATP
channels to pharmacologically effect closure of thechannels, the extent of closure is not regulated by
means other than adjustments of the administered
dose.
Preliminary studies of the potential efficacy of
GLP-1 as a means for controlling the
hyperglycaemia in patients with type 2 diabetes are
promising. The administration of GLP-1 to patients
with type 2 diabetes during meals effectively
restores the early phase of insulin secretion
characteristically absent in type 2 diabetes and
consequently attenuates the excessive prandial
increase in blood glucose levels. Also in studies
where the blood glucose levels of patients were
being monitored in response to GLP-1, it has been
seen that GLP-1 has anti-diabetogenic effects.
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CONCLUSION
It can thus be concluded that GLP-1 and many such
signal molecules offer a very specific treatment
without any side-effects. Also the efficacy of the
treatment is maximum and only desired results are
seen. Therefore it is very important in todays worldof advanced science that we look into the signalling
mechanism of molecules involved in many diseases
like Diabetes and help cure them efficiently and
safely.
REFERENCES
1. Diabetes mellitus type 2. Wikipedia. [Online]
http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2.
2. Domenico Accili, Naomi Berrie.The Struggle forMastery in Insulin Action: From Triumvirate to
Republic. s.l. : American Diabetes Association, Inc.,
2004.
3. Signal transduction mechanisms in nutrient-induced
insulin secretion. M. Prentki, K. Tornheim, B.E.
Corkey. 1997, Diabetologia, pp. S32- S41.
4. Joel F. Habener, Daniel M. Kemp.Diabetes
Mellitus: A Fundamental and Clinical Text 3rd eidtion.
s.l. : Lippincott Williams & Wilkins, 2004.
5. Signal transduction crosstalk in the endocrine system:
pancreatic -cells and the glucose competence concept.
Habener, George G. Holz and Joel F. 10, 1992,
Trends Biochem Sci, Vol. 17, pp. 388-393.
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