akhila technical report

8/2/2019 Akhila Technical Report

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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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