NUTRIENT INDUCED INSULIN SECRETION: SIGNAL TRANSDUCTION MECHANISMS

Akhila Gungi 08311a2305

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 Transduction Mechanisms 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

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-insulindependent diabetes mellitus (NIDDM) or adultonset 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) 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-dependent glucose 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 insulinresistance is seen first in the muscle and adipose tissues, Diabetes is actually a disease of the liver and pancreatic -cells. The hyperglycaemia is seen more in these areas. (2).

Figure 1: Universal blue circle symbol for diabetes.

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 actually many 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 potent incretin 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 Ca 2+ 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)

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 evidence indicates 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

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. GLUCAGON & GLUCAGON LIKE PEPTIDE (GLP-1) The search for intestinal incretins in addition to GIP was 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 the proglucagon 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, GLP1(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 GLP1(736) amide take place by an enzyme known as Dipeptidyl Peptidase IV (DPIV). Cleavage of GLP1 by DPIV attenuates its actions on the GLP- 1 receptor. The GLP-1(937) or GLP- 1(936) amide

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 cell culture, 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 render the -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 that intestinally derived factors released in response to oral glucose or nutrients augment glucosestimulated 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.

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 acids arginine (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 PANCREATIC CELLS 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.

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 in insulinoma 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 adenylate cyclase 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.

Figure 5 : Role of GLP-1 in Diabetes

The actions of GLP-1 to stimulate insulin secretion from -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 cellular mechanism 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 GLP1 (or other incretins) is required to render -cells competent to respond to glucose.

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 elucidated mechanisms 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 KATP 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 depolarizing background 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/receptormediated 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 of calcium 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-1 receptor is coupled to a stimulatory G protein (Gs) and a calcium-calmodulinsensitive adenylyl cyclase. (5)

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 of insulin. 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 the insulin 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 DNA binding 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)

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, characterized GLP-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.

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 via uptake 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.

Activation of the vagus nerve in response to meals is believed to stimulate the production of GLP-1 in the nucleus of the tenth nerve (vagus, nucleus tractus solitarus) located in the rhombencephalon (hindbrain).

Table 1 : Actions of glucagon-like peptide-1(4)

Target tissue Pancreas -cells -cells -cells Stomach Lung Hypothalamus Heart Kidney, heart, gut Liver Muscle Adipose

GLP-1 receptors Yes Yes Yes Yes Yes Yes Yes Yes ? ? ?

Actions Stimulates insulin secretion Stimulates glucagon secretion (direct) Suppresses glucagon secretion (indirect via insulin) Stimulates somatostatin secretion Decreases motility and acid secretion Increases mucous secretion, relaxes pulmonary artery Promotes satiety, suppresses energy intake Elevates blood pressure and heart rate Unknown Increases glycogenesis Increases glycogenesis 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 the early 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 the stimulatory 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,

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), would undoubtedly 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 diabetes requires 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 of GLP-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 the condition 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 portal and 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 the channels, 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.

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 world of 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 for Mastery 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.