Glucagon like peptide-1: A new therapeutic target for diabetes mellitus

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1 Educational Forum Glucagon like peptide-1: A new therapeutic target for diabetes mellitus S. K. Patel, R. K. Goyal 1, I.S. Anand, J.S. Shah, H.U. Patel, C.N. Patel Shri Sarvajanik Pharmacy College, Near Arvind Baug, Mehsana , Gujarat, 1 L.M. College of Pharmacy, Navrangpura, Ahmedabad , Gujarat, India Received: Revised: Accepted: Correspondence to: Patel Sunita Kanjibhai sunitapatel207@yahoo.com ABSTRACT Glucagon-like peptide-1 (GLP-1) is an endogenous peptide secreted from the gut in response to the presence of food. GLP-1 and its longer acting analog exendin-4 have multiple synergistic effects on glucose dependent, insulin secretion pathways of the pancreatic ß-cell and on plasticity in neuronal cells. Recently the development of these peptides as a novel therapeutic strategy for non-insulindependent (type 2) diabetes mellitus and associated neuropathy has been the focus of much interest. Here we describe the biological actions of GLP-1 and its related analogs. KEY WORDS: Exendin-4, NIDDM. Introduction Non-insulin dependent diabetes mellitus is a progressive disease that is prevalent in the elderly as well as among the youth. Unlike type 1 diabetes, people with type 2 diabetes mellitus might make healthy, even high levels of insulin, but there is a decrease in insulin action on insulin-sensitive tissues. [1] There is also evidence to indicate that type 2 diabetes, or at least impaired glucose tolerance, is associated with impaired cognition, independent of age. Therefore, the normal, age-related decline in cognitive function might be exacerbated by the development of impaired glucose tolerance and insulin resistance. [2] Diabetes has become the major cause of peripheral neuropathy, afflicting some 20% to 30% of type 2 diabetics, for which there is currently no treatment other than strict control of blood glucose levels. A major focus of endocrinology research over the past 5 years has been the development of a new therapeutic strategy for type 2 diabetes and neuropathy, based on the insulinotropic actions of endogenous peptides specifically, glucagon-like peptide-1 (7-36)- amide (GLP-1) and glucose-dependent insulinotropic peptide (GIP). They are released from entero-endocrine cells of the gastrointestinal mucosa following the ingestion of nutrients. They regulate nutrient metabolism via effects on insulin release from pancreatic islets, gastric motility and acid secretion, islet cell proliferation and nutrient disposal. [3-5] Infusion of GLP-1, at pharmacological concentrations, lowers blood glucose in type [5, 6] 2 diabetic and non-diabetic subjects. An important regulator of the biological activity of GLP-1 is N-terminal degradation by the common, endogenous, amino peptidase enzyme, dipeptidyl peptidase IV (DPP-IV). This enzyme cleaves GLP-1 at the alanine residue at position 2, [7] which not only inactivates GLP-1, but also might turn it into an antagonist at the GLP-1 receptor. [8] Several studies confirm that DPP-IV mediated inactivation of these peptides is a crucial control mechanism that regulates the biological activity of both GIP and GLP-1 in rodents [9] and humans. [7],[10] Continuous infusion of the peptide is required to maintain steady-state levels of active GLP-1 in plasma. [11],[12] Proposed signaling mechanism for GLP-1 GLP-1 action is mediated by binding to a specific, seventransmembrane G-protein coupled receptor (GLP-1 receptor) that is coupled positively to the adenylyl cyclase (AC) system. [13],[14] Ligand activation of the Gα subunit of the GLP-1 receptor stimulates AC, which leads to an increase in intracellular camp and activation of protein kinase A (PKA). GLP-1 acts directly through the camp-pka pathway to enhance and sensitize β-cells to glucose-stimulated insulin secretion. Glucose metabolism in the β-cell causes an increase in the concentration of ATP and raises the cytoplasmic ATP: ADP ratio, which leads to depolarization of the plasma membrane following closure of ATP-sensitive K + channels. This permits opening of voltage-dependent L-type Ca +2 channels and increase cytosolic Ca +2, which triggers fusion of insulincontaining secretory vesicles to the plasma membrane. Exocytosis of insulin follows rapidly. Activation of GLP-1 Indian J Pharmacol August 2006 Vol 38 Issue

2 Patel, et al. receptor by GLP-1 leads to an increase in [Ca +2 ] as a result of i activation of the L-type Ca +2 channel following phosphorylation of PKA and/or mobilization of intracellular Ca +2 stores, an effect that might or might not be PKA dependent. [15] Much is known about the signaling pathways that occur following the binding of GLP-1 to the GLP-1 receptor in pancreatic β-cells but, as yet, little has been confirmed in other cell types. [16],[17] The Gβγ dimmer activates phosphatidylinositol-3-kinase (PI3K), which subsequently activates mitogen-activated protein kinase (MAPKs) (by a PKC-dependent or independent mechanism). [16] This pathway is associated strongly with the GLP-1-induced proliferative signal in β-cells and the trophic effect in neuronal cells in culture; inhibition of PI3K (with LY294002) or MAPK (with PD98059) results in limited GLP-1-stimulated neurite outgrowth. [16] GLP-1-mediated activation of Pl3K and downstream effectors [such as the transcription factor pancreatic and duodenal homeobox gene-1 (PDX-1)] are thought to regulate expression of the gene encoding insulin, β-cell growth, and differentiation of the β-cell phenotype in islet, ductal and exocrine cells. [18][19] camp activates a GTPase of the Ras superfamily, Rap 1, following PKA-dependent phosphorylation. Certainly, camp activates multiple intracellular signaling cascades independently of its activation of PKA. An alternative, PKA-independent pathway was recently proposed in β-cells, [20] which involve two types of camp-gefs. GEFs are activated by binding to camp and activation of Rap 1A. [21] Rap 1A inhibits Ras but activates PKC and B-Raf, the latter two events both leading to activation of MAPKs. Biological effects of GLP-1 Insulinotropic action The insulinotropic effects of GLP-1 are strictly glucose dependent; it has no effect on insulin secretion at glucose concentrations below 4.5 mm. [22] In addition, GLP-1 strongly potentiates the insulinotropic actions of glucose itself. [23] It enhances all the steps of insulin biosynthesis and transcription of insulin gene, which provides a continuous, augmented supply of insulin for secretion. Indeed, the expression of genes that are essential for β-cell function, such as glucokinase and Glut 2 are up regulated following GLP-1 treatment. GLP-1 also has tropic effects on β-cells. It both stimulates β-cell proliferation and enhances the differentiation of new β-cells from progenitor cells in the epithelium of the pancreatic duct. [24],[19] Subsequently, Perfetti et al. demonstrated GLP-1 mediated endocrine proliferation in glucose-intolerant aging rats, with a resultant improvement in glucose tolerance. [12] This indicates that GLP-1 might be capable of stimulating the growth of new β-cells in individuals such as type 2 diabetic patients, who have an insufficient number of functioning cells. Inhibition of glucagon secretion GLP-1 inhibits glucagon secretion in a glucose-dependent manner. [25],[26] Glucagon opposes the effects of insulin on maintaining blood glucose levels, which contributes significantly to the development of hyperglycemia in diabetic subjects. Therefore, injectable glucagon can be used as a treatment for hypoglycemia. However, repeated hypoglycemia often results in the development of a defective counterregulatory glucagon response. [2] In the hyperglycemic condition, GLP-1 infusion suppresses glucagon secretion which suggests that glucagon suppression is on account of hyperglycemia but not an effect mediated by GLP-1. [27] Thus, the glucose lowering effect of GLP-1 might be a consequence of the inhibition of glucagon secretion but this is not the only mechanism proposed for the hypoglycemic effect of GLP-1, indicating that treatment with GLP-1 is unlikely to interfere with the glucagon mediated defense against hypoglycemia. [2] Gastrointestinal effects GLP-1 inhibits gastrointestinal secretion and motility, most notably gastric emptying. [25] The speed of gastric emptying response (within a couple of minutes) is indicative of either a neural or endocrine signaling mechanism from the upper gastrointestinal area. GLP-1 is one of the main hormones of the ileal brake, the primary, inhibitory feedback mechanism that controls the transit of meal through the upper gastrointestinal tract to optimize nutrient digestion and absorption. [2] During physiological malabsorption, GLP-1 secretion is stimulated and gastric and pancreatic secretions are inhibited. [28] Infusion of GLP-1 during the ingestion of a meal dose-dependently diminishes the insulin responses, rather than enhance them. [29] This is likely to be related to reduced gastric emptying and subsequent decrease in absorption of insulinotropic nutrients. [29] The GLP-1 mediated potentiation of nutrient stimulated insulin secretion might be achieved, in part, through the control of chyme levels in the digestive tract by retarding propulsion and digestion of gastric contents. [28],[29] CNS effects of GLP-1 GLP-1 receptor is expressed in the brains of rodents and humans. [30],[31] GLP-1 receptors are present in the hypothalamic nucleus indicating a role of GLP-1 in the central regulation of food intake. GLP-1 receptor expression has also been demonstrated in the thalamus, brainstem, lateral septum, subfornical organ and the area postrema. [31],[32] In addition to this, specific GLP-1 binding sites are also present in neurons in the caudate-putamen, cerebral cortex, hippocampus and cerebellum at lower densities. [30],[33],[34] Although the stimulus for activation of neuronal GLP-1 receptors in the CNS is unclear, it remains to be established if GLP-1 is produced by neural cells. GLP-1 in the blood stream can enter brain but its function is unknown. [17],[35] Intestinally derived peptides, such as GLP-1, are classified as both hormones and growth factors-peptides that can regulate diverse cellular processes, including mitosis, growth and differentiation. The recent study shows that GLP-1 can induce the differentiation of neuronal cells in culture in a way that is similar to nerve growth factor, reflects the GLP-1 mediated neogenesis that occurs in pancreatic β-cells. [16],[24] Effects of GLP-1 on appetite and food intake Recent studies indicate that GLP-1 dose-dependently inhibits feeding behavior in rodents, which can be reversed with exendin, the GLP-1 receptor antagonist. Such satietyrelated effects also appear to occur in humans, because peripheral administration of GLP-1 significantly enhances satiety and reduces appetite in both healthy and diabetic subjects, although such effects are transient. [5],[32],[36-38] Whether GLP-1 receptor-mediated signaling pathways are essential for the physiological control of appetite and body weight remains unclear. Certainly, inhibition of gastric emptying might account 232 Indian J Pharmacol August 2006 Vol 38 Issue

3 Glucagon like peptide-1 for the satiety after GLP-1 administration. Likewise, nutrients in the ileum are thought to have a satiating effect and decrease food intake. Since hypothalamic nuclei that control feeding behavior express GLP-1 receptors it has been suggested that peripheral GLP-1 might exert indirect effects on satiety center in the CNS through neuronal relay mechanisms. However, GLP-1 receptor knockout mice appear to be resistant to the development of obesity. [38],[39] This strongly suggests that GLP-1 receptor signaling is not essential for the long-term control of body weight. Neuroprotective effects of GLP-1 Activation of GLP-1 receptor modulates cell survival in diverse cell types. GLP-1 treatment reduces the number of apoptotic cells in the pancreas of Zuckar diabetic fatty rats and db/db mice with an associated increase in the islet size and β-cell mass. [40-42] In addition, GLP-1 also protects against H 2 O 2 induced apoptotic cell death in an insulin-secreting cell line. [42] Furthermore, in rat hippocampal neurons in culture, which express functional GLP-1 receptors, GLP-1 and exendin 4 completely protect against glutamate-induced cell death in a manner that is similar to other neurotrophic factors. [43],[44] This provided the first indication of a neuroprotective role for GLP-1 receptor agonists and demonstrates that the antiapoptotic action mediated by GLP-1 might not be restricted to insulin- secreting cells. Although much is known about the signaling pathways involved in apoptotic cell death, the precise mechanism how GLP-1 challenges pro-apoptotic stimuli in diverse cell types is unclear. PI3K, MAPK and camp are important signaling molecules involved in GLP-1 mediated cell proliferation and differentiation. Recent studies indicate a role for PI3K-dependent, MAPK-independent signaling in the antiapoptotic activity of GLP-1. [42] The amyloid-β peptide (Aβ), cellular oxidative stress and membrane-lipid peroxidation are believed to play important roles in the dysfunction and death of neurons in Alzheimers disease. Hippocampal neurons in culture have been exposed to toxic levels of Aβ and iron in the presence and absence of GLP-1 and exendin-4. [45] Both peptides dose-dependently protect neurons against the insults, which indicate possible antiapoptotic and antioxidant actions. Furthermore, GLP-1 and exendin-4 reduce the depletion of choline acetyltransferase immunoreactivity, a marker of acetylcholine-containing neurons in the basal forebrain, in a well-established model of neurodegeneration in rats. [43] Collectively, these data indicate that GLP-1 agonists are likely to play a role in protecting neurons against several types of brain injuries, including excitotoxic and oxidative damage. A study in rats infused with exendin, a GLP-1R antagonist demonstrated decreased neurotoxicity following infusion with beta amyloid protein. [45] In contrast, studies using the rat PC12 pheochromocytoma cell line, which expresses the GLP-1 receptor, suggest that GLP 1 agonists promote neurite outgrowth and NGF-induced differentiation, and may enhance cell survival following withdrawal of NGF, depending on the timing of exendin-4 administration. The differentiation actions of GLP-1 were abrogated by the kinase inhibitors LY or PD98059, but the PKA inhibitor H-89 had only modest effects on these actions. Hence, these findings suggest that GLP-1R signaling, perhaps independent of PKA activation, may be neurotrophic in the correct cellular context. [46] A follow-up study from the Greig lab demonstrated that GLP-1, and exendin-4, can completely protect cultured rat hippocampal neurons against glutamate-induced apoptosis, and both GLP-1 and exendin-4 reduced ibotenic acid-induced depletion of choline acetyltransferase immunoreactivity in rat basal forebrain cholinergic neurons. [47] Hence, these results suggest that GLP-1 action in the brain may be neuroprotective, perhaps via activation of anti-apoptotic signaling pathways in specific neurons. [48] GLP-1 in learning and memory During et al. using a variety of gene therapy, and peptidebased technologies, has shown that activation of CNS GLP-1R signaling enhances associative and spatial learning through GLP-1R. These investigators used a novel N-terminal exendin-4 derivative, [Ser(2)]exendin(1-9), which when administered peripherally, gains access to the CNS, and activates the CNS GLP-1R system. GLP-1R-deficient mice exhibit a learning deficit phenotype which is restored after hippocampal GLP-1R gene transfer. Furthermore, gain of function studies in rats over-expressing the GLP-1R in the hippocampus show improved learning and memory. GLP-1Rdeficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with correction after GLP-1R gene transfer in hippocampal somatic cells. Systemic administration of the GLP-1R agonist peptide [Ser(2)]exendin(1-9) in wild-type animals prevent kainateinduced apoptosis of hippocampal neurons. [49] GLP-1 and diabetes GLP-1 when given as a continuous intravenous infusion is effective in patients with type 2 diabetes by increasing insulin secretion and normalizing fasting as well as postprandial blood glucose; [50] even in advanced type 2 diabetes long after sulfonylurea secondary failure. [51] Unexpectedly, the effects of a single subcutaneous injection of GLP-1 were disappointing. Although high plasma levels of immunoreactive GLP-1 were achieved, insulin secretion rapidly returned to pretreatment values and blood glucose concentrations were not normalized. [52] Nevertheless, the effect of repeated subcutaneous administration on fasting blood glucose was as good as that of intravenous administration. [51] Continuous subcutaneous administration for 6 weeks also reduced fasting and postprandial glucose concentrations and lowered HbA 1c [53, 54] concentrations. The progressive loss of β-cell function and mass is an early feature of type 2 diabetes, eventually leading to insulin dependence in many patients. [55] Intervening early in the course of diabetes or perhaps in the prediabetic state to stimulate β cell differentiation and/or reduce apoptosis could theoretically halt the progression of the disease. Both GLP-1 and exenatide have shown promise in this respect. [56] Therapeutic strategies based on GLP-1 In this review we have highlighted considerable evidence that indicates that activation of the GLP-1 receptor is an important determinant for cell survival, particularly following organ and tissue damage. This makes GLP-1 an attractive therapeutic agent. However such potential is limited by the susceptibility of GLP-1 to proteolytic degradation. Many studies Indian J Pharmacol August 2006 Vol 38 Issue

4 Patel, et al. have addressed the possibility of manipulating the in vivo compound for 12 weeks significantly improved both fasting survival of GLP-1 as a novel approach to the treatment of and postprandial glucose concentrations in type 2 diabetic diabetes. In this context, two separate approaches can be patients. [67] However, many patients experienced adverse envisaged: reactions at injection site, leading to reduced compound 1) the development of analogs of GLP-1 that are not exposure [67], and its development has now been put on hold. susceptible to enzymatic degradation and Liraglutide (NN2211; 97% homologous to native GLP-1), is 2) the use of selective enzyme inhibitors to prevent in vivo in phase 2 of clinical development. Liraglutide reduces glycemia degradation and enhance the levels of biologically active in insulin-resistant murine modelsof diabetes and is associated peptides. [49] with increased β-cell mass and proliferation after 2 weeks of Enzyme-resistant GLP-1 analogs treatment. [68] Treatment with liraglutide has marked Exendin-4 is a GLP-1 receptor agonist, originally isolated antihyperglycemic effects in rodent models of beta-cell from the venom of the Gila monster lizard, which shares 53% deficiencies, and the in vivo effect of liraglutide on beta-cell sequence homology with native GLP-1. It is resistant to DPP- mass may in part depend on the metabolic state of the IV (because of the penultimate NH 2 -terminal is glycine instead animals. [69] of alanine as in GLP-1) and survives longer in the circulation In acute (single-dose) placebo-controlled crossover clinical (plasma half-life of 26 min in humans [57] compared with 1 2 studies, liraglutide reduces fasting and postprandial glucose min for intact biologically active GLP-1 [58] ). In insulin-resistant concentrations in type 2 diabetic patients [68] and is associated diabetic mice, repeated administration of exendin-4 for 13 with restoration of β-cell responsiveness to physiological weeks increased plasma insulinand reduced blood glucose and hyperglycemia. [70] Thus, studies in type 2 diabetic patients HbA 1c concentrations. [59] In Zucker rats, 8 weeks of exendin-4 indicated that 1 week treatment with once-daily liraglutide treatment was associated with both reduced glycemia and significantly reduces 24 h glucose concentrations and improves insulin levels, suggesting improved glucose tolerance, [60] and β-cell function compared with placebo [71] and the beneficial in addition, body weight gain was reduced. More recently, the effects appear to be maintained with patients showing effects of exendin-4 were examined in Goto-Kakizaki (GK) rats. significant improvements in glycemic control and a trend In these animals, a genetic neonatal β-cell mass deficit is toward weight reduction after 12 weeks, as compared with considered to be the primary defect leading to basal sulfonylurea treatment. [72] Transient, mild nausea/vomiting was hyperglycemia and subsequent development of diabetes, but reported but otherwise no serious adverse side effects were exendin-4 treatment during the first postnatal week (the pre- noted. diabetic period) increases the β-cell mass, with subsequent Other approaches involving covalent binding to albumin improvements in glycemic control at adultage. [61] In db/db mice, (e.g., CJC-1131), resulting in a plasma elimination half-life of exendin-4, given in the pre-diabetic period, expands the around 2 weeks in humans (corresponding to the circulating functional β-cell mass via effects on both proliferation and half-life of albumin itself), have also recently been reported. [73] apoptosis, delaying the development of diabetes, [62] while CJC-1131 lowers blood glucose in diabetic mice, and the effect neonatal GLP-1 or exendin-4 treatment stimulates β-cell persists up to 1 week following discontinuation of treatment. [74] neogenesis in newborn streptozotocin-injected rats (a model Enzyme inhibitors of β-cell regeneration), leading to both short- and long-term The alternative approach of inhibiting degradation of effects on β-cell mass recovery and glucose homeostasis. [63] endogenous GLP-1, has also been the focus of much interest. In healthy humans, acute intravenous infusion of exendin-4 is A DPP-IV inhibitor, valine-pyrrolidide, eliminated NH 2 -terminal insulinotropic and reduces both fasting and postprandial degradation of GLP-1 in vivo, improving the metabolic stability glucose concentrations. [61] of the intact biologically active peptide and potentiating its Exenatide (AC2993, synthetic exendin-4) has now reached insulinotropic and antihyperglycemic effects in anesthetized phase 3 of clinical development. In a placebo-controlled study pigs, [75] whereas another inhibitor, isoleucine-thiazolidide, in type 2 diabetic patients, exenatide reduced fasting glucose improved glucose tolerance in rats. [76] Subsequently, these when given acutely and postprandial glucose when given twice results were corroborated in acute studies demonstrating that daily over 5 days before breakfast and dinner. [64] However, in DPP-IV inhibition is effective in animal models of impaired the 5-day study,there was no significant effect on pre-breakfast glucose tolerance. [77][78] However, valine-pyrrolidide also fasting glucose levels, suggesting that the duration of action improves glucose tolerance in mice lacking the GLP-1 of the previous evening s dose was insufficient to maintain an receptor, [79] suggesting that DPP-IV inhibition may affect other antiglycemic effect overnight. This was confirmed in a 1-month substrates involved in glucose homeostasis.in a 12-week study study, whereonce-daily injections did not maintain satisfactory in Vancouver Zucker diabetic fatty (ZDF) rats, chronic DPP-IV glucose control, but twice-daily treatment significantly inhibition with isoleucine-thiazolidide was associated with improved HbA 1c, relative to pretreatment levels, even though sustained improvements in glucose tolerance and β-cell 24-h bloodglucose control was not achieved. [65] When combined responsiveness, which appeared to improve with time, and with ongoing oral antidiabetic agents (OAAs) (metformin and/ interestingly, by the end of the study, animals had lower body or a sulfonylurea) two or three times daily, exenatide leads to weights. [80] Moreover, chronic DPP-IV inhibition improves not further reductions in serum fructosamine and HbA 1c compared only β-cell function, but also both hepatic and peripheralinsulin with OAAs alone. [66] sensitivity. [81] LY SR is a sustained release formulation of a DPP- The longer-acting inhibitor, FE , given twice daily, IV resistant GLP-1 analog. Single daily injection of this continuously inhibits plasma DPP-IV activity and was found to 234 Indian J Pharmacol August 2006 Vol 38 Issue

5 Glucagon like peptide-1 normalize the glucose excursion after oral glucose administration in Zucker obese rats. [82] In ZDF rats, this compound actually delayed the onset of hyperglycemia and restored food and water intake to pre-diabetic levels. Active GLP-1 and pancreatic GLP-1 receptor mrna levels were increased, suggesting the possibility that the inhibitor led to a GLP-1 mediated improvement in β-cell function. [82] In human studies, a single dose of DPP-IV inhibitor reduced the glucose excursion in healthy and diabetic subjects. [83] The first chronic study, with two or three times daily administration of the short-acting inhibitor, NVP DPP728, to patients with mild type 2 diabetes gave clinical proof of the concept that DPP-IV inhibition is a viable approach to treating diabetes. Fasting and postprandial glucose concentrations were significantly reduced, and HbA 1c levels were lowered compared with placebo, even after only 4 weeks of treatment. [84] NVP DPP728 was well tolerated, with only minor adverse events, including pruritis and nasopharyngitis, being reported; which were transient and did not leadto discontinuation of treatment. LAF237, which has now reached phase III clinical development. [85] LAF237 is longer acting than NVP DPP728, and once-daily treatment for 4 weeks significantly improves metabolic control. Fasting and postprandial glucose concentrations and HbA 1c levels were significantly reduced compared with placebo, insulin secretion was sustained, and postprandial levels of active GLP-1 were increased. Moreover, glucagon concentration was significantly reduced by LAF237, [85] suggesting that GLP-1 mediated inhibition of glucagon secretion in addition to its insulinotropic effects contributes to mediating the effects of DPP-IV inhibition. To date, there are no reports of changes in body weight in humans after DPP-IV inhibitor treatment. The limited human data suggest that DPP-IV inhibitors are well tolerated, and do not seem to be associated with hypoglycemic events. Four (of 61) patients treated with NVP DPP728 for 28 days reported symptoms suggestive of hypoglycemia, but only 1 had a blood glucose level of <3.3 mmol/l, whereas no hypoglycemic incidence was reported for LAF237. [85] Preliminary studies with LAF237 indicate that it does not significantly increase the risk for hypoglycemia when given together with glibenclamide. [86] Conclusion The studies discussed above support the idea that a GLP 1 based therapy will be a safe and effective treatment for type 2 diabetes. The clinical studies reported so far indicate that this approach, whether achieved by DPP-IV inhibition or by GLP 1 receptor agonists, has the potential to reduce and may be even normalize both fasting and postprandial glucose concentrations without adverse effects such as weight gain. 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7 Glucagon like peptide-1 Diabetes Care 2004;27: Lawrence B, Drefus JF, Wen S, Guivarc h PH, Drucker DJ, Castaigne JP. CJC 1131, a long-scting GLP-1 derivative, exhibits an extended pharmacokinetic profile in healthy human volunteers. Diabetes 2003;52: Kim JG, Baggio LL, Bridon DP, Castaigne JP, Robitaille MF, Jette L, et al. Development and characterization of a glucagon-like peptide 1-albumin conjugate: The ability to activate the glucagon-like peptide 1 receptor in vivo. Diabetes 2003;52: Deacon CF, Hughes TE, Holst JJ. Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide-1 in anesthetized pigs. Diabetes 1998;47: Pederson RA, White HA, Schlenzig D, Pauly RP, McIntosh CH, Demuth HU. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isuleucine thiazolidide. Diabetes 1998;47: Balkan B, Kwasnik L, Miserendino R, Holst JJ, Li X. Inhibition of dipeptidyl peptidase IV with NVP-DPP728 increases plasma GLP-1 (7-36 amide) concentrations and improves oral glucose tolerance in obese Zucker rats. Diabetologia 1999;42: Ahrén B, Holst JJ, Martensson H, Balkan B. Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice. Eur J Pharmacol 2000;404 :239 45, 79. Marguet D, Baggio L, Kobayashi T, Bernard AM, Pierres M, Nielsen PF, et al. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci 2000;97: Pospisilik JA, Stafford SG, Demuth HU, Brownsey R, Parkhouse W, Finegood DT, et al. Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and ß-cell glucose responsiveness in VDF (fa/fa) Zucker rats. Diabetes 2002;51: Pospisilik JA, Stafford SG, Demuth HU, McIntosh CH, Pederson RA. Longterm treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: a euglycemic-hyperinsulinemic clamp study. Diabetes 2002;51: Sudre B, Broqua P, White RB, Ashworth D, Evans DM, Haigh R, et al. Chronic inhibition of circulating dipeptidyl peptidase IV by FE delays the occurrence of diabetes in male zucker diabetic fatty rats. Diabetes 2002;51: Rothenburg P, Kalbag J, Smith H, Gingerich R, Nedelman J, Villhauer E, et al. Treatment with a DPP-IV inhibitor, NVP-DPP728, increases prandial intact GLP 1 levels and reduces glucose exposure in humans (Abstract). Diabetes 2000;49: Ahrén B, Simonsson E, Larsson H, Landin-Olsson M, Torgeirsson H, Jansson PA, et al. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 2002;25: Ahrén B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004;89: El-Ouaghlidi A, Rehring ER, Schweizer A, Holmes D, Nauck MA. The dipeptidyl peptidase IV inhibitor, LAF237 does not accentuate reactive hypoglycaemia caused by the sulphonylurea glibenclamide administered before an oral glucose load in healthy subjects. Diabetes 2003;52:118. Unleash the Order power of your now literature search. IJP Archives 2005 Rs. 500/- for IPS members Rs. 2000/- for Libraries & Educational Institutes in India Full articles in PDF format from Versatile search facility Easy installation User friendly interface In-built help and instructions For details please contact: The Chief Editor - IJP Department of Pharmacology, JIPMER, Pondicherry ijp@jipmer.edu Indian J Pharmacol August 2006 Vol 38 Issue