Gliptin Therapies for Inhibiting Dipeptidyl Peptidase-4 in Type 2 Diabetes
Discovery of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) has led to the clinical development of incretin-based therapies for type 2 diabetes. Incretins are intestinal peptide hormones that stimulate post-prandial insulin secretion and improve glycaemic control. Gliptins are drugs that inhibit a ubiquitous enzyme, dipeptidyl peptidase-4 (DPP-4), preventing the physiological breakdown of incretins and thereby enhancing endogenous incretin action. Three ‘gliptins’ have recently been introduced into clinical practice: sitagliptin, vildagliptin and saxagliptin. This review provides an overview of these new antidiabetic agents and comments onsome exciting future prospects for incretins and agents that enhance incretin action.
Diabetes, incretin, gliptin, antidiabetic drugs, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), dipeptidyl peptidase-4 (DPP-4)
Disclosure: Brian D Green has no conflicts of interest to declare. Clifford J Bailey has undertaken ad-hoc consultancy in the past for pharmaceutical companies including Merck Sharp & Dohme and Takeda. Peter R Flatt has undertaken research sponsored by pharmaceutical companies, but not related to this manuscript.
Received: 2 December 2009 Accepted: 8 June 2010 Citation: European Endocrinology, 2010;6(2):19–25
Correspondence: Brian D Green, School of Biological Sciences, Queens University Belfast, Belfast, Northern Ireland, BT9 5AG, UK. E: firstname.lastname@example.org
Intestinal Hormones and Glucose Regulation
The importance of the intestine in regulating post-prandial glucose levels unfolded over the latter half of the 20th century. Observations in the early 20th century demonstrated that intestinal extracts could alleviate diabetes, but these studies were overlooked.1,2 It was not until the 1960s that the ‘enteroinsular axis’ and the incretin effect were defined. The enteroinsular axis is a network of neural and endocrine signals between the intestine and the pancreas that promote insulin release in response to feeding.3 Incretins are intestinal endocrine hormones and are important components of the enteroinsular axis.3 Thus far, two incretin hormones that potently stimulate insulin secretion at physiological concentrations have been identified: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
The Incretin Hormones – Discovery and Physiological Actions
GLP-1 was discovered in complementary DNA (cDNA) derived from the anglerfish when molecular biology techniques were employed to investigate the proglucagon gene.4 Subsequent work revealed the mammalian sequences of GLP-1 and identified GLP-1(7–36) amide as the major bioactive peptide, characterised by a potent dose-dependent insulinotropic action.5,6 GIP was identified much earlier than GLP-1 in an impure porcine enterogastrone extract.7 Initial effects on the stomach gave rise to the original name ‘gastric inhibitory polypeptide’, which was later changed to reflect its potent insulin secretory action on pancreatic beta-cells.8–11 GLP-1 and GIP are released post-prandially from intestinal L- and K-cells, respectively, and they are effective modulators of glucose-dependent insulin secretion.6,12 This glucose-dependent character has been a key feature in the clinical exploitation of incretins because it limits the risk of hypoglycaemia. In vitro studies have shown that GLP-1 and GIP can upregulate pro-insulin gene transcription and enhance the growth, differentiation, proliferation and survival of pancreatic beta-cells.13–15 Furthermore, GLP-1 and GIP appear to act as a beta-cell mitogenic and anti-apoptotic factor.16,17 The hormones have a range of extrapancreatic effects (see Figure 1), which are reviewed elsewhere.6 Regulatory actions of incretins involve effects on glucose and energy metabolism as well as having actions on the liver, skeletal muscle and adipose tissues.5,6,18–20 As a consequence of the early work characterising biological actions, the incretin hormones gradually gained a reputation as novel therapeutic agents for the treatment of diabetes and related metabolic disorders.6
- Moore B, Edia ES, Abram JH, On the treatment of diabetes mellitus by an extract of duodenal mucous membrane, Biochem J, 1906;1:28–38.
- La Barre J, Sur les possibilités d’un traitement du diabe`te par l’incrétine, Bull Acad R Med Belg, 1932;12:620–34.
- Creuzfeldt W, The incretin concept today, Diabetologia, 1979;16:75–85.
- Lund PK, Goodman RH, Dee PC, et al., Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem, Proc Natl Acad Sci U S A, 1982;79:345–9.
- Baggio LL, Drucker DJ, Biology of incretins: GLP-1 and GIP, Gastroenterology, 2007;132:2131–57.
- Green BD, Gault VA, O’Harte FP, et al., Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as future antidiabetic agents, Curr Pharm Des, 2004;10:3651–62.
- Kosaka T, Lim RKS, Demonstration of the humoral agent in fat inhibition of gastric acid secretion, Proc Soc Exp Biol Med, 1930;27:870–91.
- Brown JC, Pederson RA, Jorpes E, et al., Preparation of highly active enterogastrone, Can J Physiol Pharm, 1969;47:113–4.
- Brown JC, Mutt V, Pederson RA, Further purification of a polypeptide demonstrating enterogastrone activity, J Physiol, 1970;209:57–64.
- Dupre J, Ross SA, Watson D, et al., Stimulation of insulin secretion by gastric inhibitory polypeptide in man, J Clin Endocrinol Metab, 1973;37:826–8.
- Brown JC, Pederson RA, The insulinotropic action of gastric inhibitory polypeptide in the perfused isolated rat pancreas, Endocrinology, 1976;99:780–5.
- Pedersen RA. In: Walsh JH, Dockray GJ (eds), Gastric inhibitory polypeptide, Gut Peptides: Biochemistry and Physiology, New York: Raven Press, 1994;217–59.
- Fehmann HC, Habener JF, Insulinotropic hormone glucagon-like peptide-I(7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells, Endocrinology, 1992;130:159–66.
- Fehmann HC, Goke R, Characterization of GIP(1-30) and GIP(1-42) as stimulators of proinsulin gene transcription, Peptides, 1995;16:1149–52.
- Maida A, Hansotia T, Longuet C, et al., Differential importance of GIP vs GLP-1 receptor signaling for beta cell survival in mice, Gastroenterology, 2009;137(6): 2146–57.
- Trümper A, Trümper K, Hörsch D, Mechanisms of mitogenic and anti-apoptotic signaling by glucosedependent insulinotropic polypeptide in beta(INS-1)-cells, J Endocrinol, 2002;174:233–45.
- Vilsbøll T, The effects of glucagon-like peptide-1 on the beta cell, Diabetes Obes Metab, 2009;11(Suppl. 3):11–18.
- Eckel RH, Fujimoto WY, Brunzell JD, Gastric inhibitory polypeptide enhanced lipoprotein lipase activity in cultured preadipocytes, Diabetes, 1979; 28:1141–2.
- Oben J, Morgan LM, Fletcher J, et al., Effect of the entero-pancreatic hormones, gastric inhibitory polypeptide and glucagon-like polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue, J Endocrinol, 1991;130:267–72.
- Valverde I, Villanueva-Peñacarrillo ML, In vitro insulinomimetic [corrected] effects of GLP-1 in liver, muscle and fat, Acta Physiol Scand, 1996;157:359–60.
- Abbott CA, Gorrell, MD, The family of CD26/DPIV and related ectopeptidases in ectopeptidases: CD13/ aminopeptidase N and CD26/Dipeptidyl peptidase IV. In: Langer J, Ansorge S (eds), Medicine and Biology, New York: Kluwer/Plenum, 2002:171–91.
- Drucker DJ, Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes, Expert Opin Investig Drugs, 2003;12:87–100.
- Green BD, Flatt PR, Bailey CJ, Inhibition of dipeptidyl peptidase IV activity as a therapy of type 2 diabetes, Expert Opin Emerg Drugs, 2006;11(3):525–39.
- Mentlein R, Gallwitz B, Schmidt WE, Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum, Eur J Biochem, 1993;214:829–35.
- Kieffer TJ, McIntosh CH, Pederson RA, Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV, Endocrinology, 1995;136,3585–96.
- Deacon CF, Johnsen AH, Holst JJ, Degradation of glucagon-like peptide-1 by the human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo, J Clin Endocrinol Metab, 1995;80:952–7.
- Pridal L, Deacon CF, Kirk O, et al., Glucagon-like peptide- 1(7-37) has a larger volume of distribution than glucagon-like peptide-1(7-36)amide in dogs and is degraded more quickly in vitro by dog plasma, Eur J Drug Metab Pharmacokinet, 1996;21:51–9.
- Schmidt WE, Siegel EG, Kummel H, et al., Commercially available preparations of porcine glucose-dependent insulinotropic polypeptide (GIP) contain a biologically inactive GIP-fragment and cholecystokinin-33/-39, Endocrinology, 1987;120:835–7.
- Knudsen LB, Pridal L, Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1- (7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor, Eur J Pharmacol, 1996;318:429–35.
- Green BD, Mooney MH, Gault VA, et al., Lys9 for Glu9 substitution in glucagon-like peptide-1(7-36)amide confers dipeptidyl peptidase IV resistance with cellular and metabolic actions similar to those of established antagonists glucagon-like peptide-1(9-36)amide and exendin (9-39), Metabolism, 2004;53:252–9.
- Wettergren A, Wøjdemann M, Holst JJ, The inhibitory effect of glucagon-like peptide-1 (7-36)amide on antral motility is antagonized by its N-terminally truncated primary metabolite GLP-1 (9-36)amide, Peptides, 1998;19:877–82.
- Deacon CF, Plamboeck A, Moller S, et al., GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion, Am J Physiol Endocrinol Metab, 2002;282(4):E873–9.
- Deacon CF, Plamboeck A, Rosenkilde MM, et al., GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations, Am J Physiol Endocrinol Metab, 2006;291:E468–75.
- Gault VA, Parker JC, Harriott P, et al., Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP(3-42), is a GIP receptor antagonist in vivo, J Endocrinol, 2002;175:525–33.
- Hinke SA, Gelling RW, Pederson RA, et al., Dipeptidyl peptidase IV-resistant [D-Ala(2)]glucose-dependent insulinotropic polypeptide (GIP) improves glucose tolerance in normal and obese diabetic rats, Diabetes, 2002;51:652–61.
- Parker JC, Lavery KS, Irwin N, et al., Effects of subchronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3-42) and GLP-1(9-36)amide, on insulin secretion and glucose homeostasis in ob/ob mice, J Endocrinol, 2006;191:93–100.
- Irwin N, Flatt, PR, Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications, Diabetologia, 2009;52:1724–31.
- Green BD, Liu HK, McCluskey JT, et al., Function of a long-term, GLP-1-treated, insulin-secreting cell line is improved by preventing DPP IV-mediated degradation of GLP-1, Diabetes Obes Metab, 2005;7:563–9.
- Rahfeld J, Schierhorn M, Hartrodt B, et al., Are diprotin A (Ile-Pro-Ile) and diprotin B (Val-Pro-Leu) inhibitors or substrates of dipeptidyl peptidase IV?, Biochim Biophys Acta, 1991;1076:314–6.
- Thoma R, Löffler B, Stihle M, et al., Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV, Structure, 2003;11:947–59.
- Marguet D, Baggio L, Kobayashi T, et al., Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26, Proc Natl Acad Sci U S A, 2000;97:6874–9.
- Nagakura T, Yasuda N, Yamazaki K, et al., Enteroinsular axis of db/db mice and efficacy of dipeptidyl peptidase IV inhibition, Metabolism, 2003;52:81–6.
- Conarello SL, Li Z, Ronan J, et al., Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance, Proc Natl Acad Sci U S A, 2003;100:6825–30.
- Yasuda N, Nagakura T, Yamazaki K, et al., Improvement of high fat-diet-induced insulin resistance in dipeptidyl peptidase IV-deficient Fischer rats, Life Sci, 2002;71:227–38.
- Pederson RA, White HA, Schlenzig D, et al., Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide, Diabetes, 1998;47:1253–8.
- Pospisilik JA, Stafford SG, Demuth HU, et al., Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and betacell glucose responsiveness in VDF (fa/fa) Zucker rats, Diabetes, 2002;51:943–50.
- Pospisilik JA, Stafford SG, Demuth HU, et al., Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: a euglycemic-hyperinsulinemic clamp study, Diabetes, 2002;51:2677–83.
- Burkey BF, Li X, Bolognese L, et al., Acute and chronic effects of the incretin enhancer vildagliptin in insulinresistant rats, J Pharmacol Exp Ther, 2005;315:688–95.
- Balkan B, Kwasnik L, Miserendino R, et al., 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;42:1324–31.
- Ahrén B, Holst JJ, Mårtensson H, et al., Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice, Eur J Pharmacol, 2000;404:239–45.
- Roy S, Khanna V, Mittra S, et al., Combination of dipeptidyl peptidase IV inhibitor and low dose thiazolidinedione: Preclinical efficacy and safety in db/db mice, Life Sci, 2007;81:72–9.
- Yamazaki K, Inoue T, Yasuda N, et al., Comparison of efficacies of a dipeptidyl peptidase IV inhibitor and alphaglucosidase inhibitors in oral carbohydrate and meal tolerance tests and the effects of their combination in mice, J Pharmacol Sci, 2007;104:29–38.
- Biftu T, Feng D, Qian X, et al., (3R)-4-[(3R)-3-Amino-4- (2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4- diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, Bioorg Med Chem Lett, 2007;17:49–52.
- Thomas L, Eckhardt M, Langkopf E, et al., (R)-8-(3-aminopiperidin- 1-yl)-7-but-2-ynyl-3-methyl-1-(4-methylquinazolin- 2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors, J Pharmacol Exp Ther, 2008;325:175–82.
- Eckhardt M, Langkopf E, Mark M, et al., 8-(3-(R)- aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methylquinazolin- 2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes, J Med Chem, 2007;50:6450–3.
- Summary of Product Characteristics, Sitagliptin, Merck Sharp & Dohme Ltd, Hoddesdon, UK, June 2009 (available at: www.januvia.com, accessed 17 June 2010)
- Summary of Product Characteristics, Vildagliptin, Novartis Europharm Ltd, Horsham, UK, January 2008. Available at: www.medicines.org.uk/EMC/medicine/20734/SPC/Galvus+50+mg+Tablets/
- Summary of Product Characteristics, Saxagliptin, Bristol- Myers Squibb/AstraZeneca, Uxbridge, UK, October 2009. Available at: www.medicines.org.uk/emc/ingredient/2424/saxagliptin+hydrochloride/ (accessed 17 June 2010).
- Aschner P, Kipnes M, Lunceford J, et al., Effect of the dipeptidyl peptidase-4 sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes, Diabetes Care, 2006;29:2632–7.
- Charbonnel B, Karisik A, Liu J, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone, Diabetes Care, 2006;29:2638–43.
- Rosenstock J, Brazg R, Andryuk P, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, Clin Therapeutics, 2006;28:1556–68.
- Goldstein BJ, Feinglos MN, Lunceford, et al., Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patient with type 2 diabetes, Diabetes Care, 2007;30: 1979–87.
- Nauck MA, Meininger G, Sheng D, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, noninferiority trial, Diabetes Obes Metab, 2007;9:194–205.
- Hermansen K, Kipnes M, Luo E, et al., Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride and metformin, Diabetes Obes Metab, 2007;9:733–45.
- Ahrén B, Gomis R, Standl E, et al., Twelve and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin treated patients with type 2 diabetes, Diabetes Care, 2004;27:2874–80.
- Garber AJ, Schweizer A, Baron MA, et al., Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized placebo-controlled study, Diabetes Obes Metab, 2007;9:166–74.
- Rosenstock J, Baron MA, Dejager S, et al., Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes, Diabetes Care, 2007;30:217–23.
- Schweizer A, Couturier A, Foley J, et al., Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug-naïve patients with type 2 diabetes, Diabetic Med, 2007;24:955–61.
- Bosi E, Camisasca RP, Collober C, et al., Effect of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin, Diabetes Care, 2007;30:890–5.
- Rosenstock J, Sankoh S, List JF, Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drugnaïve patients with type 2 diabetes, Diabetes Obes Metab, 2008;10:376–86.
- DeFronzo RA, Hissa MN, Garber AJ, et al., The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes on metformin alone, Diabetes Care, 2009;32:1649–55.
- Chen R, Pfutzner A, Jadzinsky M, et al., Initial combination therapy with saxagliptin and metformin improves glycaemic control compared with either monotherapy alone in drug-naive patients with type 2 diabetes, Diabetologia, 2008;51(Suppl. 1):78.
- Ravichandran S, Chacra AR, Tan GH, et al., Saxagliptin added to sufonylurea is safe and more efficacious than up-titrating a sulfonylurea in patients with type 2 diabetes, Diabetologia, 2008;51(Suppl. 1):858.
- Allen E, Hollander P, Li J, et al., Saxagliptin added to a thiazolidinedione improves glycaemic control in patients with inadequately controlled type 2 diabetes, Diabetologia, 2008;51(Suppl. 1):859.
- Croxtall JD, Keam DSJ, Vildagliptin: a review of its use in the management of type 2 diabetes mellitus, Drugs, 2008;68:2387–409.
- Garber AJ, Foley JE, Banerji MA, Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulfonylurea, Diabetes Obes Metab, 2008;10:1047–56.
- Deacon CF, Holst JJ, Dipeptidyl peptidase-4 inhibition: advances in our understanding of diabetes management, Europ Endocrinol, 2008;4:47–9.
- Ahrén B, Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes, Expert Opin Emerging Drugs, 2008;13:593–607.
- Verspohl EJ, Novel therapeutics for type 2 diabetes: incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors, Pharmacol Ther, 2009;124:113–38.
- Matikainen N, Manttari S, Schweizer A, et al., Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes, Diabetologia, 2006;49:2049–57.
- Green BD, Flatt PR, Bailey CJ, Inhibition of dipeptidyl peptidase IV activity as a therapy of type 2 diabetes, Expert Opin Emerging Drugs, 2006;11:525–39.
- Rayasam GV, Tulasi VK, Davis JA, et al., Fatty acid receptors as new therapeutic targets for diabetes, Expert Opin Ther Targets, 2007;11:661–71.
- Evans KA, Budzik BW, Ross SA, et al., Discovery of 3-Aryl-4-isoxazolecarboxamides as TGR5 Receptor Agonists, J Med Chem, 2009;52(24):7962–5.
- Flatt PR, Bailey CJ, Green BD, Dipeptidyl peptidase IV (DPP IV) and related molecules in type 2 diabetes, Front Biosci, 2008;13:3648–60.
- Amori RE, Lau J, Pittas AG, Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and metaanalysis, JAMA, 2007;298:194–206.
- Noel RA, Braun DK, Patterson RE, et al., Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes. A retrospective cohort study, Diabetes Care, 2009;32:834–8.
- Clements Jr RS, Bell DS, Complications of diabetes. Prevalence, detection, current treatment, and prognosis, Am J Med, 1985;79:2–7.
- Garcia MJ, McNamara PM, Gordon T, et al., Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study, Diabetes, 1974;23:105–11.
- Scandinavian Simvastatin Survival Study Group, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994;344: 1383–9.
- Kannel WB, McGee DL, Diabetes and cardiovascular disease. The Framingham study, JAMA, 1979;241:2035–8.
- Ban K, Noyan-Ashraf MH, Hoefer J, et al., Cardioprotective and vasodilatory actions of glucagonlike peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and - independent pathways, Circulation, 2008;117:2340–50.
- Green BD, Hand KV, Dougan JE, et al., GLP-1 and related peptides cause concentration-dependent relaxation of rat aorta through a pathway involving KATP and cAMP, Arch Biochem Biophys, 2008;478:136–42.
- Grieve DJ, Cassidy RS, Green BD, Emerging cardiovascular actions of the incretin hormone glucagonlike peptide-1: potential therapeutic benefits beyond glycaemic control?, Br J Pharmacol, 2009;157:1340–51.
- Holst JJ, The physiology of glucagon-like peptide-1, Physiol Rev, 2007;87:1409–39.
- Burcelin R, Serino M, Cabou C, A role for the gut-to-brain GLP-1-dependent axis in the control of metabolism, Curr Opin Pharmacol, 2009;9:744–52.
- McIntosh CHS, Widenmaier S, Kim SJ, Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP), Vit Horm, 2009;80:409–71.
- Gault VA, Hölscher C, GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloi, Eur J Phamacol, 2008;587:112–7.
- Gault VA, Hölscher C, Protease resistant glucosedependent insulinotropic polypeptide agonists facilitate hippocampal LTP and reverse the impairment of LTPinduced by beta-amyloid, J Neurophysiol, 2008;99:1590–5.
- Hölscher C, Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment strategy for Alzheimer's disease, Recent Pat CNS Drug Discov, 2010 Jun;5(2):109–17.
- Abbas T, Faivre E, Hölscher C, Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer’s disease, Behav Brain Res, 2009;205:265–71.
- Larsen PJ, Holst JJ, Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter, Regul Pept, 2005;128: 97–107.
- D'Amico M, Di Filippo C, Marfella R, et al., Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer's prone mice, Exp Gerontol. 2010 Mar;45(3):202–7.
- Williams DL, Minireview: Finding the sweet spot: Peripheral versus central glucagon-like peptide 1 action in feeding and glucose homeostasis, Endocrinology, 2009;150:2997–3001.