Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes

Mentlein, 1999, Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides, Regul Pept., 85, 9, 10.1016/S0167-0115(99)00089-0

Demuth, 2005, Type 2 diabetes–therapy with dipeptidyl peptidase IV inhibitors, Biochim Biophys Acta, 1751, 33, 10.1016/j.bbapap.2005.05.010

Yu, 2010, The dipeptidyl peptidase IV family in cancer and cell biology, FEBS J., 277, 1126, 10.1111/j.1742-4658.2009.07526.x

Lambeir, 2003, Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV, Crit Rev Clin Lab Sci., 40, 209, 10.1080/713609354

Ohnuma, 2008, Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function, Trends Immunol., 29, 295, 10.1016/j.it.2008.02.010

Hühn, 2000, Molecular analysis of CD26-mediated signal transduction in T cells, Immunol Lett., 72, 127, 10.1016/S0165-2478(00)00170-X

Vora, 2009, Genetic ablation or pharmacological blockade of dipeptidyl peptidase IV does not impact T cell-dependent immune responses, BMC Immunol., 10, 19, 10.1186/1471-2172-10-19

Bell, 1983, Hamster preproglucagon contains the sequence of glucagon and two related peptides, Nature, 302, 716, 10.1038/302716a0

Ørskov, 1986, Glucagon-like peptides GLP-1 and GLP-2, predicted products of the proglucagon gene, are secreted separately from pig small intestine but not pancreas, Endocrinology, 119, 1467, 10.1210/endo-119-4-1467

Mojsov, 1987, Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas, J Clin Invest., 79, 616, 10.1172/JCI112855

Holst, 1987, Truncated glucagon-like peptide 1, an insulin-releasing hormone from the distal gut, FEBS Lett., 211, 169, 10.1016/0014-5793(87)81430-8

Orskov, 1988, Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach, Endocrinology, 123, 2009, 10.1210/endo-123-4-2009

Kreymann, 1987, Glucagon-like peptide-1 7-36, a physiological incretin in man, Lancet, 2, 1300, 10.1016/S0140-6736(87)91194-9

Nathan, 1992, Insulinotropic action of glucagonlike peptide-I-(7-37) in diabetic and nondiabetic subjects, Diabetes Care, 15, 270, 10.2337/diacare.15.2.270

Gutniak, 1992, Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus, N Engl J Med., 326, 1316, 10.1056/NEJM199205143262003

Nauck, 1993, Normalization of fasting hyperglycemia by exogenous GLP-1 (7-36 amide) in type 2 diabetic patients, Diabetologia, 36, 741, 10.1007/BF00401145

Nauck, 1996, Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM, Diabetologia, 39, 1546, 10.1007/s001250050613

Mentlein, 1993, 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., 214, 829, 10.1111/j.1432-1033.1993.tb17986.x

Deacon, 1995, Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo, J Clin Endocrinol Metab., 80, 952

Deacon, 1995, Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects, Diabetes, 44, 1126, 10.2337/diab.44.9.1126

Kieffer, 1995, Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV, Endocrinology, 136, 3585, 10.1210/endo.136.8.7628397

Carr, 2016, Drug development from the bench to the pharmacy: with special reference to dipeptidyl peptidase-4 inhibitor development, Diabet Med., 33, 718, 10.1111/dme.13066

Schön, 1991, Dipeptidyl peptidase IV in the immune system, Biol Chem Hoppe Seyler, 372, 305, 10.1515/bchm3.1991.372.1.305

Deacon, 1998, Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig, Diabetes, 47, 764, 10.2337/diabetes.47.5.764

Hansen, 1999, Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine, Endocrinology, 140, 5356, 10.1210/endo.140.11.7143

Pederson, 1998, Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide, Diabetes, 47, 1253, 10.2337/diab.47.8.1253

Pauly, 1999, Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide, Metabolism, 48, 385, 10.1016/S0026-0495(99)90090-2

Balkan, 1999, 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, 42, 1324, 10.1007/s001250051445

Ahrén, 2000, Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice, Eur J Pharmacol., 404, 239, 10.1016/S0014-2999(00)00600-2

Pospisilik, 2002, Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats, Diabetes, 51, 943, 10.2337/diabetes.51.4.943

Reimer, 2002, Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice, Eur J Endocrinol., 146, 717, 10.1530/eje.0.1460717

Ahrén, 2002, Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes, Diabetes Care, 25, 869, 10.2337/diacare.25.5.869

Ahrén, 2004, Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes, J Clin Endocrinol Metab., 89, 2078, 10.1210/jc.2003-031907

Ahrén, 2004, Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes, Diabetes Care, 27, 2874, 10.2337/diacare.27.12.2874

Deacon, 2016, Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas, Diabetes Obes Metab., 18, 333, 10.1111/dom.12610

Zhu, 2003, The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38), J Biol Chem., 278, 22418, 10.1074/jbc.M212355200

Mulvihill, 2014, Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors, Endocr Rev., 35, 992, 10.1210/er.2014-1035

Deacon, 2018, Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes, Peptides, 100, 150, 10.1016/j.peptides.2017.10.011

Scheen, 2018, The safety of gliptins: updated data in 2018, Expert Opin Drug Saf., 17, 387, 10.1080/14740338.2018.1444027

Deacon, 2000, Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide, J Clin Endocrinol Metab., 85, 3575

Deacon, 2001, Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs, Diabetes, 50, 1588, 10.2337/diabetes.50.7.1588

Nauck, 1993, Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus, J Clin Invest., 91, 301, 10.1172/JCI116186

Hansotia, 2004, Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors, Diabetes, 53, 1326, 10.2337/diabetes.53.5.1326

Aulinger, 2014, Defining the role of GLP-1 in the enteroinsulinar axis in type 2 diabetes using DPP-4 inhibition and GLP-1 receptor blockade, Diabetes, 63, 1079, 10.2337/db13-1455

Nauck, 2016, Quantification of the contribution of GLP-1 to mediating insulinotropic effects of DPP-4 inhibition with vildagliptin in healthy subjects and patients with type 2 diabetes using exendin [9-39] as a GLP-1 receptor antagonist, Diabetes, 65, 2440, 10.2337/db16-0107

Højberg, 2009, Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes, Diabetologia, 52, 199, 10.1007/s00125-008-1195-5

Aaboe, 2015, Restoration of the insulinotropic effect of glucose-dependent insulinotropic polypeptide contributes to the antidiabetic effect of dipeptidyl peptidase-4 inhibitors, Diabetes Obes Metab., 17, 74, 10.1111/dom.12395

Xu, 2007, Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes, Diabetes, 56, 1551, 10.2337/db06-1033

Hansen, 2012, Impaired incretin-induced amplification of insulin secretion after glucose homeostatic dysregulation in healthy subjects, J Clin Endocrinol Metab., 97, 1363, 10.1210/jc.2011-2594

Gasbjerg, 2018, GIP(3-30)NH2 is an efficacious GIP receptor antagonist in humans: a randomised, double-blinded, placebo-controlled, crossover study, Diabetologia, 61, 413, 10.1007/s00125-017-4447-4

Grandt, 1994, Two molecular forms of peptide YY (PYY) are abundant in human blood: characterization of a radioimmunoassay recognizing PYY 1-36 and PYY 3-36, Regul Pept., 51, 151, 10.1016/0167-0115(94)90204-6

Aaboe, 2010, Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non-glucose induced insulin secretion in patients with type 2 diabetes mellitus, Diabetes Obes Metab., 12, 323, 10.1111/j.1463-1326.2009.01167.x

Ahrén, 1996, Peptide YY does not inhibit glucose-stimulated insulin secretion in humans, Eur J Endocrinol., 134, 362, 10.1530/eje.0.1340362

Chen, 1997, PYY and NPY: control of gastric motility via action on Y1 and Y2 receptors in the DVC, Neurogastroenterol Motil., 9, 109, 10.1046/j.1365-2982.1997.d01-26.x

Holst, 2018, Oxyntomodulin: actions and role in diabetes, Peptides, 100, 48, 10.1016/j.peptides.2017.09.018

Druce, 2009, Investigation of structure-activity relationships of Oxyntomodulin (Oxm) using Oxm analogs, Endocrinology, 150, 1712, 10.1210/en.2008-0828

Liu, 2010, Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents, Int J Obes., 34, 1715, 10.1038/ijo.2010.110

Bianchi, 2013, A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic, insulinotropic and anorexigenic activity, Bioorg Med Chem., 21, 7064, 10.1016/j.bmc.2013.09.016

Liu, 2009, Stromal cell-derived factor-1 promotes survival of pancreatic beta cells by the stabilisation of beta-catenin and activation of transcription factor 7-like 2 (TCF7L2), Diabetologia, 52, 1589, 10.1007/s00125-009-1384-x

Liu, 2011, Stromal cell-derived factor-1 (SDF-1)/chemokine (C-X-C motif) receptor 4 (CXCR4) axis activation induces intra-islet glucagon-like peptide-1 (GLP-1) production and enhances beta cell survival, Diabetologia, 54, 2067, 10.1007/s00125-011-2181-x

Yano, 2007, Stromal cell derived factor-1 (SDF-1)/CXCL12 attenuates diabetes in mice and promotes pancreatic beta-cell survival by activation of the prosurvival kinase Akt, Diabetes, 56, 2946, 10.2337/db07-0291

Zaruba, 2009, Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction, Cell Stem Cell, 4, 313, 10.1016/j.stem.2009.02.013

Wang, 2014, Quantification of intact and truncated stromal cell-derived factor-1α in circulation by immunoaffinity enrichment and tandem mass spectrometry, J Am Soc Mass Spectr., 25, 614, 10.1007/s13361-013-0822-7

Lovshin, 2017, Dipeptidyl peptidase 4 inhibition stimulates distal tubular natriuresis and increases in circulating SDF-1α1-67 in patients with type 2 diabetes, Diabetes Care, 40, 1073, 10.2337/dc17-0061

Shioda, 1998, Anti-HIV-1 and chemotactic activities of human stromal cell-derived factor 1α (SDF-1α) and SDF-1β are abolished by CD26/dipeptidyl peptidase IV-mediated cleavage, Proc Natl Acad Sci USA., 95, 6331, 10.1073/pnas.95.11.6331

Fadini, 2010, The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha, Diabetes Care, 33, 1607, 10.2337/dc10-0187

Korosi, 2001, Effect of aging and diabetes on the enteroinsular axis, J Gerontol A Biol Sci Med Sci., 56, M575, 10.1093/gerona/56.9.M575

Mannucci, 2005, Hyperglycaemia increases dipeptidyl peptidase IV activity in diabetes mellitus, Diabetologia, 48, 1168, 10.1007/s00125-005-1749-8

Pala, 2010, Relationship between GLP-1 levels and dipeptidyl peptidase-4 activity in different glucose tolerance conditions, Diabet Med., 27, 691, 10.1111/j.1464-5491.2010.03010.x

Meneilly, 2000, Effect of ageing and diabetes on glucose-dependent insulinotropic polypeptide and dipeptidyl peptidase IV responses to oral glucose, Diabet Med., 17, 346, 10.1046/j.1464-5491.2000.00236.x

McKillop, 2008, Decreased dipeptidyl peptidase-IV activity and glucagon-like peptide-1 (7-36) amide degradation in type 2 diabetic subjects, Diabetes Res Clin Pract., 79, 79, 10.1016/j.diabres.2007.08.001

Ryskjaer, 2006, Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake, Eur J Endocrinol., 155, 485, 10.1530/eje.1.02221

Fadini, 2012, The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients, Diabetes Obes Metab., 14, 518, 10.1111/j.1463-1326.2011.01550.x

Deacon, 1996, Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig, Am J Physiol., 271, E458

Holst, 2005, Glucagon-like peptide-1 mediates the therapeutic actions of DPP-IV inhibitors, Diabetologia, 48, 612, 10.1007/s00125-005-1705-7

Pala, 2003, Dipeptidyl peptidase-IV expression and activity in human glomerular endothelial cells, Biochem Biophys Res Commun., 310, 28, 10.1016/j.bbrc.2003.08.111

Pala, 2012, Different modulation of dipeptidyl peptidase-4 activity between microvascular and macrovascular human endothelial cells, Acta Diabetol., 10.1007/s00592-010-0195-3

Lugari, 2004, Glucagon-like peptide 1 (GLP-1) secretion and plasma dipeptidyl peptidase IV (DPP-IV) activity in morbidly obese patients undergoing biliopancreatic diversion, Horm Metab Res., 36, 111, 10.1055/s-2004-814222

Lamers, 2011, Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome, Diabetes, 60, 1917, 10.2337/db10-1707

Kirino, 2012, Plasma dipeptidyl peptidase 4 activity correlates with body mass index and the plasma adiponectin concentration in healthy young people, Endocr J., 59, 949, 10.1507/endocrj.EJ12-0158

Sell, 2013, Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro, Diabetes Care, 36, 4083, 10.2337/dc13-0496

Varin, 2018, Circulating levels of soluble dipeptidyl peptidase-4 are dissociated from inflammation and induced by enzymatic DPP4 inhibition, Cell Metab., 29, 320, 10.1016/j.cmet.2018.10.001

Ghorpade, 2018, Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance, Nature, 555, 673, 10.1038/nature26138

Firneisz, 2010, Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker, PLoS ONE, 5, e12226, 10.1371/journal.pone.0012226

Miyazaki, 2012, Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism, Mol Med Rep., 5, 729, 10.3892/mmr.2011.707

Baumeier, 2017, Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease, Mol Metab., 6, 1254, 10.1016/j.molmet.2017.07.016

Baumeier, 2017, Hepatic DPP4 DNA methylation associates with fatty liver, Diabetes, 66, 25, 10.2337/db15-1716

Ahmed, 2017, Altered circulating concentrations of active glucagon-like peptide (GLP-1) and dipeptidyl peptidase 4 (DPP4) in obese subjects and their association with insulin resistance, Clin Biochem., 50, 746, 10.1016/j.clinbiochem.2017.03.008

Röhrborn, 2016, Reduced DPP4 activity improves insulin signaling in primary human adipocytes, Biochem Biophys Res Commun., 471, 348, 10.1016/j.bbrc.2016.02.019

Gorrell, 2005, Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders, Clin Sci., 108, 277, 10.1042/CS20040302

Ohnuma, 2004, CD26 up-regulates expression of CD86 on antigen-presenting cells by means of caveolin-1, Proc Natl Acad Sci USA., 101, 14186, 10.1073/pnas.0405266101

Cohen, 2003, Role of caveolin and caveolae in insulin signaling and diabetes, Am J Physiol Endocrinol Metab., 285, E1151, 10.1152/ajpendo.00324.2003

Catalán, 2008, Expression of caveolin-1 in human adipose tissue is upregulated in obesity and obesity-associated type 2 diabetes mellitus and related to inflammation, Clin Endocrinol., 68, 213, 10.1111/j.1365-2265.2007.03021.x

Palacios-Ortega, 2015, Effects of high glucose on caveolin-1 and insulin signaling in 3T3-L1 adipocytes, Adipocyte, 5, 65, 10.1080/21623945.2015.1122856

Rufinatscha, 2017, Dipeptidyl peptidase-4 impairs insulin signaling and promotes lipid accumulation in hepatocytes, Biochem Biophys Res Commun., 485, 366, 10.1016/j.bbrc.2017.02.071

Poulsen, 1993, Dipeptidyl peptidase IV is sorted to the secretory granules in pancreatic islet A-cells, J Histochem Cytochem., 41, 81, 10.1177/41.1.8093256

Segerstolpe, 2016, Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes, Cell Metab., 24, 593, 10.1016/j.cmet.2016.08.020

Zhang, 2017, Differential effects of linagliptin on the function of human islets isolated from non-diabetic and diabetic donors, Sci Rep., 7, 7964, 10.1038/s41598-017-08271-9

Bugliani, 2018, DPP-4 is expressed in human pancreatic beta cells and its direct inhibition improves beta cell function and survival in type 2 diabetes, Mol Cell Endocrinol., 473, 186, 10.1016/j.mce.2018.01.019

Grondin, 1999, Specific localization of membrane dipeptidase and dipeptidyl peptidase IV in secretion granules of two different pancreatic islet cells, J Histochem Cytochem., 47, 489, 10.1177/002215549904700407

Shah, 2013, The DPP-4 inhibitor linagliptin restores beta-cell function and survival in human isolated islets through GLP-1 stabilization, J Clin Endocrinol Metab., 98, E1163, 10.1210/jc.2013-1029

Liu, 2014, Dipeptidyl peptidase-4 (DPP-4): Localization and activity in human and rodent islets, Biochem Biophys Res Commun., 453, 398, 10.1016/j.bbrc.2014.09.096

Augstein, 2015, Localization of dipeptidyl peptidase-4 (CD26) to human pancreatic ducts and islet alpha cells, Diabetes Res Clin Pract., 110, 291, 10.1016/j.diabres.2015.10.010

Omar, 2014, Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes, Diabetologia, 57, 1876, 10.1007/s00125-014-3299-4

Rouille, 1995, Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide, J Biol Chem., 270, 26488, 10.1074/jbc.270.44.26488

Nie, 2000, Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats, J Clin Invest., 105, 955, 10.1172/JCI7456

Wideman, 2007, A switch from prohormone convertase (PC)-2 to PC1/3 expression in transplanted alpha-cells is accompanied by differential processing of proglucagon and improved glucose homeostasis in mice, Diabetes, 56, 2744, 10.2337/db07-0563

Whalley, 2011, Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells?, J Endocrinol., 211, 99, 10.1530/JOE-11-0094

Marchetti, 2012, A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets, Diabetologia, 55, 3262, 10.1007/s00125-012-2716-9

Sancho, 2017, Metabolic regulation of GLP-1 and PC1/3 in pancreatic α-cell line, PLoS ONE, 12, e0187836, 10.1371/journal.pone.0187836

Svendsen, 2018, Insulin secretion depends on intra-islet glucagon signaling, Cell Rep., 25, 1127, 10.1016/j.celrep.2018.10.018

Ellingsgaard, 2011, Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells, Nat Med., 17, 1481, 10.1038/nm.2513

Hansen, 2011, Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus - an adaptive response to hyperglycaemia?, Diabetologia, 54, 1379, 10.1007/s00125-011-2080-1

Traub, 2017, Pancreatic α cell-derived glucagon-related peptides are required for β cell adaptation and glucose homeostasis, Cell Rep., 18, 3192, 10.1016/j.celrep.2017.03.005

Chambers, 2017, The role of pancreatic preproglucagon in glucose homeostasis in mice, Cell Metab., 25, 927, 10.1016/j.cmet.2017.02.008

Davies, 2018, Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), Diabetologia, 61, 2461, 10.1007/s00125-018-4729-5

Garber, 2018, Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm - 2018 executive summary, Endocr Pract., 24, 91, 10.4158/CS-2017-0153

He, 2007, Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus, Clin Pharmacokinet, 46, 577, 10.2165/00003088-200746070-00003

Pratley, 2009, Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies, J Am Geriatr Soc., 57, 2011, 10.1111/j.1532-5415.2009.02484.x

Lehrke, 2014, Safety and tolerability of linagliptin in patients with type 2 diabetes: a comprehensive pooled analysis of 22 placebo-controlled studies, Clin Ther., 36, 1130, 10.1016/j.clinthera.2014.06.008

Hirshberg, 2014, Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus, Diabetes Metab Res Rev., 30, 556, 10.1002/dmrr.2502

Engel, 2013, Safety and tolerability of sitagliptin in type 2 diabetes: pooled analysis of 25 clinical studies, Diabetes Ther., 4, 119, 10.1007/s13300-013-0024-0

Schweizer, 2011, Assessing the general safety and tolerability of vildagliptin: value of pooled analyses from a large safety database versus evaluation of individual studies, Vasc Health Risk Manag., 7, 49, 10.2147/VHRM.S16925

White, 2013, Alogliptin after acute coronary syndrome in patients with type 2 diabetes, N Engl J Med., 369, 1327, 10.1056/NEJMoa1305889

Rosenstock, 2018, Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial, JAMA, 10.1001/jama.2018.18269

Green, 2015, Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes, N Engl J Med., 373, 232, 10.1056/NEJMoa1501352

Scirica, 2013, Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus, N Engl J Med., 369, 1317, 10.1056/NEJMoa1307684

Anz, 2014, The dipeptidylpeptidase-IV inhibitors sitagliptin, vildagliptin and saxagliptin do not impair innate and adaptive immune responses, Diabetes Obes Metab., 16, 569, 10.1111/dom.12246

Raz, 2014, Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin, Diabetes Care, 37, 2435, 10.2337/dc13-2546

Buse, 2017, Pancreatic safety of sitagliptin in the TECOS study, Diabetes Care, 40, 164, 10.2337/dc15-2780

Egan, 2014, Pancreatic safety of incretin-based drugs–FDA and EMA assessment, N Engl J Med., 370, 794, 10.1056/NEJMp1314078

Zannad, 2015, Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial, Lancet, 385, 2067, 10.1016/S0140-6736(14)62225-X

McGuire, 2016, Association between sitagliptin use and heart failure hospitalization and related outcomes in type 2 diabetes mellitus: secondary analysis of a randomized clinical trial, JAMA Cardiol., 1, 126, 10.1001/jamacardio.2016.0103

McGuire, 2019, Linagliptin effects on heart failure and related outcomes in individuals with type 2 diabetes mellitus at high cardiovascular and renal risk in CARMELINA, Circulation, 139, 351, 10.1161/CIRCULATIONAHA.118.038352

Koyani, 2017, Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure, Biochem Pharmacol., 145, 64, 10.1016/j.bcp.2017.08.021

Koyani, 2018, Saxagliptin but not sitagliptin inhibits CaMKII and PKC via DPP9 inhibition in cardiomyocytes, Front Physiol., 9, 1622, 10.3389/fphys.2018.01622