The effects of incretins on energy homeostasis: Physiology and implications for the treatment of type 2 diabetes mellitus and obesity

Current Vascular Pharmacology

Volumn 10, Issue 6, 2012, Pages 781-791

  Karras, Spyridon ^a,b   Goulis, Dimitrios G ^a   Mintziori, Gesthimani ^a   Katsiki, Niki ^c   Tzotzas, Themistoklis ^b  

^a ARISTOTLE UNIVERSITY MEDICAL SCHOOL   (Greece)

^b PANAGIA GENERAL HOSPITAL   (Greece)

^c Agios Dimitrios General Hospital   (Greece)

Author keywords

Energy homeostasis; Gastric inhibitory peptide (GIP); Glucagon like peptide 1 (GLP 1); Incretins; Obesity; Type 2 diabetes mellitus

Indexed keywords

AMINOTRANSFERASE; C REACTIVE PROTEIN; CHOLECYSTOKININ; CHOLESTEROL; COCAINE AND AMPHETAMINE REGULATED TRANSCRIPT PEPTIDE; CYCLIC AMP DEPENDENT PROTEIN KINASE; DAPAGLIFLOZIN; EXENDIN 4; GASTRIC INHIBITORY POLYPEPTIDE; GLUCAGON; GLUCAGON LIKE PEPTIDE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCOSE; HEMOGLOBIN A1C; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INCRETIN; LEPTIN; LIRAGLUTIDE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MELANOCORTIN 3 RECEPTOR; MELANOCORTIN 4 RECEPTOR; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; SAXAGLIPTIN; SITAGLIPTIN; SODIUM GLUCOSE COTRANSPORTER 2; TRIACYLGLYCEROL; UNINDEXED DRUG; VILDAGLIPTIN;

ADIPOSE TISSUE; CALORIC INTAKE; CARDIOVASCULAR RISK; DIASTOLIC BLOOD PRESSURE; ENERGY; FEEDBACK SYSTEM; HOMEOSTASIS; HUMAN; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REGULATORY MECHANISM; REVIEW; SATIETY; SYSTOLIC BLOOD PRESSURE; WEIGHT REDUCTION;

ANIMALS; ANTI-OBESITY AGENTS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; DRUG DESIGN; ENERGY METABOLISM; FEEDBACK, PHYSIOLOGICAL; HOMEOSTASIS; HUMANS; HYPOGLYCEMIC AGENTS; INCRETINS; OBESITY; RISK FACTORS; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

EID: 84870217834     PISSN: 15701611     EISSN: 18756212     Source Type: Journal    
DOI: 10.2174/157016112803520909     Document Type: Review

References (140)

1. Swanson M, Studts CR, Bardach SH, Bersamin A, Schoenberg NE. Intergenerational energy balance interventions: a systematic literature review. Health Educ Behav 2011; 38: 171-97.
2. Kenny PJ. Reward mechanisms in obesity: new insights and future directions. Neuron 2011; 69: 664-79.
3. Schwartz MW, Woods SC, Porte D, Jr., Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404: 661-71.
4. Barber TM, Begbie H, Levy J. The incretin pathway as a new therapeutic target for obesity. Maturitas 2010; 67: 197-202.
5. Torekov SS, Madsbad S, Holst JJ. Obesity-an indication for GLP-1 treatment? Obesity pathophysiology and GLP-1 treatment potential. Obes Rev 2011; 12: 593-601.
6. Moore B. On the treatment of Diabetus mellitus by acid extract of Duodenal Mucous Membrane. Biochem J 1906; 1: 28-38.
7. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964; 24: 1076-82.
8. McIntyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet 1964; 2: 20-1.
9. Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. J Clin Invest 1967; 46: 1954-62.
10. Brown JC, Dryburgh JR, Ross SA, Dupre J. Identification and actions of gastric inhibitory polypeptide. Recent Prog Horm Res 1975; 31: 487-532.
11. Pederson RA, Brown JC. The insulinotropic action of gastric inhibitory polypeptide in the perfused isolated rat pancreas. Endocrinology 1976; 99: 780-5.
12. Ross SA, Dupre J. Effects of ingestion of triglyceride or galactose on secretion of gastric inhibitory polypeptide and on responses to intravenous glucose in normal and diabetic subjects. Diabetes 1978; 27: 327-33.
13. Grimelius L, Capella C, Buffa R, Polak JM, Pearse AG, Solcia E. Cytochemical and ultrastructural differentiation of enteroglucagon and pancreatic-type glucagon cells of the gastrointestinal tract. Virch Arch B Cell Pathol 1976; 20: 217-28.
14. Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia 1985; 28: 704-7.
15. Fehmann HC, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev 1995; 16: 390-410.
16. Jepeal LI, Boylan MO, Wolfe MM. Cell-specific expression of the glucose-dependent insulinotropic polypeptide gene functions through a GATA and an ISL-1 motif in a mouse neuroendocrine tumor cell line. Regul Pept 2003; 113: 139-47.
17. Offield MF, Jetton TL, Labosky PA, et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 1996; 122: 983-95.
18. Jepeal LI, Fujitani Y, Boylan MO, Wilson CN, Wright CV, Wolfe MM. Cell-specific expression of glucose-dependent-insulinotropic polypeptide is regulated by the transcription factor PDX-1. Endocrinology 2005; 146: 383-91.
19. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev 1999; 20: 876-913.
20. Fujita Y, Asadi A, Yang GK, Kwok YN, Kieffer TJ. Differential processing of pro-glucose-dependent insulinotropic polypeptide in gut. Am J Physiol Gastrointest Liver Physiol 2010; 298: 608-14.
21. Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 1983; 302: 716-8.
22. Novak U, Wilks A, Buell G, McEwen S. Identical mRNA for preproglucagon in pancreas and gut. Eur J Biochem 1987; 164: 553-8.
23. Larsen PJ, Tang-Christensen M, Holst JJ, Orskov C. Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem. Neuroscience 1997; 77: 257-70.
24. Mojsov S, Heinrich G, Wilson IB, Ravazzola M, Orci L, Habener JF. Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. J Biol Chem 1986; 261: 11880-9.
25. Hill ME, Asa SL, Drucker DJ. Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription. Mol Endocrinol 1999; 13: 1474-86.
26. Habener JF, Kemp DM, Thomas MK. Minireview: transcriptional regulation in pancreatic development. Endocrinology 2005; 146: 1025-34.
27. Trinh DK, Zhang K, Hossain M, Brubaker PL, Drucker DJ. Pax-6 activates endogenous proglucagon gene expression in the rodent gastrointestinal epithelium. Diabetes 2003; 52: 425-33.
28. Yi F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J Biol Chem 2005; 280: 1457-64.
29. Yi F, Sun J, Lim GE, Fantus IG, Brubaker PL, Jin T. Cross talk between the insulin and Wnt signaling pathways: evidence from intestinal endocrine L cells. Endocrinology 2008; 149: 2341-51.
30. Bataille D. Pro-protein convertases in intermediary metabolism: islet hormones, brain/gut hormones and integrated physiology. J Mol Med (Berl) 2007; 85: 673-84.
31. von Eggelkraut-Gottanka R, Beck-Sickinger AG. Biosynthesis of peptide hormones derived from precursor sequences. Curr Med Chem 2004; 11: 2651-65.
32. Ugleholdt R, Zhu X, Deacon CF, Orskov C, Steiner DF, Holst JJ. Impaired intestinal proglucagon processing in mice lacking prohormone convertase 1. Endocrinology 2004; 145: 1349-55.
33. Baldissera FG, Holst JJ. Glucagon-related peptides in the human gastrointestinal mucosa. Diabetologia 1984; 26: 223-8.
34. Baldissera FG, Holst JJ. Glicentin 1-61 probably represents a major fraction of glucagon-related peptides in plasma of anaesthetized uraemic pigs. Diabetologia 1986; 29: 462-7.
35. Orskov C, Holst JJ, Knuhtsen S, Baldissera FG, Poulsen SS, Nielsen OV. Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas. Endocrinology 1986; 119: 1467-75.
36. Holst JJ, Orskov C, Nielsen OV, Schwartz TW. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett 1987; 211: 169-74.
37. Holst JJ, Bersani M, Johnsen AH, Kofod H, Hartmann B, Orskov C. Proglucagon processing in porcine and human pancreas. J Biol Chem 1994; 269: 18827-33.
38. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87: 1409-39.
39. Eissele R, Goke R, Willemer S, et al. Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest 1992; 22: 283-91.
40. Drucker DJ. The biology of incretin hormones. Cell Metab 2006; 3: 153-65.
41. Brubaker PL, Anini Y. Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2. Can J Physiol Pharmacol 2003; 81: 1005-12.
42. Sjolund K, Ekelund M, Hakanson R, Moody AJ, Sundler F. Gastric inhibitory peptide-like immunoreactivity in glucagon and glicentin cells: properties and origin. An immunocytochemical study using several antisera. J Histochem Cytochem 1983; 31: 811-7.
43. Wideman RD, Kieffer TJ. Glucose-dependent insulinotropic polypeptide as a regulator of beta cell function and fate. Horm Metab Res 2004; 36: 782-6.
44. Herrmann C, Goke R, Richter G, Fehmann HC, Arnold R, Goke B. Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients. Digestion 1995; 56: 117-26.
45. Brubaker PL. Control of glucagon-like immunoreactive peptide secretion from fetal rat intestinal cultures. Endocrinology 1988; 123: 220-6.
46. Reimann F, Habib AM, Tolhurst G, Parker HE, Rogers GJ, Gribble FM. Glucose sensing in L cells: a primary cell study. Cell Metab 2008; 8: 532-9.
47. Cani PD, Holst JJ, Drucker DJ, et al. GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion. Mol Cell Endocrinol 2007; 276: 18-23.
48. Simpson AK, Ward PS, Wong KY, et al. Cyclic AMP triggers glucagon-like peptide-1 secretion from the GLUTag enteroendocrine cell line. Diabetologia 2007; 50: 2181-9.
49. Nielsen LB, Ploug KB, Swift P, et al. Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes. Eur J Endocrinol 2007; 156: 663-71.
50. Jetton TL, Liang Y, Pettepher CC, et al. Analysis of upstream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut. J Biol Chem 1994; 269: 3641-54.
51. Murphy R, Tura A, Clark PM, Holst JJ, Mari A, Hattersley AT. Glucokinase, the pancreatic glucose sensor, is not the gut glucose sensor. Diabetologia 2009; 52: 154-9.
52. Gribble FM, Williams L, Simpson AK, Reimann F. A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line. Diabetes 2003; 52: 1147-54.
53. Fujita Y, Wideman RD, Speck M, et al. Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo. Am J Physiol Endocrinol Metab 2009; 296: 473-9.
54. Hirasawa A, Tsumaya K, Awaji T, et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 2005; 11: 90-4.
55. Edfalk S, Steneberg P, Edlund H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 2008; 57: 2280-7.
56. Theodorakis MJ, Carlson O, Michopoulos S, et al. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am J Physiol Endocrinol Metab 2006; 290: 550-9.
57. Hansen L, Deacon CF, Orskov C, Holst JJ. 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 1999; 140: 5356-63.
58. Boonacker E, Van Noorden CJ. The multifunctional or moonlighting protein CD26/DPPIV. Eur J Cell Biol 2003; 82: 53-73.
59. Mayo KE, Miller LJ, Bataille D, et al. International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 2003; 55: 167-94.
60. Thorens B, Porret A, Buhler L, Deng SP, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes 1993; 42: 1678-82.
61. Lin F, Wang R. Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists. J Mol Model 2009; 15: 53-65.
62. Goke R, Fehmann HC, Linn T, et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem 1993; 268: 19650-5.
63. Knudsen LB, Kiel D, Teng M, et al. Small-molecule agonists for the glucagon-like peptide 1 receptor. Proc Natl Acad Sci USA 2007; 104: 937-42.
64. Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 1993; 133: 2861-70.
65. Wheeler MB, Gelling RW, McIntosh CH, Georgiou J, Brown JC, Pederson RA. Functional expression of the rat pancreatic islet glucose-dependent insulinotropic polypeptide receptor: ligand binding and intracellular signaling properties. Endocrinology 1995; 136: 4629-39.
66. Miyawaki K, Yamada Y, Ban N, et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 2002; 8: 738-42.
67. Meier JJ, Nauck MA, Schmidt WE, Gallwitz B. Gastric inhibitory polypeptide: the neglected incretin revisited. Regul Pept 2002; 107: 1-13.
68. Yip RG, Wolfe MM. GIP biology and fat metabolism. Life Sci 2000; 66: 91-103.
69. Eckel RH, Fujimoto WY, Brunzell JD. Gastric inhibitory polypeptide enhanced lipoprotein lipase activity in cultured preadipocytes. Diabetes 1979; 28: 1141-2.
70. Oben J, Morgan L, Fletcher J, Marks V. Effect of the enteropancreatic hormones, gastric inhibitory polypeptide and glucagonlike polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue. J Endocrinol 1991; 130: 267-72.
71. Ogawa E, Hosokawa M, Harada N, et al. The effect of gastric inhibitory polypeptide on intestinal glucose absorption and intestinal motility in mice. Biochem Biophys Res Commun 2011; 404: 115-20.
72. Daousi C, Wilding JP, Aditya S, et al. Effects of peripheral administration of synthetic human glucose-dependent insulinotropic peptide (GIP) on energy expenditure and subjective appetite sensations in healthy normal weight subjects and obese patients with type 2 diabetes. Clin Endocrinol (Oxf) 2009; 71: 195-201.
73. Althage MC, Ford EL, Wang S, Tso P, Polonsky KS, Wice BM. Targeted ablation of glucose-dependent insulinotropic polypeptideproducing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet. J Biol Chem 2008; 283: 18365-76.
74. Gault VA, Irwin N, Green BD, et al. Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3)GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes. Diabetes 2005; 54: 2436-46.
75. Isken F, Pfeiffer AF, Nogueiras R, et al. Deficiency of glucosedependent insulinotropic polypeptide receptor prevents ovariectomy-induced obesity in mice. Am J Physiol Endocrinol Metab 2008; 295: 350-5.
76. Kalra SP, Kalra PS. Neuroendocrine control of energy homeostasis: update on new insights. Prog Brain Res 2010; 181: 17-33.
77. Konturek SJ, Konturek JW, Pawlik T, Brzozowski T. Brain-gut axis and its role in the control of food intake. J Physiol Pharmacol 2004; 55: 137-54.
78. Turton MD, O'Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996; 379: 69-72.
79. Meeran K, O'Shea D, Edwards CM, et al. Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. Endocrinology 1999; 140: 244-50.
80. Verdich C, Flint A, Gutzwiller JP, et al. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab 2001; 86: 4382-9.
81. Woods SC, Seeley RJ, Porte D, Jr., Schwartz MW. Signals that regulate food intake and energy homeostasis. Science 1998; 280: 1378-83.
82. Ma X, Bruning J, Ashcroft FM. Glucagon-like peptide 1 stimulates hypothalamic proopiomelanocortin neurons. J Neurosci 2007; 27: 7125-9.
83. Seo S, Ju S, Chung H, Lee D, Park S. Acute effects of glucagonlike peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. Endocr J 2008; 55: 867-74.
84. McMahon LR, Wellman PJ. PVN infusion of GLP-1-(7-36) amide suppresses feeding but does not induce aversion or alter locomotion in rats. Am J Physiol 1998; 274: 23-9.
85. Tritos NA, Vicent D, Gillette J, Ludwig DS, Flier ES, Maratos-Flier E. Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus. Diabetes 1998; 47: 1687-92.
86. Thiele TE, Van DG, Campfield LA, et al. Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats. Am J Physiol 1997; 272: 726-30.
87. Kim D, MacConell L, Zhuang D, et al. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 2007; 30: 1487-93.
88. Kinzig KP, D'Alessio DA, Seeley RJ. The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J Neurosci 2002; 22: 10470-6.
89. Hisadome K, Reimann F, Gribble FM, Trapp S. Leptin directly depolarizes preproglucagon neurons in the nucleus tractus solitarius: electrical properties of glucagon-like Peptide 1 neurons. Diabetes 2010; 59: 1890-8.
90. Bojanowska E, Nowak A. Interactions between leptin and exendin-4, a glucagon-like peptide-1 agonist, in the regulation of food intake in the rat. J Physiol Pharmacol 2007; 58: 349-60.
91. Ahren B. GLP-1 and extra-islet effects. Horm Metab Res 2004; 36: 842-5.
92. Williams DL. Minireview: finding the sweet spot: peripheral vs. central glucagon-like peptide 1 action in feeding and glucose homeostasis. Endocrinology 2009; 150: 2997-3001.
93. Holmes GM, Browning KN, Tong M, Qualls-Creekmore E, Travagli RA. Vagally mediated effects of glucagon-like peptide 1: in vitro and in vivo gastric actions. J Physiol 2009; 587: 4749-59.
94. Abbott CR, Monteiro M, Small CJ, et al. The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagalbrainstem-hypothalamic pathway. Brain Res 2005; 1044: 127-31.
95. Baggio LL, Huang Q, Brown TJ, Drucker DJ. A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes 2004; 53: 2492-500.
96. Neary NM, Small CJ, Druce MR, et al. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively. Endocrinology 2005; 146: 5120-7.
97. Talsania T, Anini Y, Siu S, Drucker DJ, Brubaker PL. Peripheral exendin-4 and peptide YY(3-36) synergistically reduce food intake through different mechanisms in mice. Endocrinology 2005; 146: 3748-56.
98. Spiller RC, Trotman IF, Higgins BE, et al. The ileal brake--inhibition of jejunal motility after ileal fat perfusion in man. Gut 1984; 25: 365-74.
99. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993; 38: 665-73.
100. Nogueiras R, Perez-Tilve D, Veyrat-Durebex C, et al. Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity. J Neurosci 2009; 29: 5916-25.
101. Sancho V, Trigo MV, Martin-Duce A, et al. Effect of GLP-1 on Dglucose transport, lipolysis and lipogenesis in adipocytes of obese subjects. Int J Mol Med 2006; 17: 1133-7.
102. Smeets AJ, Soenen S, Luscombe-Marsh ND, Ueland O, Westerterp-Plantenga MS. Energy expenditure, satiety, and plasma ghrelin, glucagon-like peptide 1, and peptide tyrosine-tyrosine concentrations following a single high-protein lunch. J Nutr 2008; 138: 698-702.
103. Cernea S, Raz I. Therapy in the early stage: incretins. Diabetes Care 2011; 34 Suppl 2: 264-71.
104. Addison D, Aguilar D. Diabetes and cardiovascular disease: the potential benefit of incretin-based therapies. Curr Atheroscler Rep 2011; 13: 115-22.
105. Anagnostis P, Athyros VG, Adamidou F, et al. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes Metab 2011; 13: 302-12.
106. Davidson MH. Cardiovascular effects of glucagonlike peptide-1 agonists. Am J Cardiol 2011; 108: 33-41.
107. Mafong DD, Henry RR. The role of incretins in cardiovascular control. Curr Hypertens Rep 2009; 11: 18-22.
108. Cefalu WT, Richards RJ, Melendez-Ramirez LY. Redefining treatment success in type 2 diabetes mellitus: Comprehensive targeting of core defects. Cleve Clin J Med 2009; 76 Suppl 5: 39-47.
109. Giorgino F, Leonardini A, Natalicchio A, Laviola L. Multifactorial intervention in Type 2 diabetes: the promise of incretin-based therapies. J Endocrinol Invest 2011; 34: 69-77.
110. Niswender K. Diabetes and obesity: therapeutic targeting and risk reduction-a complex interplay. Diabetes Obes Metab 2010; 12: 267-87.
111. Rizzo M, Rizvi AA, Spinas GA, Rini GB, Berneis K. Glucose lowering and anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4-inhibitors. Expert Opin Investig Drugs 2009; 18: 1495-503.
112. Unger J. Incretins: clinical perspectives, relevance, and applications for the primary care physician in the treatment of patients with type 2 diabetes mellitus. Mayo Clin Proc 2010; 85: 38-49.
113. Eleftheriadou I, Grigoropoulou P, Katsilambros N, Tentolouris N. The effects of medications used for the management of diabetes and obesity on postprandial lipid metabolism. Curr Diabetes Rev 2008; 4: 340-56.
114. Kolovou GD, Mikhailidis DP, Nordestgaard BG, Bilianou H, Panotopoulos G. Definition of postprandial lipaemia. Curr Vasc Pharmacol 2011; 9: 292-301.
115. Ovalle F. Cardiovascular implications of antihyperglycemic therapies for type 2 diabetes. Clin Ther 2011; 33: 393-407.
116. Tanaka T, Nangaku M, Nishiyama A. The role of incretins in saltsensitive hypertension: the potential use of dipeptidyl peptidase-IV inhibitors. Curr Opin Nephrol Hypertens 2011; 20: 476-81.
117. Chilton R, Wyatt J, Nandish S, Oliveros R, Lujan M. Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide-1-based therapies. Am J Med 2011; 124: 35-53.
118. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Hyperuricaemia and Non-Alcoholic Fatty Liver Disease (NAFLD): A Relationship with Implications for Vascular Risk? Curr Vasc Pharmacol 2011; 9; 698-705.
119. Van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of non-alcoholic steatohepatitis. Therap Adv Gastroenterol 2011; 4: 249-63.
120. Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N, Harrison SA. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol 2010; 105: 2707-9.
121. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008; 24: 275-86.
122. Davidson JA. Incorporating incretin-based therapies into clinical practice: differences between glucagon-like Peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors. Mayo Clin Proc 2010; 85: 27-37.
123. Ghosh RK, Ghosh SM, Chawla S, Jasdanwala SA. SGLT2 Inhibitors: A New Emerging Therapeutic Class in the Treatment of Type 2 Diabetes Mellitus. J Clin Pharmacol 2011. [Epub ahead of print].
124. Katsiki N, Papanas N, Mikhailidis DP. Dapagliflozin: more than just another oral glucose-lowering agent? Expert Opin Investig Drugs 2010; 19: 1581-9.
125. Papanas N, Katsiki N, Papatheodorou K, et al. Peripheral neuropathy is associated with increased serum levels of uric acid in type 2 diabetes mellitus. Angiology 2011; 62: 291-5.
126. Papanas N, Demetriou M, Katsiki N, et al. Increased serum levels of uric acid are associated with sudomotor dysfunction in subjects with type 2 diabetes mellitus. Exp Diabetes Res 2011; 2011: 346051.
127. Yamaoka-Tojo M, Tojo T, Takahira N, et al. Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease. Cardiovasc Diabetol 2010; 9: 17.
128. Jellinger PS. Focus on incretin-based therapies: targeting the core defects of type 2 diabetes. Postgrad Med 2011; 123: 53-65.
129. Neumiller JJ. Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors. J Am Pharm Assoc (2003) 2009; 49 (Suppl 1): 16-29.
130. 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.
131. Florentin M, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Sitagliptin in clinical practice: a new approach in the treatment of type 2 diabetes. Expert Opin Pharmacother 2008; 9: 1705-20.
132. Gerich J. DPP-4 inhibitors: what may be the clinical differentiators? Diabetes Res Clin Pract 2010; 90: 131-40.
133. Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes Res 2004; 12: 1197-211.
134. Mancini MC, Halpern A. Investigational therapies in the treatment of obesity. Expert Opin Investig Drugs 2006; 15: 897-915.
135. Hayes MR, Kanoski SE, Alhadeff AL, Grill HJ. Comparative effects of the long-acting GLP-1 receptor ligands, liraglutide and exendin-4, on food intake and body weight suppression in rats. Obesity (Silver Spring) 2011; 19: 1342-9.
136. Reidelberger RD, Haver AC, Apenteng BA, Anders KL, Steenson SM. Effects of exendin-4 alone and with peptide YY(3-36) on food intake and body weight in diet-induced obese rats. Obesity (Silver Spring) 2011; 19: 121-7.
137. Astrup A, Rossner S, Van GL, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebocontrolled study. Lancet 2009; 374: 1606-16.
138. Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond) 2011. [Epub ahead of print].
139. Barrera JG, Sandoval DA, D'Alessio DA, Seeley RJ. GLP-1 and energy balance: an integrated model of short-term and long-term control. Nat Rev Endocrinol 2011; 7: 507-16.
140. Katsiki N, Mikhailidis DP, Gotzamani-Psarrakou A, Yovos JG, Karamitsos D. Effect of various treatments on leptin, adiponectin, ghrelin and neuropeptide Y in patients with type 2 diabetes mellitus. Expert Opin Ther Targets 2011; 15: 401-20.