• 1
    Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.
  • 2
    Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011; 17(Suppl. 2): 153.
  • 3
    Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004; 287: E199206.
  • 4
    Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 1902; 28: 32553.
  • 5
    Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964; 24: 107682.
  • 6
    McIntyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet 1964; 2: 201.
  • 7
    Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 213157.
  • 8
    Pederson RA, Brown JC. Inhibition of histamine-, pentagastrin-, and insulin-stimulated canine gastric secretion by pure “gastric inhibitory polypeptide”. Gastroenterology 1972; 62: 393400.
  • 9
    Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 1973; 37: 8268.
  • 10
    Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 1983; 302: 7168.
  • 11
    Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC. Exon duplication and divergence in the human preproglucagon gene. Nature 1983; 304: 36871.
  • 12
    Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci USA 1987; 84: 34348.
  • 13
    Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7–36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 1993; 76: 9127.
  • 14
    Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept 2003; 114: 11521.
  • 15
    Buchan AM, Polak JM, Capella C, Solcia E, Pearse AG. Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) in man. Histochemistry 1978; 56: 3744.
  • 16
    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: 28391.
  • 17
    Crockett SE, Cataland S, Falko JM, Mazzaferri EL. The insulinotropic effect of endogenous gastric inhibitory polypeptide in normal subjects. J Clin Endocrinol Metab 1976; 42: 1098103.
  • 18
    Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V. Glucagon-like peptide-1 (7–36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol 1993; 138: 15966.
  • 19
    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: 11726.
  • 20
    Vilsboll T, Krarup T, Sonne J, et al. Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J Clin Endocrinol Metab 2003; 88: 270613.
  • 21
    Carr RD, Larsen MO, Winzell MS, et al. Incretin and islet hormonal responses to fat and protein ingestion in healthy men. Am J Physiol Endocrinol Metab 2008; 295: E77984.
  • 22
    Besterman HS, Cook GC, Sarson DL, et al. Gut hormones in tropical malabsorption. Br Med J 1979; 2: 12525.
  • 23
    Rocca AS, Brubaker PL. Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology 1999; 140: 168794.
  • 24
    Roberge JN, Brubaker PL. Regulation of intestinal proglucagon-derived peptide secretion by glucose-dependent insulinotropic peptide in a novel enteroendocrine loop. Endocrinology 1993; 133: 23340.
  • 25
    Herrmann-Rinke C, Voge A, Hess M, Goke B. Regulation of glucagon-like peptide-1 secretion from rat ileum by neurotransmitters and peptides. J Endocrinol 1995; 147: 2531.
  • 26
    Persson K, Gingerich RL, Nayak S, Wada K, Wada E, Ahren B. Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice. Am J Physiol Endocrinol Metab 2000; 279: E95662.
  • 27
    Miguel JC, Abdel-Wahab YH, Green BD, Mathias PC, Flatt PR. Cooperative enhancement of insulinotropic action of GLP-1 by acetylcholine uncovers paradoxical inhibitory effect of beta cell muscarinic receptor activation on adenylate cyclase activity. Biochem Pharmacol 2003; 65: 28392.
  • 28
    Balks HJ, Holst JJ, von zur Muhlen A, Brabant G. Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors. J Clin Endocrinol Metab 1997; 82: 78690.
  • 29
    Chia CW, Carlson OD, Kim W, et al. Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes. Diabetes 2009; 58: 13429.
  • 30
    Roberge JN, Brubaker PL. Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients. Endocrinology 1991; 128: 316974.
  • 31
    Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences. FEBS Lett 1995; 358: 21924.
  • 32
    Vrang N, Hansen M, Larsen PJ, Tang-Christensen M. Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei. Brain Res 2007; 1149: 11826.
  • 33
    Shimizu I, Hirota M, Ohboshi C, Shima K. Identification and localization of glucagon-like peptide-1 and its receptor in rat brain. Endocrinology 1987; 121: 107682.
  • 34
    Nakagawa A, Satake H, Nakabayashi H, et al. Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci 2004; 110: 3643.
  • 35
    Egan JM, Montrose-Rafizadeh C, Wang Y, Bernier M, Roth J. Glucagon-like peptide-1(7–36) amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-L1 adipocytes: one of several potential extrapancreatic sites of GLP-1 action. Endocrinology 1994; 135: 20705.
  • 36
    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: 286170.
  • 37
    Gautier JF, Choukem SP, Girard J. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab 2008; 34(Suppl. 2): S6572.
  • 38
    Luque MA, Gonzalez N, Marquez L, et al. Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. J Endocrinol 2002; 173: 46573.
  • 39
    O'Harte FP, Gray AM, Flatt PR. Gastric inhibitory polypeptide and effects of glycation on glucose transport and metabolism in isolated mouse abdominal muscle. J Endocrinol 1998; 156: 23743.
  • 40
    Asmar M, Simonsen L, Madsbad S, Stallknecht B, Holst JJ, Bulow J. Glucose-dependent insulinotropic polypeptide may enhance fatty acid re-esterification in subcutaneous abdominal adipose tissue in lean humans. Diabetes 2010; 59: 21603.
  • 41
    Hartmann H, Ebert R, Creutzfeldt W. Insulin-dependent inhibition of hepatic glycogenolysis by gastric inhibitory polypeptide (GIP) in perfused rat liver. Diabetologia 1986; 29: 1124.
  • 42
    Prigeon RL, Quddusi S, Paty B, D'Alessio DA. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab 2003; 285: E7017.
  • 43
    Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet 1987; 2: 13004.
  • 44
    Nauck M, Schmidt WE, Ebert R, et al. Insulinotropic properties of synthetic human gastric inhibitory polypeptide in man: interactions with glucose, phenylalanine, and cholecystokinin-8. J Clin Endocrinol Metab 1989; 69: 65462.
  • 45
    Trumper A, Trumper K, Trusheim H, Arnold R, Goke B, Horsch D. Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. Mol Endocrinol 2001; 15: 155970.
  • 46
    Buteau J, Foisy S, Joly E, Prentki M. Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 2003; 52: 12432.
  • 47
    Farilla L, Bulotta A, Hirshberg B, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003; 144: 514958.
  • 48
    Kim SJ, Winter K, Nian C, Tsuneoka M, Koda Y, McIntosh CH. Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. J Biol Chem 2005; 280: 22297307.
  • 49
    Alarcon C, Wicksteed B, Rhodes CJ. Exendin 4 controls insulin production in rat islet beta cells predominantly by potentiation of glucose-stimulated proinsulin biosynthesis at the translational level. Diabetologia 2006; 49: 29209.
  • 50
    Pamir N, Lynn FC, Buchan AM, et al. Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis. Am J Physiol Endocrinol Metab 2003; 284: E9319.
  • 51
    Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998; 101: 51520.
  • 52
    Meier JJ, Gallwitz B, Siepmann N, et al. Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia. Diabetologia 2003; 46: 798801.
  • 53
    Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA. Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7–36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 1996; 81: 32732.
  • 54
    Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 271925.
  • 55
    Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997; 273: E9818.
  • 56
    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 vagal-brainstem-hypothalamic pathway. Brain Res 2005; 1044: 12731.
  • 57
    Burcelin R, Cani PD, Knauf C. Glucagon-like peptide-1 and energy homeostasis. J Nutr 2007; 137: 2534S8S.
  • 58
    Holz G, Kuhtreiber WM, Habener JF. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7–37). Nature 1993; 361: 3625.
  • 59
    Schmidtler J, Schepp W, Janczewska I, et al. GLP-1-(7–36) amide, -(1–37), and -(1–36) amide: potent cAMP-dependent stimuli of rat parietal cell function. Am J Physiol 1991; 260: G94050.
  • 60
    Gutzwiller JP, Drewe J, Goke B, et al. Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol 1999; 276: R15414.
  • 61
    DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092100.
  • 62
    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: 535663.
  • 63
    Deacon CF, Pridal L, Klarskov L, Olesen M, Holst JJ. Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am J Physiol 1996; 271: E45864.
  • 64
    Balkan B, Li X. Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol Regul Integr Comp Physiol 2000; 279: R144954.
  • 65
    Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986; 29: 4652.
  • 66
    Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. 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 1993; 91: 3017.
  • 67
    Mannucci E, Ognibene A, Cremasco F, et al. Glucagon-like peptide (GLP)-1 and leptin concentrations in obese patients with type 2 diabetes mellitus. Diabet Med 2000; 17: 7139.
  • 68
    Toft-Nielsen MB, Damholt MB, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001; 86: 371723.
  • 69
    Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes 2001; 50: 60913.
  • 70
    Muscelli E, Mari A, Casolaro A, et al. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 2008; 57: 13408.
  • 71
    Orskov C, Jeppesen J, Madsbad S, Holst JJ. Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine. J Clin Invest 1991; 87: 41523.
  • 72
    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: E5509.
  • 73
    Ahren B, Larsson H, Holst JJ. Reduced gastric inhibitory polypeptide but normal glucagon-like peptide 1 response to oral glucose in postmenopausal women with impaired glucose tolerance. Eur J Endocrinol 1997; 137: 12731.
  • 74
    Vollmer K, Holst JJ, Baller B, et al. Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance. Diabetes 2008; 57: 67887.
  • 75
    Knop FK, Vilsboll T, Hojberg PV, et al. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes 2007; 56: 19519.
  • 76
    Amylin Pharmaceuticals, Inc. Byetta (Exenatide) Injection: US Prescribing Information (Revised December 2011). San Diego, CA: Amylin Pharmaceuticals, Inc., 2011.
  • 77
    Novo Nordisk, Inc. Victoza (Liraglutide [RDNA Origin] Injection) Solution for Subcutaneous use: US Prescribing Information (Revised April 2012). Princeton, NJ: Novo Nordisk Inc., 2012.
  • 78
    Riddle MC, Henry RR, Poon TH, et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev 2006; 22: 48391.
  • 79
    Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 262835.
  • 80
    Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 3947.
  • 81
    Anderson SL, Trujillo JM. Association of pancreatitis with glucagon-like peptide-1 agonist use. Ann Pharmacother 2010; 44: 9049.
  • 82
    Lee PH, Stockton MD, Franks AS. Acute pancreatitis associated with liraglutide. Ann Pharmacother 2011; 45: e22.
  • 83
    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: 82935.
  • 84
    Heike M, Mobius U, Knuth A, Meuer S, Meyer zum Buschenfelde KH. Tissue distribution of the T cell activation antigen Ta1. Serological, immunohistochemical and biochemical investigations. Clin Exp Immunol 1988; 74: 4314.
  • 85
    Hegen M, Niedobitek G, Klein CE, Stein H, Fleischer B. The T cell triggering molecule Tp103 is associated with dipeptidyl aminopeptidase IV activity. J Immunol 1990; 144: 290814.
  • 86
    Fox DA, Hussey RE, Fitzgerald KA, et al. Ta1, a novel 105 KD human T cell activation antigen defined by a monoclonal antibody. J Immunol 1984; 133: 12506.
  • 87
    Marguet D, Baggio L, Kobayashi T, et al. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA 2000; 97: 68749.
  • 88
    Conarello SL, Li Z, Ronan J, et al. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci USA 2003; 100: 682530.
  • 89
    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 with metformin alone. Diabetes Care 2009; 32: 164955.
  • 90
    Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. 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, non-inferiority trial. Diabetes Obes Metab 2007; 9: 194205.
  • 91
    Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug-naive patients with type 2 diabetes. Diabetes Res Clin Pract 2007; 76: 1328.
  • 92
    Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011; 13: 6574.
  • 93
    Ahren B, Foley JE, Ferrannini E, et al. Changes in prandial glucagon levels after a 2-year treatment with vildagliptin or glimepiride in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care 2010; 33: 7302.
  • 94
    Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91: 46129.
  • 95
    Boehringer Ingelheim Pharmaceuticals, Inc. Tradjenta (Linagliptin) Tablets: US Prescribing Information (Revised May 2012). Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc., 2012.
  • 96
    Bristol-Myers Squibb. Onglyza (Saxagliptin) Tablets: US Prescribing Information (Revised December 2011). Princeton, NJ: Bristol-Myers Squibb, 2011.
  • 97
    Merck & Co. Januvia (Sitagliptin) Tablets: US Prescribing Information (Revised April 2012). Whitehouse Station, NJ: Merck & Co, 2012.
  • 98
    Committee for Medicinal Products for Human Use. Summary of Opinion (Post Authorisation) - Galvus (Vildagliptin). London, UK: European Medicines Agency, 2011. Available at: 2012.
  • 99
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 122131.
  • 100
    Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107: 4505.
  • 101
    Lazo M, Hernaez R, Bonekamp S, et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ 2011; 343: d6891.
  • 102
    Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006; 43: S99112.
  • 103
    Clark JM, Brancati FL, Diehl AM. Nonalcoholic fatty liver disease. Gastroenterology 2002; 122: 164957.
  • 104
    Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114: 14752.
  • 105
    Davis RC, Castellani LW, Hosseini M, et al. Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice. Diabetes 2010; 59: 161625.
  • 106
    Sung KC, Kim SH. Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. J Clin Endocrinol Metab 2011; 96: 10937.
  • 107
    Chang Y, Ryu S, Sung E, Jang Y. Higher concentrations of alanine aminotransferase within the reference interval predict nonalcoholic fatty liver disease. Clin Chem 2007; 53: 68692.
  • 108
    Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005; 54: 6038.
  • 109
    Sullivan S, Kirk EP, Mittendorfer B, Patterson BW, Klein S. Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease. Hepatology 2012; 55: 173845.
  • 110
    Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010; 52: 79104.
  • 111
    Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297307.
  • 112
    Boettcher E, Csako G, Pucino F, Wesley R, Loomba R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012; 35: 6675.
  • 113
    Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2009; 29: 17282.
  • 114
    Garinis GA, Fruci B, Mazza A, et al. Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study. Int J Obes (Lond) 2010; 34: 125564.
  • 115
    Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005; 100: 108290.
    Direct Link:
  • 116
    Mazza A, Fruci B, Garinis GA, Giuliano S, Malaguarnera R, Belfiore A. The role of metformin in the management of NAFLD. Exp Diabetes Res 2012; 2012: 716404.
  • 117
    de Oliveira CP, Stefano JT, de Siqueira ER, et al. Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis. Hepatol Res 2008; 38: 15965.
  • 118
    Saha AK, Avilucea PR, Ye JM, Assifi MM, Kraegen EW, Ruderman NB. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem Biophys Res Commun 2004; 314: 5805.
  • 119
    Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 116774.
  • 120
    Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310: 16426.
  • 121
    Haukeland JW, Konopski Z, Eggesbo HB, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009; 44: 85360.
  • 122
    Omer Z, Cetinkalp S, Akyildiz M, et al. Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2010; 22: 1823.
  • 123
    Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol 2009; 46: 1138.
  • 124
    Schreurs M, Kuipers F, van der Leij FR. Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome. Obes Rev 2010; 11: 3808.
  • 125
    Schoonderwoerd K, Stam H. Lipid metabolism of myocardial endothelial cells. Mol Cell Biochem 1992; 116: 1719.
  • 126
    Kuhajda FP, Ronnett GV. Modulation of carnitine palmitoyltransferase-1 for the treatment of obesity. Curr Opin Investig Drugs 2007; 8: 3127.
  • 127
    Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009; 89: 14791.
  • 128
    Staels B, Fonseca VA. Bile acids and metabolic regulation: mechanisms and clinical responses to bile acid sequestration. Diabetes Care 2009; 32(Suppl. 2): S23745.
  • 129
    Andersen E, Karlaganis G, Sjovall J. Altered bile acid profiles in duodenal bile and urine in diabetic subjects. Eur J Clin Invest 1988; 18: 16672.
  • 130
    Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 2000; 14: 12141.
  • 131
    Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 2012; 13: 21324.
  • 132
    Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999; 284: 13658.
  • 133
    Kobayashi M, Ikegami H, Fujisawa T, et al. Prevention and treatment of obesity, insulin resistance, and diabetes by bile acid-binding resin. Diabetes 2007; 56: 23947.
  • 134
    Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 2006; 116: 11029.
  • 135
    Zhang Y, Lee FY, Barrera G, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci USA 2006; 103: 100611.
  • 136
    Wright WL. The management of type 2 diabetes mellitus: a novel approach for addressing glycemic and lipid control with colesevelam HCl. Adv Nurse Pract 2009; 17(Suppl.): 116.
  • 137
    Goodwin B, Jones SA, Price RR, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 2000; 6: 51726.
  • 138
    Edwards PA, Kast HR, Anisfeld AM. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res 2002; 43: 212.
  • 139
    Kong B, Luyendyk JP, Tawfik O, Guo GL. Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J Pharmacol Exp Ther 2009; 328: 11622.
  • 140
    Cariou B, van Harmelen K, Duran-Sandoval D, et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 2006; 281: 1103949.
  • 141
    Holt JA, Luo G, Billin AN, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev 2003; 17: 158191.
  • 142
    Fu L, John LM, Adams SH, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. Endocrinology 2004; 145: 2594603.
  • 143
    Xu J, Lloyd DJ, Hale C, et al. Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 2009; 58: 2509.
  • 144
    Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 2002; 298: 7149.
  • 145
    Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003; 278: 943540.
  • 146
    Staels B, Handelsman Y, Fonseca V. Bile acid sequestrants for lipid and glucose control. Curr Diab Rep 2010; 10: 707.
  • 147
    Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006; 439: 4849.
  • 148
    Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun 2005; 329: 38690.
  • 149
    Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009; 10: 16777.
  • 150
    Knop FK. Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes? Am J Physiol Endocrinol Metab 2010; 299: E103.
  • 151
    Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med 2008; 168: 197583.
  • 152
    Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care 2008; 31: 147984.
  • 153
    Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med 2008; 168: 153140.
  • 154
    Hofmann AF. Bile acid sequestrants improve glycemic control in type 2 diabetes: a proposed mechanism implicating glucagon-like peptide 1 release. Hepatology 2011; 53: 1784.
  • 155
    Shang Q, Saumoy M, Holst JJ, Salen G, Xu G. Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing the release of GLP-1. Am J Physiol Gastrointest Liver Physiol 2010; 298: G41924.
  • 156
    Beysen C, Murphy EJ, Deines K, et al. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia 2012; 55: 43242.
  • 157
    Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004; 292: 172437.
  • 158
    Pories WJ, MacDonald KG Jr, Morgan EJ, et al. Surgical treatment of obesity and its effect on diabetes: 10-y follow-up. Am J Clin Nutr 1992; 55: 582S5S.
  • 159
    Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995; 222: 33950.
  • 160
    Schauer PR, Burguera B, Ikramuddin S, et al. Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus. Ann Surg 2003; 238: 46784.
  • 161
    Clements RH, Gonzalez QH, Long CI, Wittert G, Laws HL. Hormonal changes after Roux-en Y gastric bypass for morbid obesity and the control of type-II diabetes mellitus. Am Surg 2004; 70: 14.
  • 162
    le Roux CW, Aylwin SJ, Batterham RL, et al. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 2006; 243: 10814.
  • 163
    Patti ME, Houten SM, Bianco AC, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity 2009; 17: 16717.
  • 164
    Nakatani H, Kasama K, Oshiro T, Watanabe M, Hirose H, Itoh H. Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery. Metabolism 2009; 58: 14007.