Biologic actions and therapeutic potential of the proglucagon-derived peptides


The actions of the structurally related proglucagon-derived peptides (PGDPs)—glucagon, glucagon-like peptide (GLP)-1 and GLP-2—are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores β-cell sensitivity to glucose, increases β-cell proliferation, and reduces apoptosis, leading to expansion of the β-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.

Key Points

  • The structurally related proglucagon-derived peptides are produced in the pancreas, gut and brain, and regulate complementary aspects of energy homeostasis

  • The glucagon-like peptide 1 receptor agonist exenatide has recently been approved for treatment of type 2 diabetes

  • Exenatide (exendin 4) and the amylin agonist pramlintide (another drug used to treat type 2 diabetes) also inhibit glucagon secretion

  • Dipeptidyl peptidase IV cleaves incretin hormones such as glucagon-like peptide 1, and drugs that inhibit this enzyme are in phase III trials for treatment of type 2 diabetes

  • Glucagon-like peptide 2 is currently in phase III clinical trials for treatment of short-bowel syndrome

  • Thus various strategies that modulate proglucagon-derived peptides show therapeutic potential in both diabetes and intestinal disease

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Structure of proglucagon and the proglucagon-derived peptides
Figure 2: Representation of normal glucagon action on the liver and pancreas
Figure 3: Actions of glucagon-like peptide 1 on multiple target tissues
Figure 4: The actions of glucagon-like peptide 2 in the gastrointestinal mucosa


  1. 1

    Bell GI et al. (1983) Exon duplication and divergence in the human preproglucagon gene. Nature 304: 368–371

    CAS  Article  Google Scholar 

  2. 2

    Mayo KE et al. (2003) International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 55: 167–194

    CAS  Article  Google Scholar 

  3. 3

    Patzelt C and Schiltz E (1984) Conversion of proglucagon in pancreatic alpha cells: the major endproducts are glucagon and a single peptide, the major proglucagon fragment, that contains two glucagon-like sequences. Proc Natl Acad Sci USA 81: 5007–5011

    CAS  Article  Google Scholar 

  4. 4

    Furuta M et al. (1999) Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2. Proc Natl Acad Sci USA 94: 6646–6651

    Article  Google Scholar 

  5. 5

    Unger RH and Orci L (1975) The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1: 14–16

    CAS  Article  Google Scholar 

  6. 6

    Cryer PE (2004) Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 350: 2272–2279

    CAS  Article  Google Scholar 

  7. 7

    Hope KM et al. (2004) Regulation of alpha-cell function by the beta-cell in isolated human and rat islets deprived of glucose: the “switch-off” hypothesis. Diabetes 53: 1488–1495

    CAS  Article  Google Scholar 

  8. 8

    Gosmanov NR et al. (2005) Role of the decrement in intraislet insulin for the glucagon response to hypoglycemia in humans. Diabetes Care 28: 1124–1131

    CAS  Article  Google Scholar 

  9. 9

    Gelling RW et al. (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 100: 1438–1443

    CAS  Article  Google Scholar 

  10. 10

    Liang Y et al. (2004) Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes 53: 410–417

    CAS  Article  Google Scholar 

  11. 11

    Sloop KW et al. (2004) Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest 113: 1571–1581

    CAS  Article  Google Scholar 

  12. 12

    Jiang G and Zhang BB (2003) Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 284: 671–678

    Article  Google Scholar 

  13. 13

    Petersen KF and Sullivan JT (2001) Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia 44: 2018–2024

    CAS  Article  Google Scholar 

  14. 14

    Schmitz O et al. (2004) Amylin agonists: a novel approach in the treatment of diabetes. Diabetes 53 (Suppl 3): S233–S238

    CAS  Article  Google Scholar 

  15. 15

    Ahren B et al. (2004) Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 89: 2078–2084

    CAS  Article  Google Scholar 

  16. 16

    Zhu X et al. (2002) Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci USA 99: 10293–10298

    CAS  Article  Google Scholar 

  17. 17

    Drucker DJ et al. (1996) Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci USA 93: 7911–7916

    CAS  Article  Google Scholar 

  18. 18

    Goke R et al. (1993) 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 β-cells. J Biol Chem 268: 19650–19655

    CAS  PubMed  Google Scholar 

  19. 19

    Dakin CL et al. (2004) Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology 145: 2687–2695

    CAS  Article  Google Scholar 

  20. 20

    Cohen MA et al. (2003) Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 88: 4696–4701

    CAS  Article  Google Scholar 

  21. 21

    Wynne K et al. (2005) Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 54: 2390–2395

    CAS  Article  Google Scholar 

  22. 22

    Baggio LL et al. (2004) Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 127: 546–558

    CAS  Article  Google Scholar 

  23. 23

    Brubaker PL and Anini Y (2003) Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2. Can J Physiol Pharmacol 81: 1005–1012

    CAS  Article  Google Scholar 

  24. 24

    Orskov C et al. (1993) Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes 42: 658–661

    CAS  Article  Google Scholar 

  25. 25

    Nauck MA et al. (2002) Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 87: 1239–1246

    CAS  Article  Google Scholar 

  26. 26

    Drucker DJ et al. (1987) Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci USA 84: 3434–3438

    CAS  Article  Google Scholar 

  27. 27

    Drucker DJ (2003) Glucagon-like peptide-1 and the islet beta-cell: augmentation of cell proliferation and inhibition of apoptosis. Endocrinology 144: 5145–5148

    CAS  Article  Google Scholar 

  28. 28

    Xu G et al. (1999) Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48: 2270–2276

    CAS  Article  Google Scholar 

  29. 29

    Kim JG et al. (2003) Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Diabetes 52: 751–759

    CAS  Article  Google Scholar 

  30. 30

    Drucker DJ (2003) Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol 17: 161–171

    CAS  Article  Google Scholar 

  31. 31

    Li Y et al. (2003) Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 278: 471–478

    CAS  Article  Google Scholar 

  32. 32

    Wang Q et al. (2004) Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic (INS-1) beta-cells. Diabetologia 47: 478–487

    CAS  Article  Google Scholar 

  33. 33

    Farilla L et al. (2003) GLP-1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 144: 5149–5158

    CAS  Article  Google Scholar 

  34. 34

    Buteau J et al. (2004) Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia 47: 806–815

    CAS  Article  Google Scholar 

  35. 35

    Turton MD et al. (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379: 69–72

    CAS  Article  Google Scholar 

  36. 36

    Flint A et al. (1998) Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 101: 515–520

    CAS  Article  Google Scholar 

  37. 37

    Nauck MA et al. (1997) Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol Endocrinol Metab 273: 981–988

    Article  Google Scholar 

  38. 38

    Imeryuz N et al. (1997) Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol Gastrointest Liver Physiol 273: 920–927

    Article  Google Scholar 

  39. 39

    Baggio LL et al. (2004) Chronic exposure to GLP-1R agonists promotes homologous GLP-1 receptor desensitization in vitro but does not attenuate GLP-1R-dependent glucose homeostasis in vivo. Diabetes 53 (Suppl 3): S205–S214

    CAS  Article  Google Scholar 

  40. 40

    Abbott CR et al. (2005) 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 1044: 127–131

    CAS  Article  Google Scholar 

  41. 41

    Nikolaidis LA et al. (2004) Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation 110: 955–961

    CAS  Article  Google Scholar 

  42. 42

    Bose AK et al. (2005) Glucagon-like peptide-1 (GLP-1) can directly protect the heart against ischemia/reperfusion injury. Diabetes 54: 146–151

    CAS  Article  Google Scholar 

  43. 43

    Nikolaidis LA et al. (2004) Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation 109: 962–965

    CAS  Article  Google Scholar 

  44. 44

    Scrocchi LA et al. (1996) Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide receptor gene. Nature Med 2: 1254–1258

    CAS  Article  Google Scholar 

  45. 45

    Gutniak M et al. (1992) Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326: 1316–1322

    CAS  Article  Google Scholar 

  46. 46

    Rachman J et al. (1997) Near normalization of diurnal glucose concentrations by continuous administration of glucagon-like peptide 1 (GLP-1) in subjects with NIDDM. Diabetologia 40: 205–211

    CAS  Article  Google Scholar 

  47. 47

    Dupre J et al. (1995) Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM. Diabetes 44: 626–630

    CAS  Article  Google Scholar 

  48. 48

    Vilsboll T et al. (2003) The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype. J Clin Endocrinol Metab 88: 4897–4903

    CAS  Article  Google Scholar 

  49. 49

    Zander M et al. (2002) Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359: 824–830

    CAS  Article  Google Scholar 

  50. 50

    Meneilly GS et al. (2003) Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care 26: 2835–2841

    CAS  Article  Google Scholar 

  51. 51

    Eng J et al. (1992) Isolation and characterization of exendin 4, an exendin 3 analogue from Heloderma suspectum venom. J Biol Chem 267: 7402–7405

    CAS  PubMed  Google Scholar 

  52. 52

    Chen YE and Drucker DJ (1997) Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard. J Biol Chem 272: 4108–4115

    CAS  Article  Google Scholar 

  53. 53

    Buse JB et al. (2004) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27: 2628–2635

    CAS  Article  Google Scholar 

  54. 54

    DeFronzo RA et al. (2005) Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28: 1092–1100

    CAS  Article  Google Scholar 

  55. 55

    Kendall DM et al. (2005) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 28: 1083–1091

    CAS  Article  Google Scholar 

  56. 56

    Degn K B et al. (2004) Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes 53: 2397–2403

    Article  Google Scholar 

  57. 57

    Agerso H et al. (2002) The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 45: 195–202

    CAS  Article  Google Scholar 

  58. 58

    Madsbad S et al. (2004) Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care 27: 1335–1342

    CAS  Article  Google Scholar 

  59. 59

    Baggio LL et al. (2004) 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 53: 2492–2500

    CAS  Article  Google Scholar 

  60. 60

    Mentlein R (1999) Dipeptidyl-peptidase IV (CD26)—role in the inactivation of regulatory peptides. Regul Pept 85: 9–24

    CAS  Article  Google Scholar 

  61. 61

    Meier JJ and Nauck MA (2004) Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab 18: 587–606

    CAS  Article  Google Scholar 

  62. 62

    Hansotia T et al. (2004) Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP4 inhibitors. Diabetes 53: 1326–1335

    CAS  Article  Google Scholar 

  63. 63

    Marguet D et al. (2000) Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA 97: 6874–6879

    CAS  Article  Google Scholar 

  64. 64

    Ahren B et al. (2002) Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 25: 869–875

    CAS  Article  Google Scholar 

  65. 65

    Ahren B et al. (2005) Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care 28: 1936–1940

    CAS  Article  Google Scholar 

  66. 66

    Ahren B et al. (2004) Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 27: 2874–2880

    CAS  Article  Google Scholar 

  67. 67

    Conarello SL et al. (2003) Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci USA 100: 6825–6830

    CAS  Article  Google Scholar 

  68. 68

    Aytac U and Dang NH (2004) CD26/dipeptidyl peptidase IV: a regulator of immune function and a potential molecular target for therapy. Curr Drug Targets Immune Endocr Metabol Disord 4: 11–18

    CAS  Article  Google Scholar 

  69. 69

    Drucker DJ et al. (1997) Regulation of the biological activity of glucagon-like peptide 2 in vivo by dipeptidyl peptidase IV. Nat Biotechnol 15: 673–677

    CAS  Article  Google Scholar 

  70. 70

    Munroe DG et al. (1999) Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2. Proc Natl Acad Sci USA 96: 1569–1573

    CAS  Article  Google Scholar 

  71. 71

    Xiao Q et al. (2000) Circulating levels of glucagon-like peptide-2 in human subjects with inflammatory bowel disease. Am J Physiol Regul Integr Comp Physiol 278: 1057–1063

    Article  Google Scholar 

  72. 72

    Schmidt PT et al. (2003) Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety. Regul Pept 116: 21–25

    CAS  Article  Google Scholar 

  73. 73

    Shin ED et al. (2005) Mucosal adaptation to enteral nutrients is dependent on the physiologic actions of glucagon-like peptide-2 in mice. Gastroenterology 128: 1340–1353

    CAS  Article  Google Scholar 

  74. 74

    Boushey RP et al. (1999) Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. Am J Physiol Endocrinol Metab 277: 937–947

    Article  Google Scholar 

  75. 75

    Burrin DG et al. (2005) Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets. Endocrinology 146: 22–32

    CAS  Article  Google Scholar 

  76. 76

    Haderslev KV et al. (2002) Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon. Scand J Gastroenterol 37: 392–398

    CAS  Article  Google Scholar 

  77. 77

    Henriksen DB et al. (2003) Role of gastrointestinal hormones in postprandial reduction of bone resorption. J Bone Miner Res 18: 2180–2189

    CAS  Article  Google Scholar 

  78. 78

    Jeppesen PB et al. (2001) Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology 120: 806–815

    CAS  Article  Google Scholar 

  79. 79

    Jeppesen PB et al. (2005) Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut 54: 1224–1231

    CAS  Article  Google Scholar 

  80. 80

    Service GJ et al. (2005) Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 353: 249–254

    CAS  Article  Google Scholar 

  81. 81

    Patti ME et al. Severe hypoglycemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia, in press

Download references


DJD is supported by a Canada Research Chair in Regulatory Peptides. Work on the glucagon-like peptides in DJD's laboratory is supported by operating grants from the Canadian Institutes for Health Research, the Juvenile Diabetes Research Foundation, and the Canadian Diabetes Association.

Author information



Corresponding author

Correspondence to Daniel J Drucker.

Ethics declarations

Competing interests

D Drucker is a Consultant to Abbott Labs, Amylin Pharmaceuticals Inc, Bristol Myers Squibb, and Eli Lilly Inc, Glaxosmithkline, Merck & Co, Novartis, PPD, Syrrx, and Triad Pharmaceuticals Inc.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Drucker, D. Biologic actions and therapeutic potential of the proglucagon-derived peptides. Nat Rev Endocrinol 1, 22–31 (2005).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing