The Role of GLP-1 in the Life and Death of Pancreatic Beta Cells

Abstract

Glucagon-like peptide-1 (GLP-1), a peptide hormone produce by intestinal cells, has recently been shown to be capable of modulating islet cell mass. Administration of GLP-1 to rodent models of type 2 diabetes ameliorates insulin secretion, induces the replication of islet cells, and promotes islet-cell neogenesis from pancreatic ductal cells susceptible to transdifferentiate in insulin-producing cells. In addition, an anti-apoptotic effect of GLP-1 has been described in hyperglycemic animal models, using freshly isolated human islets or cultured beta cell lines exposed to various pro-apoptotic stimuli. The aim of this article is to review those reports that have emphasized the role of GLP-1 as a regulator of islet cell mass.

Key words

Beta-cells · Insulin · Differentiation · Regeneration and apoptosis · Diabetes

References

• 1 Hellestrom C, Andersson A, Gunnarsson R. Regeneration of islet cells.  Acta Endocrinologica. 1996;  83 145-158
• 2 Lipsett M, Finegood D T. Beta-cell neogenesis during prolonged hyperglycemia in rats.  Diabetes. 2002;  51 1834-1841
• 3 Guz Y, Nasir I, Teitelman G. Regeneration of pancreatic beta cells from intra-islet precursor cells in an experimental model of diabetes.  Endocrinology. 2001;  142 4956-4968
• 4 Bonner-Weir S, Baxter L A, Schuppin G T, Smith F E. A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development.  Diabetes. 1993;  42 1715-1720
• 5 Wang R N, Rehfeld J F, Nielsen F C, Klöppel G. Expression of gastrin and transforming growth factor-α during duct to islet cell differentiation in the pancreas of duct-ligated adult rats.  Diabetologia. 1997;  40 887-893
• 6 Vinik A, Rafaeloff R, Pittenger G, Rosenberg L, Duguid W. Induction of pancreatic islet neogenesis.  Symposium Report Horm Metab Res. 1997;  29 278-293
• 7 Tourrel C, Bailbe D, Meile M J, Kergoat M, Portha B. Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age.  Diabetes. 2001;  50 1562-1570
• 8 Drucker D J. Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes.  Curr Pharm Des. 2001;  7 1399-1412
• 9 Wang Y, Perfetti R, Greig N H, Holloway H W, DeOre K A, Montrose-Rafizadeh C, Elahi D, Egan J M. Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats.  J Clin Invest. 1997;  99 2883-2889
• 10 Perfetti R, Zhou J, Doyle M E, Egan J M. GLP-1 induces cell proliferation, PDX-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats.  Endocrinology. 2000;  141 4600-4605
• 11 Xu G, Stoffers D A, Habener J F, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats.  Diabetes. 1999;  48 2270-2276
• 12 Abraham E J, Leech C A, Lin J C, Zulewski H, Habener J F. Insulinotropic hormone glucagons-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells.  Endocrinology. 2002;  143 3152-3161
• 13 Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, Perfetti R. Glucagon-like Peptide-1 promotes islet cell growth and inhibits apoptosis in zucker diabetic rats.  Endocrinology. 2002;  143 4397-4408
• 14 Hui H, Nourparvar A, Zhao X, Perfetti R. Glucagon-like peptide-1 inhibits apoptosis of insulin secreting cells via a cAMP-dependent protein-kinase-A (PKA) and a phosphatidylinositol 3-kinase (PI3K)-dependent pathway.  Endocrinology. 2003;  144 1444-1455
• 15 Stoffers D A, Kieffer T J, Hussain M A, Drucker D J, Bonner-Weir S, Habener J F, Egan J M. Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas.  Diabetes. 2000;  49 741-748
• 16 Drucker D J, Philippe J, Mojsov S, Chick W L, Habener J F. 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 3434-3438
• 17 Fehmann H C, Habener J F. Insulinotropic hormone glucagon-like peptide-I (7 - 37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma β TC-1 cells.  Endocrinology. 1992;  130 159-166
• 18 Wang Y, Egan J M, Raygada M, Nadiv O, Roth J, Montrose-Rafizadeh C. Glucagon-like peptide-1 affects gene transcription and messenger ribonucleic acid stability of components of the insulin secretory system in RIN 1046-38 cells.  Endocrinology. 1995;  136 4910-4917
• 19 Wang X, Cahill C M, Pineyro M A, Zhou J, Doyle M E, Egan J M. Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells.  Endocrinology. 1999;  140 4904-4907
• 20 Zhou J, Wang X, Pineyro M A, Egan J M. Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells.  Diabetes. 1999;  48 2358-2366
• 21 Susini S, Roche E, Prentki M, Schlegel W. Glucose and glucoincretine peptides synergize to induce c-fos, c-jun, junB, zif-268, and nur-77 gene expression in pancreatic β (INS-1) cells.  FASEB J. 1998;  12 1173-1182
• 22 Montrose-Rafizadeh C, Egan J M, Roth J. Incretin hormones regulate glucose-dependent insulin secretion in RIN 1046 - 38 cells: mechanisms of action.  Endocrinology. 1994;  135 589-594
• 23 Hui H, Wright C, Perfetti R. Glucagon-like-peptide-1 induces differentiation of islet-duodenal homeobox-1-positive pancreatic ductal cells into insulin-secreting cells.  Diabetes. 2001;  50 785-796
• 24 Bulotta A, Hui H, Anastasi E, Bertolotto C, Boros L G, Di Mario U, Perfetti R. Cultured pancreatic ductal cells undergo cell cycle re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1.  J Mol Endocrinol. 2002;  29 347-360
• 25 Thorens B, Waeber G. Glucagon-like peptide-I and the control of insulin secretion in the normal state and in NIDDM.  Diabetes. 1993;  42 1219-1225
• 26 Habener J F, Stoffers D A. A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus.  Proc Assoc Am Physicians. 1998;  110 12-21
• 27 Stoffers D A, Thomas M K, Habener J F. Homeodomain protein IDX-1: a master regulator of pancreas development and insulin gene expression.  Trends Endocrinol Metab. 1997;  8 145-151
• 28 Edlund H. Transcribing pancreas.  Diabetes. 1998;  47 1817-1823
• 29 Buteau J, Roduit R, Susini S, Prentki M. Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells.  Diabetologia. 1999;  42 856-864
• 30 Scrocchi L A, Brown T J, McClusky N, Brubaker P L, Auerbach A B, Joyner A L, Drucker D J. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene.  Nat Med. 1996;  2 1254-1258
• 31 Scrocchi L A, Marshall B A, Cook S M, Brubaker P L, Drucker D. Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling.  Diabetes. 1998;  47 632-639
• 32 Pederson R A, Satkunarajah M, McIntosh C H, Scrocchi L A, Flamez D, Schuit F, Drucker D J, Wheeler M B. Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor-/- mice.  Diabetes. 1998;  47 1046-1052
• 33 Wang R N, Klöppel G, Bouwens L. Duct-to-islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats.  Diabetologia. 1995;  38 1405-1411
• 34 Gu D. Sarvetnick N. Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice.  Development. 1998;  118 33-46
• 35 Bonner-Weir S, Taneja M, Weir G C, Tatarkiewicz K, Song K H, Sharma A, O’Neil J J. In vitro cultivation of human islets from expanded ductal tissue.  Proc Natl Acad Sci U S A. 2000;  97 7999-8004
• 36 Ramiya V K, Maraist M, Arfors K E, Schatz D A, Peck A B, Cornelius J G. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells.  Nat Med. 2000;  6 278-282
• 37 Edvell A, Lindstrom P. Initiation of increased pancreatic islet growth in young normoglycemic mice (Umea +/?).  Endocrinology. 1999;  140 778-783
• 38 Pederson R A, White H A, Schlenzig D, Pauly R P, McIntosh C HS, Demuth H U. Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide.  Diabetes. 1998;  47 1253-1258
• 39 Nauck M A, Heimesaat M M, Orskov C, Holst J J, Ebert R, Creutzfeldt W. Normalization of fasting hyperglycemia by exogenous glucagon-like peptide-1 [7-36 amide] in type 2 (non-insulin dependent) diabetic patients.  Diabetologia. 1993;  36 741-744
• 40 Gutniak M, Orskov C, Holst J J, Ahren B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus.  N Engl J Med. 1992;  326 1316-1322
• 41 Egan J M, Clocquet A R, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes.  J Clin Endocrinol Metab. 2002;  87 1282-1290
• 42 Nauck M A, Sauerwald A, Ritzel R, Holst J, Schmiegel W. Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure.  Diabetes Care. 1998;  21 1925-1931
• 43 Nie Y, Nakashima M, Brubaker P L, Li Q L, Perfetti R, Jansen E, Zambre Y, Pipeleers D, Friedman T C. Regulation of pancreatic PC1 and PC2 associated with increased glucagon and GLP-1 immunoreactivity in diabetic rats.  J Clin Invest. 2000;  105 955-965
• 44 Pick A, Clark J, Kubstrup C, Levisetti M, Pugh W, Bonner-Weir S, Polonsky K S. Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat.  Diabetes. 1998;  47 358-364
• 45 Kasiske B L, O’Donnell M P, Keane W F. The Zucker rat model of obesity, insulin resistance, hyperlipidemia, and renal injury.  Hypertension. 1992;  19 110-115
• 46 Clark J B, Palmer C J, Shaw W N. The diabetic Zucker fatty rat.  Proc Soc Exp Biol Med. 1983;  173 68-75
• 47 Finegood D T, McArthur M D, Kojwang D, Thomas M J, Topp B G, Leonard T, Buckingham R E. Beta-cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death.  Diabetes. 2001;  50 1021-1029
• 48 Li Y, Hansotia T, Yusta B, Ris F, Halban P A, Drucker D J. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis.  J Biol Chem. 2003;  278 471-478
• 49 Wang Q, Li L, Xu E, Wong V, Rhodes C, Brubaker P L. Glucagon-like peptide 1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells.  Diabetologia. 2004;  47 478-487
• 50 Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmer H, Bertootto C, Harlan D H, Di Mario U, Perfetti R. GLP-1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets.  Endocrinology. 2003;  144 5149-5158