The observations that GLP-1R agonists including exendin-4 may play a role in islet neogenesis or differentiation have engendered considerable interest and excitement given the potential of these actions to enhance b-cell function in subjects with Type 2 diabetes. Furthermore, the possibility that GLP-1 receptor activation may enhance b-cell mass in patients with Type 1 diabetes is also under active investigation, in a NIH sponsored clinical trial.
GLP-1 receptor signaling, cell survival and apoptosis
Complementary findings from several labs, using a variety of experimental rodent and cell models, indicate that GLP-1 agonists may modulate b-cell mass in part via reduction of b-cell apoptosis. These actions may be directly relevant to protection of human islet β cells as incubation of human islets with native GLP-1 for 5 days preserved islet morphology, reduced the expression of pro-apoptotic genes, decreased cell death, and improved glucose-stimulated insulin secretion. See Glucagon-like Peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003 Dec;144(12):5149-58 and the Editorial Glucagon-Like Peptide-1 and the Islet Glucagon-Like Peptide-1 and the Islet b-Cell: Augmentation of Cell Proliferation and Inhibition of Apoptosis. Endocrinology. 2003 Dec; 144 (12): 5145-5148.
The anti-apoptotic properties of GLP-1 agonists have been demonstrated in Zucker diabetic rats and db/db mice. A 2 day infusion of GLP-1 increased islet size and b-cell mass, and reduced the numbers of aptotic cells in the exocrine portion of the pancreas. The percentage of a poptotic b-cells in this study was surprisingly high at greater than 20%, and was significantly reduced by GLP-1 treatment. See Glucagon-Like Peptide-1 Promotes Islet Cell Growth and Inhibits Apoptosis in Zucker Diabetic Rats. Endocrinology. 2002 Nov 1;143(11): 4397-4408
Treatment of normoglycemic db/db
mice with daily exendin-4 for 14 days
Similarly, treatment of mice with exendin-4 reduced b-cell apoptosis induced by streptozotocin (STZ), whereas GLP-1R-/- mice exhibited increased susceptibility to STZ-induced b-cell apoptosis. Furthermore, exendin-4 directly reduced the extent of apoptotic cell death in purified rat b-cells ex
Exendin-4 has been examined in a model of type 1 diabetes, the NOD mouse. Initiation of exendin-4 alone after the development of diabetes had little therapeutic benefit. In contrast, exendin-4 together with lysophiline for 28 days, markedly improved glucose control in NOD mice, even 6-14 weeks after cessation of therapy. Furthermore, the combination therapy preserved the number of intact islets, and appeared to reduce the extent of inflammatory cell infiltration in the remaining islets. See Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes. Biochem Biophys Res Commun. 2006 Jun 9;344(3):1017-22.
Similarly, continuous administration of native GLP-1 to 8 week old female NOD mice for 4 or 8 weeks lowered blood glucose, increased formation of new b-cells and suppressed b-cell apoptosis and delayed the onset of diabetes as described in Continuous stimulation of human glucagon-like peptide-1 (7-36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes. Diabetologia. 2007 Jul 14; [Epub ahead of print]
In contrast, twice daily administration of exendin-4 at two different doses, 100 ng, and 2 ug twice daily, prior to the development of clinical diabetes in NOD mice, produced only modest effects on the numbers of disease-free mice, with detectable but small increased in beta cell mass and reductions in insulitis. Intriguingly, GLP-1 receptor expression was also detected in different immune compartments as outlined in Endocrinology published December 6, 2007 as doi: 10.1210/en.2007-1137
Treatment of Min6 mouse islet cells with GLP-1 reduced the extent of hydrogen peroxide-induced apoptosis in vitro. The anti-apoptotic effects of GLP-1 were partially blocked by either the cAMP 'antagonist' Rp-cAMP, or the PI 3-kinase inhibitor LY294002. GLP-1 prevented cell death only when applied prior to exposure of cells to peroxide. See Glucagon-Like Peptide-1 Inhibits Apoptosis of Insulin-Secreting Cells via a Cyclic 5'-Adenosine Monophosphate-Dependent Protein Kinase A- and a Phosphatidylinositol 3-Kinase-Dependent Pathway. Endocrinology. 2003 Apr;144(4):1444-55
Similarly, induction of fatty acid induced apoptosis in Rinm5F cells with palmitate was markedly reduced by agents that increased levels of cyclic AMP, including Cyclic AMP dose-dependently prevents palmitate-induced apoptosis by both PKA- and cAMP- GEF- dependent pathways in beta -cells. J Biol Chem. 2003 Dec 19. Related studies using rat INS-1 cells demonstrated that protein kinase B (Akt) is rapidly activated by Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells. Diabetologia. 2004 Feb 5. Treatment of mouse b-cells or INS-1 cells with dexamethasone induces apoptosis, which was reduced in the presence of exendin-4 in a PKA-dependent manner as shown in Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes. 2006 May;55(5):1380-90.
The anti-a
The calpain-10 molecule has also been linked to β cell apoptosis, and may be modified by GLP-1 receptor activation. GLP-1 decreased calpain activity, reversed ryanodine-induced calpain activation and apoptosis in β cells and MIN6 cells, as shown in RyR2 and calpain-10 delineate a novel apoptosis pathway in pancreatic islets. J Biol Chem. 2004 Mar 25 [Epub ahead of print]
GLP-1 and endoplasmic reticulum stress
Type 2 diabetes is associated with gradual loss of insulin secretion and a progressive reduction in b-cell mass. Insulin resistance produces a sustained increase in demand for insulin, and over time, the b-cell is unable to sustain augmented levels of insulin biosynthesis and secretion. GLP-1 and GIP appear to maintain insulin biosynthesis via interaction with ER stress pathways in the b-cell. The GLP-1R agonist exendin-4 significantly reduced biochemical markers of islet ER stress in islets from db/db mice in vivo and both exendin-4 and GIP attenuated translational downregulation of insulin and improved cell survival in purified rat b-cells and in INS-1 cells following induction of ER stress in vitro. The actions of GLP-1 to enhance translation are mediated via induction of ATF-4, and accelerated recovery from ER stress-mediated translational repression in islet b-cells in a PKA-dependent manner. Exendin-4 also reduced ER stress-associated b-cell death in a PKA-dependent manner. See GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006 Nov;4(5):391-406 and the accompanying Editorial EXtENDINg beta cell survival by UPRegulating ATF4 translation. Cell Metab. 2006 Nov;4(5):333-4.
Islet Cell Proliferation
GLP-1 receptor activation couples to multiple signal transduction pathways important for control of b-cell proliferation. Wnt signaling appears to be an important downstream target for GLP-1R-dependent pathways as GLP-1R agonists increase wnt signaling in b-cells and inhibition of wnt signaling reduces both basal and GLP-1R-dependent regulation of b-cell proliferation, as described in Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta-cell proliferation J Biol Chem. 2008 Jan 23; [Epub ahead of print]
Additional evidence that GLP-1 stimulates islet cell proliferation in vitro is illustrated in Glucose and glucoincretin peptides synergize to induce c-fos, c-jun, junB, zif-268, and nur-77 gene expression in pancreatic beta(INS-1) cells. FASEB J. 1998 Sep;12(12):1173-82 and in 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 Jul;42(7):856-64
The signal transduction system activated by the GLP-1R signaling system which leads to cell growth depends on the islet cell model under study, with cAMP, PKC and PI-3-kinase activated by the GLP-1R in several studies. Protein Kinase Czeta Activation Mediates Glucagon-Like Peptide-1-Induced Pancreatic beta-Cell Proliferation. Diabetes. 2001 Oct;50(10):2237-2243. The transcription factor FoxO1 is an essential mediator required for the proliferative and anti-apoptotic actions of GLP-1 on the b-cell. GLP-1 stimulated the nuclear to cytoplasmic translocation of Foxo1, in an EGFR-and -PI-3K-dependent manner. A constitutively active mutant of Foxo1 blocked the actions of GLP-1 on b-cell proliferation. FoxO1 may exert its effects via repression of Pdx-1 and Foxa2 expression as described in Transcription Factor FoxO1 Mediates Glucagon-Like Peptide-1 Effects on Pancreatic b-cell mass Diabetes. 2006 May;55(5):1190-6.
The importance of Pdx-1 as a downstream target for GLP-1 action is consistent with findings made using mice with b-cell-specific inactivation of the Pdx-1 gene as shown in beta-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes. 2005 Feb;54(2):482-91.
Provocative experiments using the INS-1 cell line demonstrate the potential involvement of the EGFR and EGFR ligands such as betacellulin in the direct and indirect GLP-1R-dependent activation of cell proliferation as shown in Glucagon-Like Peptide 1 Induces Pancreatic beta-Cell Proliferation Via Transactivation of the Epidermal Growth Factor Receptor. Diabetes. 2003 Jan; 52(1): 124-32
The cyclic AMP-dependent transcription factor CREB has been linked to GLP-1-mediated cell growth and survival, as outlined in cAMP promotes pancreatic beta-cell survival via CREB- mediated induction of IRS2. Genes Dev. 2003 Jul 1;17(13):1 575-80
GLP-1 and islet cell proliferation in vivo
Several lines of evidence support a role for GLP-1 in the control of islet proliferation and regeneration in rodent studies in vivo. Administration of subcutaneous GLP-1 for 2 days to lean mice increased the islet labeling index, as shown in Endocrinology 1999 Feb;140(2):778-83 Initiation of increased pancreatic islet growth in young normoglycemic mice (Umea +/?). β cell proliferation. Furthermore, exendin-4 attenuates glucose intolerance following partial pancreatectomy in the rat. Diabetes 1999 Dec;48(12):2270-6 Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Similarly, infusion of GLP-1 β cell mass and promoted enhanced pdx-1 expression and islet neogenesis Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 2000 Dec;141(12):4600-5
If administered to young 6 week old prediabetic db/db mice, daily exendin-4 treatment for 2 weeks prevented the progression to more severe diabetes, in association with expansion of islet mass and improved glucose tolerance and insulin secretion. See Similarly, NN2211 and exendin-4 increased β cell proliferation in db/db mice, but not in ob/ob mice, as shown in The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrinol Metab. 2002 Oct;283(4):E745-52 and islet proliferative effects were also detected following a 2 week treatment period with exendin-4 in young db/db mice. See Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice. Diabetologia. 2002 Sep;45(9):1263-73.
Conversely, age appears to be an important determinant regulating b-cell proliferation, including the response to GLP-1R agonists. Using the partial pancreatectomy or low dose STZ injury model, Rankin and Kushner demonstrated b-cell regeneration was robustly detected in young (2 months) or 8 month old mice. Conversely, no b-cell proliferation was observed in 19-month old mice, although acinar cell regeneration was detected in the same experiments. Similarly 14-month old mice failed to exhibit a proliferative response to exendin-4. Hence adaptive changes in the capacity for b-cell proliferation may restrict the adaptive b-cell response to older islets. However the response to exendin-4 was not studied in mice that also received a PPx or STZ. See ADAPTIVE BETA CELL PROLIFERATION IS SEVERELY RESTRICTED WITH ADVANCED AGE. Diabetes. 2009 Mar 5. [Epub ahead of print]
Administration of the GLP-1R agonist Liraglutide (NN2211) to normal and ZDF rats as well as to 60% pancreatectomized rats demonstrated that the ability of Liraglutide to expand β cell mass was correlated with the metabolic milieu, and the duration of treatment, with normoglycemic normal animals failing to show an increase in β cell mass, whereas hyperglycemic animals responded to Liraglutidewith an increase in β cell mass. Similarly, β cell mass was increased in non-diabetic Sprague-Dawley rats treated with for 1 week, but after 6 weeks of treatment, β-cell mass was comparable in treated vs control rats, as described in The endocrine pancreas in non-diabetic rats after short-term and long-term treatment with the long-acting GLP-1 derivative NN2211. APMIS. 2003 Dec;111(12):1117-1124. Hence, the trophic effects of GLP-1R agonists in the islet, like their insulinotropic properties, are probably coupled to the presence of hyperglycemia. See GLP-1 derivative liraglutide in rats with b-cell deficiencies: influence of metabolic state on b-cell mass dynamics. Br J Pharmacol. 2003 Sep;140(1):123-132.
Complementary studies of GLP-1 or exendin-4 administration for 5 days in the neonatal GK rat demonstrate persistent improvement in glucose homeostasis, enhanced pancreatic insulin content and total beta-cell mass due to stimulation of beta-cell neogenesis and regeneration. Follow-up from day 7 to adult age (2 months) demonstrated GLP-1 or Ex-4 treated rats maintained enhanced beta-cell mass and improved glycemic control at adult (2 months) age. See Persistent Improvement of Type 2 Diabetes in the Goto-Kakizaki Rat Model by Expansion of the beta-Cell Mass During the Prediabetic Period With Glucagon-Like Peptide-1 or Exendin-4. Diabetes. 2002 May;51(5):1443-1452
Is GLP-1 receptor activation essential for stimulation of islet neogenesis and
proliferation? The finding of only modest and subtle abnormalities in islet
development in GLP-1R-/- mice suggest that islets develop normally in the
absence of GLP-1R
signaling. Furthermore, the development of islet hyperplasia
and hyperinsulinemia in the setting of insulin resistance, hyperglycemia and
leptin deficiency is not compromised in the ob/ob:GLP-1R-/- mutant mouse.Hence
it appears that although activation of GLP-1R
signaling stimulates islet
neogenesis and proliferation, the GLP-1R
signaling pathway is not required for
islet adaptation in the mouse in vivo. See Elimination
of glucagon-like peptide 1R signaling does not modify weight gain and islet
adaptation in mice with combined disruption of leptin and GLP-1 action Diabetes 2000 Sep; 49(9): 1552-6
A complementary approach to address the importance of endogenous GLP-1 receptor expression for β cell regeneration involves analysis of the islet regenerative responsive to partial pancreatectomy. Wildtype mice subjected to partial pancreatectomy were infused with the antagonist exendin(9-39); partial pancreatectomy was also carried out in GLP-1R-/- mice. In Ex(9-39)-treated sham-operated mice, persistent fasting hyperglycemia was observed, but β cell mass was not diminished. In pancreatectomized mice, persistent glucose intolerance was noted, but this was not further exacerbated by Ex(9-39) and recovery of β cell mass in Ppx mice was not impaired. In contrast, GLP-1R(-/-) mice exhibited greater hyperglycemia after pancreatectomy compared with wild-type mice, and this correlated with a significant defect in regeneration of β cell mass. Hence, the importance of endogenous GLP-1R signaling following partial pancreatectomy depends on the experimental context. See Role of Endogenous Glucagon-Like Peptide-1 in Islet Regeneration After Partial Pancreatectomy. Diabetes. 2003 Feb;52(2): 365-371.
Similarly, b-cell regeneration that develops in neonatal rats following administration of streptozotocin appears to be partially GLP-1-dependent, as the extent of islet and b-cell regeneration was diminished in the presence of the GLP-1R antagonist exendin (9-39), as outlined in ONTOGENY OF REGENERATION OF {beta}-CELLS IN THE NEONATAL RAT FOLLOWING TREATMENT WITH STREPTOZOTOCIN. Endocrinology. 2006 Feb 16; [Epub ahead of print]
These new findings add yet another important mechanism to the broad spectrum of GLP-1 actions which converge on lowering blood glucose in vivo. Furthermore, the possibility that activation of GLP-1 signaling might be therapeutically useful for regeneration of b-cell mass has important implications for the treatment of Type 1 and Type 2 Diabetes.
Islet Cell Differentiation
GLP-1 or exendin-4 promotes differentiation of the AR42J cell line to an endocrine phenotype. Differentiated cells exhibited increased expression of β cell genes and the capacity for glucose-dependent insulin secretion Diabetes 1999 Dec;48(12):2358-66 Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon-and insulin-producing cells ; Glucagon-like peptide-1. Recent Prog Horm Res. 2001;56:377-99. GLP-1 See b-Cell Differentiation from a Human Pancreatic Cell Line in Vitro and in Vivo. Mol Endocrinol. 2001 Mar 1;15(3):476-483.
Although the mechanisms underlying the GLP-1 dependent-stimulation of exocrine-endocrine differentiation are poorly understood, Yew and colleagues demonstrated that very low doses of GLP-1 or exendin-4 are sufficient to induce an endocrine differentiation program in AR42J cells. Furthermore, activation of GLP-1R signaling was associated with release of TGF-b and changes in expression of SMAD proteins. Moreover, modulation of SMAD expression significantly impacted the extent of endocrine differentiation. See Interplay of Glucagon-Like Peptide-1 and Transforming Growth Factor-{beta} Signaling in Insulin-Positive Differentiation of AR42J Cells. Diabetes. 2004 Nov;53(11):2824-2835.
Similarly, treatment of fetal (75-90 day gestational age) pig islet clusters with GLP-1promoted glucose-dependent insulin secretion and after several days of treatment with GLP-1R agonists, the cells exhibited increased Pdx-1 expression and enhanced differentiation along the β cell pathway. Furthermore, transplantation of the GLP-1-treated islet clusters into SCID mice revealed a significantly increased number of functionally mature β cells after 8 weeks in vivo. See Functional maturation of fetal porcine beta-cells by glucagon-like peptide 1 and cholecystokinin. Endocrinology. 2002 Sep;1 43(9) :3505-14.
Exendin-4 has also been shown to promote transdifferentiation of liver cells in the context of ectopic pdx-1 expression. Although expression of the known GLP-1R was not identified in liver cells, either prior to or following the transdifferentiation process, Ex-4 increased levels of cAMP in human liver cells, and increased levels of phosphoCREB, Akt, PKC, and ERK1/2. Following Pdx-1 transduction, Ex-4 increased insulin promoter activity and insulin gene expression in transduced liver cells. Similarly, Ex-4 induced expression of a broad number of transcription factors and proteins associated with specialized beta cell function. Ex-4 was also found to increase liver cell proliferation and likely increases the proportion of cells susceptible to transduction by Pdx-1 Exendin-4 promotes liver cell proliferation and enhances PDX-1-induced liver to pancreas transdifferentiation J Biol Chem. 2009 Sep 15. [Epub ahead of print]
GLP-1(1-37) and Intestinal Endocrine Differentiation
The vast majority of GLP-1 produced in gut endocrine cells is either GLP-1(7-36)amide or GLP-1(7-37). Very little is known about the generation and biological activity of GLP-1(1-37). . Suzuki et al demonstrate that GLP-1(1-37) β cell-like differentiation, in association with development of glucose-dependent insulin secretion. These effects were observed using organ culture in vitro, blocked by the GLP-1 in vivo. See Glucagon-like peptide 1 (1-37) converts intestinal epithelial cells into insulin-producing cells. Proc Natl Acad Sci U S A. 2003 Apr 17
GLP-1 and human b-cell differentiation
Will gut hormones such as GLP-1 promote proliferation of human islet b-cells? There is insufficient information to answer this question. Intriguingly, six patients with hyperinsulinemic hypoglycemia detected 0.5-8 years following Roux-en-Y gastric bypass surgery were initially reported to exhibit histological evidence for nesidioblastosis following resection of pancreatic tissue-one patient was found to have multiple insulinomas as described in the July 21 2005 New England Journal of Medicine Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005 Jul 21;353(3):249-54. The authors speculated, as further discussed in an accompanying editorial, that excessive secretion of gut hormones such as GLP-1 may have contributed to the development of islet proliferation in these human subjects. A similar clinical picture was reported in 3 subjects following gastric bypass, and plasma levels of GLP-1 were markedly elevated in these studies Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005 Sep 30; [Epub ahead of print]. However, a subsequent re-analysis of the pancreas histology, together with control slides obtained from 31 obese subjects and 16 lean control subjects, yielded somewhat modified conclusions. Meier and colleagues reported that b-cell area was not increased in the subjects with gastric bypass-associated hypoglycemia and no evidence of increased islet neogenesis or b-cell proliferation was detected in this group. These findings further emphasis the importance of functional defects, namely changes in gut motility and the acute b-cell response to nutrients/gut hormones in the pathogenesis of the hyperinsulinemic hypoglycemia syndrome seen in some subjects. See Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia. 2006 Aug;49(8):1838-44
Indeed, different types of intestinal surgery have been associated with increased secretion of gut hormones in experimental preclinical models, as described in Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E447-53. Although there is limited human data in patients undergoing this type of surgery, the available evidence does not support a uniform robust increase in plasma levels of gut hormones such as GLP-1 in most patients as reviewed in Hormonal changes after Roux-en Y gastric bypass for morbid obesity and the control of type-II diabetes mellitus. Am Surg. 2004 Jan;70(1):1-4; and The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg. 2004 Aug;240(2):236-42. In contrast, patients studied 20 years after jejunoilealbypass did exhibit increased circulating levels of GLP-1 and GIP as shown in Importance of small bowel peptides for the improved glucose metabolism 20 years after jejunoileal bypass for obesity. Obes Surg. 1998 Jun;8(3):253-60. Hence, there is a possibility that in some subjects, sustained increased secretion of multiple gut hormones may contribute to prolonged stimulation of b-cell growth.
For an overview of the effects of gastric bypass surgery on plasma levels of gut hormones, see Gut hormones and bariatric surgery
The effect of Exenatide on human pancreatic cancer cell growth and survival was examined in studies using several different human pancreatic cancer cell lines that express the endogenous GLP-1 receptor. Although Exenatide was able to activate several different signal transduction pathways in these cells, no significant effects were observed on stimulation of cell growth or cell survival in vitro. Furthermore, Exenatide had no effect on tumor growth in vivo following implantation of tumors into nude mice. See Activation of Glucagon-Like Peptide-1 Receptor Signaling Does Not Modify the Growth or Apoptosis of Human Pancreatic Cancer Cells Diabetes 2006 55: 1369-1379
What is the role of GLP-1 receptor signaling in the modulation of b cell differentiation in human β cells? A series of elegant experiments now demonstrates that a combination of GLP-1 receptor agonists (such as exendin-4), pdx-1 expression, and cell-cell contact, promotes the development of a more differentiated b cell in vitro. See b-Cell Differentiation from a Human Pancreatic Cell Line in Vitro and in Vivo. Mol Endocrinol. 2001 Mar 1;15(3):476-483. Similarly, incubation of the human ductal cell line Capan-1, which expresses the GLP-1R, with exendin-4 results in a significant increase in the number of cells exhibiting immunopositivity for insulin or glucagon, and induction of islet genes such as PDX-1, BETA2/NeuroD, and HNF-3b. Increased binding of HNF-3b to Pdx-1 promoter elements may represent one component of the differentiation mechanism activated by the GLP-1R in these cells. See Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: Involvement of PDX-1 and HNF3beta transcription factors. J Cell Physiol. 2002 Sep;192(3):304-14
The GLP-1R has also been localized to nestin positive islet-derived progenitor cells (NIPs) identified in islets and duct cells. About 60% of NIPs exhibit GLP-1R immunopositivity, and the GLP-1R is capable of transducing a functional [Ca2+]i response that is blocked by the GLP-1R antagonist exendin(9-39); this response was detected at normal but not elevated glucose concentrations. Incubation of human NIP cells with GLP-1 induced insulin expression in subsets of cells, and also produced changes in cellular morphology. GLP-1R agonists also induced insulin secretion in ~ 30% of NIP clones. Intriguingly, NIP cultures that approached confluence expressed the proglucagon gene and secreted GLP-1 into the culture medium, raising the possibility of an autocrine GLP-1-differentiation loop in these cells. See These intriguing findings are currently being pursued in part by Viacell Endocrine Science,
Does the islet α cell ever produce GLP-1 in the context of islet development or regeneration?
Several studies address this possibility by demonstrating induction of PC1 expression in α cells, the prohormone convertase responsible for liberating from proglucagon. Pancreatic and α cell expression of PC1 is induced in rats given streptozotocin, leading to small but significant increases in the levels of bioactive in the rat pancreas A second study documents the developmental expression of proglucagon and PC1 in the embryonic mouse pancreas from E10.5 to E 15.5 raising the possibility that bioactive might be liberated from these cells with potential implications for β cell growth and development. These studies do not prove that bioactive exerts a role during development or regeneration, but they certainly expand our concepts to include a potential for some islet α cells to produce in the correct developmental or experimental setting. Furthermore, mice with genetic ablation of the glucagon receptor (Gcgr-/- α cell hyperplasia and marked increases in the levels of both circulating and pancreatic intact GLP-1. Hence, under specific circumstances, the islet a-cell can switch its prohormone processing phenotype and produce intact bioactive See Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1438-43 and Hepatic and glucagon-like peptide-1–mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors J. Clin. Invest. 113:1571-1581 and ONTOGENY OF REGENERATION OF {beta}-CELLS IN THE NEONATAL RAT FOLLOWING TREATMENT WITH STREPTOZOTOCIN. Endocrinology. 2006 Feb 16; [Epub ahead of print]