BADERC- Joel Habener

Joel Habener, M.D.

Endocrine Pancreas Regeneration and Function

The prevalence of the metabolic disease diabetes mellitus in the population world-wide is increasing at epidemic proportions. In the USA, 10% of individuals are afflicted and the health care costs incurred by the

associated morbidity are in excess of $140B/year. Diabetes manifests in two distinct forms: type 1 (juvenile) and type 2 (adult onset), characterized by absolute or relative deficiency in the production of insulin by the pancreas. The studies we are pursuing are based on the premise that the fundamental morphological causation of both forms of diabetes is the occurrence of a reduction in the numbers of insulin-producing beta cells in the pancreas. As a consequence of this circumstance, there is an insufficient mass of beta cells available for the production of insulin in the amounts required to meet the metabolic needs of the body. Our goals are to develop strategies to maintain or to restore beta cell mass in diabetes. Three lines of investigation are being pursued to achieve these goals.

1) Islet-derived Renewable Beta Cells
A proven efficacious treatment of diabetes is the administration of insulin-producing tissue, e.g. islet to liver transplants. A scarcity of donor islet tissue severely limits this therapy. Alternative sources of insulin-producing tissue are needed. We believe that insulin-producing beta cells in the endocrine pancreas (islets) have the capacity to de-differentiate into islet progenitor cells (IPCs) in culture in vitro, proliferate, and expand, while retaining their identity as beta cells, and can then be re-differentiated into islet-like clusters (ILCs) that produce insulin in regulated, meaningful amounts. A premise of this hypothesis is that the beta cells maintain the chromatin of the insulin gene, and other beta cell specific genes, in an open euchromatic configuration even when de-differentiated. Human beta cells may have this property, not shared by mouse or rat, perhaps due to the unique environment of beta cells in human islets adjacent to alpha cells that produce glucagon-like peptide-1 (GLP-1), a potent stimulator of beta cell proliferation and survival. We propose that the efficiencies of ILCs in making insulin is directly related to the relative participation of beta cells in the formation of de-differentiated proliferative cells. To explore this concept we employ a double selection approach to enrich human IPCs for beta cell progenitor cells; 1) Beta cell lineage selection by flow cytometry, and 2) GLP-1 selection under nutrient-deprivation. Selected IPCs are expanded in nutrient-deprived media with GLP-1, and re-differentiated into ILCs which are characterized for insulin (C-peptide) production and responsiveness to glucose, and transplanted (subrenal capsule) of streptozotocin-diabetic NOD/SCID mice with GLP-1 injections after transplantation. We anticipate that the ILCs prepared from selected IPCs will achieve glycemic control in the diabetic mice. If successful, the procedure could be adapted to the commercial production of insulin producing ILCs for transplantation in human subjects.

2) Hormonal Stimulation of the Growth, Survival, and Regeneration of Pancreatic Beta Cells
In human islets the alpha cells that express proglucagon are mixed in with the beta cells so that >70% of alpha cells are in heterotypic contact with beta cells. The alpha cells express proglucagon that encodes glucagon and glucagon-like peptides (GLPs). Proglucagon is alternatively cleaved by the prohomone convertases (PCs): PC2 produces glucagon and PC1/3 produces GLP-1. Normally alpha cells express PC2 and produce glucagon, a metabolic hormone that regulates glucose production. We propose a paracrine B>A>B hypothesis in which injured beta cells produce and release the chemokine, stromal cell-derived factor-1 (SDF-1) that acts locally on adjacent alpha cells to stimulate their proliferation and to activate the expression of PC1/3 resulting in the production of GLP-1, an identified growth factor for beta cells. The concept of the hypothesis is derived from our findings that the receptors for both SDF-1 and GLP-1 are highly expressed on alpha and beta cells. SDF-1 promotes the survival and GLP-1 stimulates the growth of beta cells. Both SDF-1 and GLP-1 signal via the canonical Wnt signaling pathway involving beta-catenin and TCF7L2. We hypothesize that locally produced, paracrine GLP-1 secreted from alpha cells, along with SDF-1 secreted from injured beta cells, stimulates the regeneration of adjacent beta cells by enhancing their replication and survival. In preliminary studies we observe the induction of PC1/3, PDX-1, and GLP-1R expression in alpha cells in response to SDF-1. To test the B>A>B hypothesis we are exploring: 1) the actions of SDF-1 and GLP-1 on alpha cell induction of PC1/3, and the switching in the production of glucagon to that of GLP-1. 2) SDF-1 promotion of beta cell survival depends on activation of the beta-catenin/TCF7L2 Wnt signaling pathway. 3) synergy between SDF-1 and GLP-1 in beta cell regeneration. If these studies show that alpha cells are involved in beta cell regeneration in the adult pancreas, they will open up new avenues of investigations mechanisms that may identify drugable targets for the regeneration of beta cells in diabetes.

3) Insulin-like Actions of GLP-1 On Insulin-Responsive Tissues

Type 2 diabetes is caused by a combination of a failure of the beta cells of the pancreas to produce sufficient amounts of insulin and a failure of peripheral tissues to respond to the actions of the insulin that is produced (insulin resistance). The hyperglycemia characteristic of obesity-related T2D is determined to a large extent by impaired hepatic glucose disposal (glycolysis) and increased hepatic glucose production (gluconeogenesis) due to generalized insulin resistance. Increased hepatic glucose output is a major contributor to the fasting hyperglycemia of T2D. Much of the increased hepatic glucose production and glucose output is driven by enhanced and uncontrolled fatty acid oxidation. Glucagon-like peptide-1 is a gut-derived insulinotropic hormone that stimulates glucose-dependent insulin secretion and may also promote the growth and survival of beta cells. GLP-1 is released from the intestine in response to meals by cleavages from proglucagon, as the insulinotropic peptide, GLP-1(7-36) [and GLP-1(7-37)], that acts on its receptor on beta cells to stimulate insulin secretion. GLP-1(7-36) is rapidly (T1/2=1-2 min) modified in the circulation by removal of the N-terminal two amino acids by the diaminopeptidyl peptidase, Dpp-4, to yield GLP-1(9-36), devoid of insulinotropic activity. GLP-1(9-36) is often referred to the inactive degradation product of GLP-1, because it no longer stimulates insulin secretion. We hypothesize that Dpp-4 does not degrade GLP-1, but rather modifies its biological actions from that of an insulinotropic hormone, GLP-1(7-36), to that of an insulinomimetic hormone, GLP-1(9-36). Further we find that the insulin-like actions of GLP-1(9-36) are primarily exerted on the liver in insulin resistant states where it suppresses hepatic glucose output and stimulates glucose utilization, perhaps by the inhibition of excessive fatty acid oxidation. In support of the hypothesis, several studies in vivo and vitro have demonstrated insulin-independent stimulation of glucose disposal by GLP-1(7-36), however, in conditions that did not control for conversion of GLP-1(7-36) to GLP-1(9-36) by Dpp-4. We are exploring the direct actions of GLP-1(9-36) on gluconeogenesis and lipid metabolism in cultured hepatocytes in vitro and in the livers of lean and obese mice in vivo. These studies may reveal important unappreciated insulin-like actions of GLP-1, apart from its known insulinotropic actions, that may be relevant to the use of Dpp-4 inhibitors for the treatment of T2D, particularly obesity-related T2D.

References:

Schmitt-Ney M, Habener JF. Cell density-dependent regulation of actin gene expression due to changes in actin treadmilling. Exp Cell Res. 2004; 295:236-244.
Abraham EJ, Kodama S, Lin JC, Ubeda-Minarro M, Smith RN, Faustman DL, Habener JF. Human pancreatic islet-derived progenitor cell engraftment in immunocompetent mice. Am J Pathol. 2004; 164(3):817-830.
Lechner A, Yang Y-G, Blacken RA, Nolan AL, Habener JF. No evidence for significant transdifferentiation of bone marrow into pancreatic b-cells in vivo. Diabetes. 2004; 53: 616-623.
Ubeda M, Kemp DM, Habener JF. Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer’s disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology. 2004; 145(6):3023-3031.
Gragnoli C, Von Preussenthal GM, Habener JF. Triple genetic variation in the hnf-4a gene is associated with early-onset type 2 diabetes mellitus in a Philippino family. Metabolism. 2004; 53(8):959-963.
Stanojevic V, Habener JF, Thomas MK. Pancreas duodenum homeobox (PDX-1) transcriptional activation requires interactions with p300. Endocrinology. 2004; 145(6):2918-2928.
Ogawa N, List JF, Habener JF, Maki T. Cure of overt diabetes in NOD mice by transient treatment with anti-lymphocyte serum and exendin-4. Diabetes. 2004; 53(7):1700-1705.
Lechner A, Nolan AL, Blacken RA, Habener, JF. Redifferentiation of insulin-secreting cells after expansion of adult human pancreatic tissue in vitro. Biochem Biophys Res Commun. 2005; 327:581-588.
Gragnoli C, Stanojevic V, Gorini A, Von Preussenthal GM, Thomas MK, Habener JF. A missense mutation in the insulin promoter factor-1 gene in an Italian MODY4 family with and type 2 and gestational diabetes. Metabolism. 2005; 54:983-988.
Rukstalis JM, Ubeda M, Johnson MV, Habener JF. Transcription factor snail modulates hormone expression in established endocrine pancreatic cell lines. Endocrinology.2006; 147:2997-3006.
Rukstalis JM, Habener JF. Islets break off from the mainland. Nat Med. 2006; 12:273-274.
List JF, He H, Habener JF. Glucagon-like peptide-1 receptor and proglucagon expression in mouse skin. Regul Pept. 2006; 134:149-157.
Ubeda, M, Rukstalis, JM, Habener JF. Inhibition of cyclin-dependent kinase 5 activity protects pancreatic beta cells from glucotoxicity. J. Biol Chem. 2006; 281;28858-28864.
Rukstalis JM, Habener JF Snail2, a mediator of epithelial-mesenchymal transitions expressed in progenitor cells of the developing endocrine pancreas. Gene Expr Patterns. 2007; 7:471-479.
Yano T, Liu Z, Donovan J, Thomas MK, Habener JF. Sstromal cell-derived factor-1 (SDF-1/CXCL12) attenuates diabetes in mice and promotes pancreatic beta-cell survival by activation of the prosurvival kinase Akt. Diabetes. 2007. 56:2946-2957.
Liu Z, Habener JF. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem. 2008 Mar 28;283:8723-8735.
Elahi D, Egan JM, Shannon RP, Meneilly GS, Khatri A, Habener JF, Andersen DK.GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide. Obesity 2008 16:1501-1509.
Stanojevic V, Habener JF, Holz GG, Leech CA. Cytosolic adenylate kinases regulate K-ATP channel activity in human beta-cells Biochem Biophys Res Commun. 2008 368:614-619.
Liu Z, Habener JF. Stroal Cell-derived Factor-1 Promotes Survival of Pancreatic Beta Cells by the Stabilization of Beta-Catenin and Activation of TCF7L2. Diabetologia (in press).
Thomas MK, Habener JF. IDX-1: Pancreatic agenesis and type 2 diabetes. In: Erickson P, Epstein CJ, Wynshaw-Boris A, eds. Molecular Basis of Inborn Errors of Development. Oxford University Press 2004; 552-556.
Habener JF and Kieffer TJ. Glucagon and glucagon-like peptides. In: Kahn CR, Weir GC, et al. eds. Joslin’s Diabetes Mellitus, 14th ed., Lippincott Williams & Wilkins, Boston (Dec. 2004 ).
Kemp DM, Habener JF. Glucagon and glucagon-like peptides. In: Martini, L., ed. Encyclopedia of Endocrine Diseases. Elsevier Inc., Milan, Italy, 2004; 2:220-224.
Leech CA, Habener JF. Persistent hyperinsulinemic hypoglycemia of infancy. In: Endocrinology Rounds, Massachusetts General Hospital. 2003; 2(10).
Lechner AL, Habener JF. Bone marrow stem cells find a path to the pancreas. Nat Biotechnol. 2003; 21(7):755-756.
List JF, Habener JF. Glucagon-like peptide-1 agonists and the development and growth of pancreatic beta-cells. Am J Physiol Endocrinol Metab. 2004; 286:E875-E881.
Habener JF. A perspective on pancreatic stem/progenitor cells. Pediatr Diabetes. 2004; 5:29-37.
Kemp D, Habener JF. Functional genomics in the clinic: A path toward personalized Medicine. Preclinica. 2004; 2(6).
Habener JF, Kemp D, Thomas MK. Minireview: Transcriptional regulation in pancreatic development. Endocrinology. 2005; 146(3): 1025-1034.
Habener JF Perspectives Recent Advances in the GLP-1 Pathway. In: Perspectives On Type 2 Diabetes Treatments, Endocrine Society, June 2007.
Liu Z, Habener JF. Wnt signalling in Pancreatic Islets. 2009 Advances in Experimental Medicine and Biology. 2009 in press.
Rukstalis JM, Habener JF. Neurogenin-3: A master regulator of Pancreatic Islet Differentiation and Regeneration. Islets 2009 in press.






			Joel Habener, M.D. Endocrine Pancreas Regeneration and Function The prevalence of the metabolic disease diabetes mellitus in the population world-wide is increasing at epidemic proportions. In the USA, 10% of individuals are afflicted and the health care costs incurred by the associated morbidity are in excess of $140B/year. Diabetes manifests in two distinct forms: type 1 (juvenile) and type 2 (adult onset), characterized by absolute or relative deficiency in the production of insulin by the pancreas. The studies we are pursuing are based on the premise that the fundamental morphological causation of both forms of diabetes is the occurrence of a reduction in the numbers of insulin-producing beta cells in the pancreas. As a consequence of this circumstance, there is an insufficient mass of beta cells available for the production of insulin in the amounts required to meet the metabolic needs of the body. Our goals are to develop strategies to maintain or to restore beta cell mass in diabetes. Three lines of investigation are being pursued to achieve these goals. 1) Islet-derived Renewable Beta Cells A proven efficacious treatment of diabetes is the administration of insulin-producing tissue, e.g. islet to liver transplants. A scarcity of donor islet tissue severely limits this therapy. Alternative sources of insulin-producing tissue are needed. We believe that insulin-producing beta cells in the endocrine pancreas (islets) have the capacity to de-differentiate into islet progenitor cells (IPCs) in culture in vitro, proliferate, and expand, while retaining their identity as beta cells, and can then be re-differentiated into islet-like clusters (ILCs) that produce insulin in regulated, meaningful amounts. A premise of this hypothesis is that the beta cells maintain the chromatin of the insulin gene, and other beta cell specific genes, in an open euchromatic configuration even when de-differentiated. Human beta cells may have this property, not shared by mouse or rat, perhaps due to the unique environment of beta cells in human islets adjacent to alpha cells that produce glucagon-like peptide-1 (GLP-1), a potent stimulator of beta cell proliferation and survival. We propose that the efficiencies of ILCs in making insulin is directly related to the relative participation of beta cells in the formation of de-differentiated proliferative cells. To explore this concept we employ a double selection approach to enrich human IPCs for beta cell progenitor cells; 1) Beta cell lineage selection by flow cytometry, and 2) GLP-1 selection under nutrient-deprivation. Selected IPCs are expanded in nutrient-deprived media with GLP-1, and re-differentiated into ILCs which are characterized for insulin (C-peptide) production and responsiveness to glucose, and transplanted (subrenal capsule) of streptozotocin-diabetic NOD/SCID mice with GLP-1 injections after transplantation. We anticipate that the ILCs prepared from selected IPCs will achieve glycemic control in the diabetic mice. If successful, the procedure could be adapted to the commercial production of insulin producing ILCs for transplantation in human subjects. 2) Hormonal Stimulation of the Growth, Survival, and Regeneration of Pancreatic Beta Cells In human islets the alpha cells that express proglucagon are mixed in with the beta cells so that >70% of alpha cells are in heterotypic contact with beta cells. The alpha cells express proglucagon that encodes glucagon and glucagon-like peptides (GLPs). Proglucagon is alternatively cleaved by the prohomone convertases (PCs): PC2 produces glucagon and PC1/3 produces GLP-1. Normally alpha cells express PC2 and produce glucagon, a metabolic hormone that regulates glucose production. We propose a paracrine B>A>B hypothesis in which injured beta cells produce and release the chemokine, stromal cell-derived factor-1 (SDF-1) that acts locally on adjacent alpha cells to stimulate their proliferation and to activate the expression of PC1/3 resulting in the production of GLP-1, an identified growth factor for beta cells. The concept of the hypothesis is derived from our findings that the receptors for both SDF-1 and GLP-1 are highly expressed on alpha and beta cells. SDF-1 promotes the survival and GLP-1 stimulates the growth of beta cells. Both SDF-1 and GLP-1 signal via the canonical Wnt signaling pathway involving beta-catenin and TCF7L2. We hypothesize that locally produced, paracrine GLP-1 secreted from alpha cells, along with SDF-1 secreted from injured beta cells, stimulates the regeneration of adjacent beta cells by enhancing their replication and survival. In preliminary studies we observe the induction of PC1/3, PDX-1, and GLP-1R expression in alpha cells in response to SDF-1. To test the B>A>B hypothesis we are exploring: 1) the actions of SDF-1 and GLP-1 on alpha cell induction of PC1/3, and the switching in the production of glucagon to that of GLP-1. 2) SDF-1 promotion of beta cell survival depends on activation of the beta-catenin/TCF7L2 Wnt signaling pathway. 3) synergy between SDF-1 and GLP-1 in beta cell regeneration. If these studies show that alpha cells are involved in beta cell regeneration in the adult pancreas, they will open up new avenues of investigations mechanisms that may identify drugable targets for the regeneration of beta cells in diabetes. 3) Insulin-like Actions of GLP-1 On Insulin-Responsive Tissues Type 2 diabetes is caused by a combination of a failure of the beta cells of the pancreas to produce sufficient amounts of insulin and a failure of peripheral tissues to respond to the actions of the insulin that is produced (insulin resistance). The hyperglycemia characteristic of obesity-related T2D is determined to a large extent by impaired hepatic glucose disposal (glycolysis) and increased hepatic glucose production (gluconeogenesis) due to generalized insulin resistance. Increased hepatic glucose output is a major contributor to the fasting hyperglycemia of T2D. Much of the increased hepatic glucose production and glucose output is driven by enhanced and uncontrolled fatty acid oxidation. Glucagon-like peptide-1 is a gut-derived insulinotropic hormone that stimulates glucose-dependent insulin secretion and may also promote the growth and survival of beta cells. GLP-1 is released from the intestine in response to meals by cleavages from proglucagon, as the insulinotropic peptide, GLP-1(7-36) [and GLP-1(7-37)], that acts on its receptor on beta cells to stimulate insulin secretion. GLP-1(7-36) is rapidly (T1/2=1-2 min) modified in the circulation by removal of the N-terminal two amino acids by the diaminopeptidyl peptidase, Dpp-4, to yield GLP-1(9-36), devoid of insulinotropic activity. GLP-1(9-36) is often referred to the inactive degradation product of GLP-1, because it no longer stimulates insulin secretion. We hypothesize that Dpp-4 does not degrade GLP-1, but rather modifies its biological actions from that of an insulinotropic hormone, GLP-1(7-36), to that of an insulinomimetic hormone, GLP-1(9-36). Further we find that the insulin-like actions of GLP-1(9-36) are primarily exerted on the liver in insulin resistant states where it suppresses hepatic glucose output and stimulates glucose utilization, perhaps by the inhibition of excessive fatty acid oxidation. In support of the hypothesis, several studies in vivo and vitro have demonstrated insulin-independent stimulation of glucose disposal by GLP-1(7-36), however, in conditions that did not control for conversion of GLP-1(7-36) to GLP-1(9-36) by Dpp-4. We are exploring the direct actions of GLP-1(9-36) on gluconeogenesis and lipid metabolism in cultured hepatocytes in vitro and in the livers of lean and obese mice in vivo. These studies may reveal important unappreciated insulin-like actions of GLP-1, apart from its known insulinotropic actions, that may be relevant to the use of Dpp-4 inhibitors for the treatment of T2D, particularly obesity-related T2D. References: Schmitt-Ney M, Habener JF. Cell density-dependent regulation of actin gene expression due to changes in actin treadmilling. Exp Cell Res. 2004; 295:236-244. Abraham EJ, Kodama S, Lin JC, Ubeda-Minarro M, Smith RN, Faustman DL, Habener JF. Human pancreatic islet-derived progenitor cell engraftment in immunocompetent mice. Am J Pathol. 2004; 164(3):817-830. Lechner A, Yang Y-G, Blacken RA, Nolan AL, Habener JF. No evidence for significant transdifferentiation of bone marrow into pancreatic b-cells in vivo. Diabetes. 2004; 53: 616-623. Ubeda M, Kemp DM, Habener JF. Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer’s disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology. 2004; 145(6):3023-3031. Gragnoli C, Von Preussenthal GM, Habener JF. Triple genetic variation in the hnf-4a gene is associated with early-onset type 2 diabetes mellitus in a Philippino family. Metabolism. 2004; 53(8):959-963. Stanojevic V, Habener JF, Thomas MK. Pancreas duodenum homeobox (PDX-1) transcriptional activation requires interactions with p300. Endocrinology. 2004; 145(6):2918-2928. Ogawa N, List JF, Habener JF, Maki T. Cure of overt diabetes in NOD mice by transient treatment with anti-lymphocyte serum and exendin-4. Diabetes. 2004; 53(7):1700-1705. Lechner A, Nolan AL, Blacken RA, Habener, JF. Redifferentiation of insulin-secreting cells after expansion of adult human pancreatic tissue in vitro. Biochem Biophys Res Commun. 2005; 327:581-588. Gragnoli C, Stanojevic V, Gorini A, Von Preussenthal GM, Thomas MK, Habener JF. A missense mutation in the insulin promoter factor-1 gene in an Italian MODY4 family with and type 2 and gestational diabetes. Metabolism. 2005; 54:983-988. Rukstalis JM, Ubeda M, Johnson MV, Habener JF. Transcription factor snail modulates hormone expression in established endocrine pancreatic cell lines. Endocrinology.2006; 147:2997-3006. Rukstalis JM, Habener JF. Islets break off from the mainland. Nat Med. 2006; 12:273-274. List JF, He H, Habener JF. Glucagon-like peptide-1 receptor and proglucagon expression in mouse skin. Regul Pept. 2006; 134:149-157. Ubeda, M, Rukstalis, JM, Habener JF. Inhibition of cyclin-dependent kinase 5 activity protects pancreatic beta cells from glucotoxicity. J. Biol Chem. 2006; 281;28858-28864. Rukstalis JM, Habener JF Snail2, a mediator of epithelial-mesenchymal transitions expressed in progenitor cells of the developing endocrine pancreas. Gene Expr Patterns. 2007; 7:471-479. Yano T, Liu Z, Donovan J, Thomas MK, Habener JF. Sstromal cell-derived factor-1 (SDF-1/CXCL12) attenuates diabetes in mice and promotes pancreatic beta-cell survival by activation of the prosurvival kinase Akt. Diabetes. 2007. 56:2946-2957. Liu Z, Habener JF. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem. 2008 Mar 28;283:8723-8735. Elahi D, Egan JM, Shannon RP, Meneilly GS, Khatri A, Habener JF, Andersen DK.GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide. Obesity 2008 16:1501-1509. Stanojevic V, Habener JF, Holz GG, Leech CA. Cytosolic adenylate kinases regulate K-ATP channel activity in human beta-cells Biochem Biophys Res Commun. 2008 368:614-619. Liu Z, Habener JF. Stroal Cell-derived Factor-1 Promotes Survival of Pancreatic Beta Cells by the Stabilization of Beta-Catenin and Activation of TCF7L2. Diabetologia (in press). Thomas MK, Habener JF. IDX-1: Pancreatic agenesis and type 2 diabetes. In: Erickson P, Epstein CJ, Wynshaw-Boris A, eds. Molecular Basis of Inborn Errors of Development. Oxford University Press 2004; 552-556. Habener JF and Kieffer TJ. Glucagon and glucagon-like peptides. In: Kahn CR, Weir GC, et al. eds. Joslin’s Diabetes Mellitus, 14th ed., Lippincott Williams & Wilkins, Boston (Dec. 2004 ). Kemp DM, Habener JF. Glucagon and glucagon-like peptides. In: Martini, L., ed. Encyclopedia of Endocrine Diseases. Elsevier Inc., Milan, Italy, 2004; 2:220-224. Leech CA, Habener JF. Persistent hyperinsulinemic hypoglycemia of infancy. In: Endocrinology Rounds, Massachusetts General Hospital. 2003; 2(10). Lechner AL, Habener JF. Bone marrow stem cells find a path to the pancreas. Nat Biotechnol. 2003; 21(7):755-756. List JF, Habener JF. Glucagon-like peptide-1 agonists and the development and growth of pancreatic beta-cells. Am J Physiol Endocrinol Metab. 2004; 286:E875-E881. Habener JF. A perspective on pancreatic stem/progenitor cells. Pediatr Diabetes. 2004; 5:29-37. Kemp D, Habener JF. Functional genomics in the clinic: A path toward personalized Medicine. Preclinica. 2004; 2(6). Habener JF, Kemp D, Thomas MK. Minireview: Transcriptional regulation in pancreatic development. Endocrinology. 2005; 146(3): 1025-1034. Habener JF Perspectives Recent Advances in the GLP-1 Pathway. In: Perspectives On Type 2 Diabetes Treatments, Endocrine Society, June 2007. Liu Z, Habener JF. Wnt signalling in Pancreatic Islets. 2009 Advances in Experimental Medicine and Biology. 2009 in press. Rukstalis JM, Habener JF. Neurogenin-3: A master regulator of Pancreatic Islet Differentiation and Regeneration. Islets 2009 in press.