In vivo treatment with glucagon-like peptide 1 promotes the graft function of fetal islet-like cell clusters in transplanted mice

Suen, Po Man; Li, Karen; Chan, Juliana C.N.; Leung, Po Sing

doi:10.1016/j.biocel.2005.08.005

Cited by 27 publications

(23 citation statements)

References 27 publications

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“…We discovered that neither baseline (pre-glucose administration) serum insulin nor blood glucose levels were statistically different between liraglutide and vehicle-treated animals. After stimulation with glucose, liraglutidetreated animals showed much higher serum insulin when compared with vehicle-treated animals (mean 39.3 vs. 16.0 mU/ liter; P Ͻ 0.001 by two-way ANOVA), resulting in lower blood glucose (mean 7.3 vs. 16.2 mm; P Ͻ 0.001 by two-way ANOVA).…”

Section: Liraglutide Improves Glucose-dependent Insulin Secretionmentioning

confidence: 88%

“…However, GLP-1 analogs, including exenatide (half-life 60 -90 min) and liraglutide (half-life 13 h when administered sc) (10), are more promising candidates. GLP-1 analogs have recently been discovered to have beneficial effects as adjunct therapy in type 1 diabetes mellitus models (11,12), and in pancreatic islet transplant preclinical models (13)(14)(15)(16). Furthermore, some groups have studied these analogs in human islet transplantation, which has provided evidence that isolated islets remain responsive to GLP-1R agonists (17,18).…”

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confidence: 97%

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Liraglutide, a Long-Acting Human Glucagon-Like Peptide 1 Analog, Improves Glucose Homeostasis in Marginal Mass Islet Transplantation in Mice

et al. 2008

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The current scarcity of high-quality deceased pancreas donors prevents widespread application of islet transplantation for treatment of labile type 1 diabetes mellitus. Opportunities for the improvement of current techniques include optimization of islet isolation and purification, use of culture with pharmacological insulinotropic agents, strategies to reduce graft rejection and inflammation, and the search for alternative insulin producing tissue. Here, we report our findings on the efficacy of the long-acting human glucagon-like peptide 1 analog, liraglutide, in a mouse model of marginal mass islet transplantation. Liraglutide was administered (200 microg/kg sc twice daily) after a marginal mass syngeneic islet transplant in streptozotocin-induced diabetic BALB/c mice. Time-to-normoglycemia was significantly shorter in liraglutide-treated animals (median 1 vs. 7 d; P = 0.0003), even in recipients receiving sirolimus (median 1 vs. 72.5 d; P < 0.0001). Liraglutide-treated animals also demonstrated improved glucose tolerance as assessed by an ip glucose tolerance test. Liraglutide discontinuation at postoperative d 90 resulted in diminished glucose tolerance during the ip glucose tolerance test, whereas a late-start liraglutide therapy 90 d after transplant resulted in no improvement. These findings suggest that liraglutide therapy mediates early and late insulinotropic effects. In accord with this hypothesis, insulin/terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick end labeling fluorescence microscopy showed reduced transplanted beta-cell apoptosis in liraglutide-treated recipients 48 h after transplant. In addition, liraglutide resulted in improved glucose-dependent insulin secretion. Overall, our data show that liraglutide has a beneficial impact on the engraftment and function of syngeneic islet transplants in mice, when administered continuously starting on the day of transplant.

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Section: Liraglutide Improves Glucose-dependent Insulin Secretionmentioning

confidence: 88%

mentioning

confidence: 97%

Liraglutide, a Long-Acting Human Glucagon-Like Peptide 1 Analog, Improves Glucose Homeostasis in Marginal Mass Islet Transplantation in Mice

et al. 2008

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“…In another study, there was evidence that exendin-4 could promote revascularisation and the formation of insulin-producing cells in the graft-bearing kidney in mice transplanted with fetal islet-cell clusters [88]. In human fetal pancreatic cells, exendin-4 up-regulates expression of PDX 1 and increases differentiation and maturation [89].…”

Section: The Effect Of Glp-1 Treatment On Islet Function After Islet mentioning

confidence: 97%

Treatment of Type 1 Diabetic Patients with Glucagon-Like Peptide-1 (GLP-1) and GLP-1R Agonists

Kielgast¹,

Holst²,

Madsbad

2009

CDR

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GLP-1 (glucagon-like peptide-1) is a peptide hormone secreted from endocrine cells in the intestinal mucosa in response to meals. The major effects of GLP-1 are to increase glucose-induced insulin secretion and reduce glucagon release, but GLP-1 also inhibits gastric emptying rate and reduces appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence for a beta-cell preserving effect. This review summarizes the present knowledge of GLP-1 and its analogues regarding its role as a possible treatment in patients with type 1 diabetes. The studies that address the effect of GLP-1 and GLP-1 analogues on beta-cell mass in both type 2 and type 1 diabetes, as well as the potential of GLP-1 as an adjuvant therapy in islet cell transplantation, will be reviewed. Suggestions for future studies of GLP-1 treatment in type 1 diabetes may include early treatment in order to preserve beta-cell mass and prolong the remission period, but should also take a potential insulin sparing effect and changes in the risk of hypoglycemia into account.

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“…These immature cells also express several mesenchymal stem cell (MSC)-like markers, including CD44, CD90 and CD147. Importantly, the pancreatic progenitor cells were able to form the islet cell-like clusters (ICCs) when cultured ex vivo and give rise to diverse pancreatic cell lineages, including the insulin-secreting cells and reversed hyperglycaemia in non-obese diabetic and severe combined immunodeficient (NOD-SCID) mice in vivo 15 60 – 63. The SP cell fraction isolated from ICCs also generated the insulin-producing beta cells in vitro 61.…”

Section: Embryonic and Fetal Development Of The Pancreasmentioning

confidence: 99%

“…Among them, there are the fetal and umbilical cord blood-derived stem/progenitor cells, placenta derived-multipotent stem cells (PDMSCs), human amniotic epithelial cells (hAECs), and diverse adult stem cells, including bone marrow-resident HSCs and MSCs, hepatic oval cells (HOCs), neural stem cells (NSCs) and adipose tissue-derived stem cells (ADSCs) 7 10 11 15 17 20 21 63 74 80 82 93 – 100. The differentiation of these stem/progenitor cells into pancreatic insulin-producing beta cell-like progenitors has been performed in vitro by using specific growth factors such as bFGF, SCF, EGF, gastrin, nicotinamide, betacellulin, glucagon-like peptide-1, and/or activin A 7 10 11 15 17 20 21 24 63 74 80 82 93 – 100. Importantly, the insulin-producing cells generated from certain stem/progenitor cells were also effective at reducing the blood glucose levels in diabetic animal models in vivo 15 63 80 96 97.…”

Section: Stem Cell-based Therapies For the Treatment Of Type 1 Or 2 Dmentioning

confidence: 99%

Recent progress on normal and malignant pancreatic stem/progenitor cell research: therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer

Mimeault

Batra

2008

Gut

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Recent progress on pancreatic stem/progenitor cell research has revealed that the putative multipotent pancreatic stem/progenitor cells and/or more committed beta cell precursors may persist in the pancreatic gland in adult life. The presence of immature pancreatic cells with stem cell-like properties offers the possibility of stimulating their in vivo expansion and differentiation or to use their ex vivo expanded progenies for beta cell replacement-based therapies for type 1 or 2 diabetes mellitus in humans. In addition, the transplantation of either insulin-producing beta cells derived from embryonic, fetal and other tissue-resident adult stem/progenitor cells or genetically modified adult stem/progenitor cells may also constitute alternative promising therapies for treating diabetic patients. The genetic and/or epigenetic alterations in putative pancreatic adult stem/progenitor cells and/or their early progenies may, however, contribute to their acquisition of a dysfunctional behaviour as well as their malignant transformation into pancreatic cancer stem/progenitor cells. More particularly, the activation of distinct tumorigenic signalling cascades, including the hedgehog, epidermal growth factor-epidermal growth factor receptor (EGF-EGFR) system, wingless ligand (Wnt)/β-catenin and/or stromal cell-derived factor-1 (SDF-1)-CXC chemokine receptor 4 (CXCR4) pathways may play a major role in the sustained growth, survival, metastasis and/or drug resistance of pancreatic cancer stem/progenitor cells and their further differentiated progenies. The combination of drugs that target the oncogenic elements in pancreatic cancer stem/progenitor cells and their microenvironment, with the conventional chemotherapeutic regimens, could represent promising therapeutic strategies. These novel targeted therapies should lead to the development of more effective treatments of locally advanced and metastatic pancreatic cancers, which remain incurable with current therapies.Recent advancements in embryonic, fetal and adult pancreatic stem/progenitor cell research have revealed that these immature cells may provide critical functions for pancreas organogenesis as well as pancreatic regeneration after intense injury in adult life. The presence Correspondence to: Dr M Mimeault and Dr S K Batra, Department of Biochemistry and Molecular Biology, Eppley Institute for Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; mmimeault@unmc.edu and sbatra@unmc.edu. Competing interests: None. NIH Public Access Author ManuscriptGut. Author manuscript; available in PMC 2010 March 11. Published in final edited form as:Gut. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of multipotent adult pancreatic stem/progenitor cells (PSCs) and/or further differentiated beta cell precursors in the ductal regions and/or within the islet compartment, respectively, is of great therapeutic interest (fig 1). [1][2][3][4][5][6][7][8][9][10][11][12][13] The in vivo stimulation of these poor...

show abstract

In vivo treatment with glucagon-like peptide 1 promotes the graft function of fetal islet-like cell clusters in transplanted mice

Cited by 27 publications

References 27 publications

Liraglutide, a Long-Acting Human Glucagon-Like Peptide 1 Analog, Improves Glucose Homeostasis in Marginal Mass Islet Transplantation in Mice

Liraglutide, a Long-Acting Human Glucagon-Like Peptide 1 Analog, Improves Glucose Homeostasis in Marginal Mass Islet Transplantation in Mice

Treatment of Type 1 Diabetic Patients with Glucagon-Like Peptide-1 (GLP-1) and GLP-1R Agonists

Recent progress on normal and malignant pancreatic stem/progenitor cell research: therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer

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