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1.
J Clin Invest ; 127(12): 4217-4227, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29202475

RESUMO

The discovery, characterization, and clinical development of glucagon-like-peptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance.


Assuntos
Descoberta de Drogas , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Humanos , Síndrome do Intestino Curto/tratamento farmacológico , Relação Estrutura-Atividade
2.
Cell Metab ; 25(4): 757-758, 2017 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-28380367

RESUMO

The gut is believed to be the source of GLP-1 that augments insulin secretion in response to oral nutrients. In this issue of Cell Metabolism, Chambers et al. (2017) shift the paradigm by finding that GLP-1 produced within the islets of the pancreas, and not the gut, is responsible for the incretin effect in mice.


Assuntos
Peptídeo 1 Semelhante ao Glucagon , Incretinas , Animais , Glucagon , Insulina , Camundongos , Pâncreas , Fragmentos de Peptídeos
3.
Endocr Res ; 41(1): 16-20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26186406

RESUMO

PURPOSE/AIM: Negative feedback controls in endocrine regulatory systems are well recognized. The incretins and their role in glucose regulation have been of major interest recently. Whether the same negative control system applies to the regulation of incretin secretion is not clear. We sought to examine the hypothesis that exogenous administration of glucagon like peptide-1, GLP-1(7-36) amide or its metabolite GLP-1(9-36) amide, reduces the endogenous basal release of this incretin. MATERIALS AND METHODS: We evaluated the endogenous basal release of GLP-1 using two separate study designs. In protocol A we examined the GLP-1(7-36) amide levels during the infusion of GLP-1(9-36) amide. In protocol B, we used PYY and GLP-2 as biomarkers for the endogenous basal release of GLP-1(7-36) amide and assessed the endogenous basal release of these two hormones during the GLP-1(7-36) infusion. Twelve lean and 12 obese subjects were enrolled in protocol A and 10 obese volunteers in protocol B. RESULTS: The plasma levels of GLP-1(7-36) amide in protocol A and PYY and GLP-2 in protocol B remained unchanged during the exogenous infusion of GLP-1(9-36) and GLP-1(7-36) amide, respectively. CONCLUSIONS: The negative feedback control system as described by inhibition of the release of endogenous hormone while infusing it exogenously was not observed for the basal secretion of GLP-1(7-36) amide.


Assuntos
Retroalimentação Fisiológica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Adulto , Metabolismo Basal/efeitos dos fármacos , Glicemia/metabolismo , Feminino , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Insulina/sangue , Masculino , Obesidade/metabolismo , Magreza/metabolismo
4.
Best Pract Res Clin Endocrinol Metab ; 29(6): 859-71, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26696515

RESUMO

The alpha cells that co-occupy the islets in association with beta cells have been long recognized as the source of glucagon, a hyperglycemia-producing and diabetogenic hormone. Although the mechanisms that control the functions of alpha cells, glucagon secretion, and the role of glucagon in diabetes have remained somewhat enigmatic over the fifty years since their discovery, seminal findings during the past few years have moved alpha cells into the spotlight of scientific discovery. These findings obtained largely from studies in mice are: Alpha cells have the capacity to trans-differentiate into insulin-producing beta cells. Alpha cells contain a GLP-1 generating system that produces GLP-1 locally for paracrine actions within the islets that likely promotes beta cell growth and survival and maintains beta cell mass. Impairment of glucagon signaling both prevents the occurrence of diabetes in conditions of the near absence of insulin and expands alpha cell mass. Alpha cells appear to serve as helper cells or guardians of beta cells to ensure their health and well-being. Of potential relevance to the possibility of promoting the transformation of alpha to beta cells is the observation that impairment of glucagon signaling leads to a marked increase in alpha cell mass in the islets. Such alpha cell hyperplasia provides an increased supply of alpha cells for their transdifferentiation into new beta cells. In this review we discuss these recent discoveries from the perspective of their potential relevance to the treatment of diabetes.


Assuntos
Transdiferenciação Celular , Células Secretoras de Glucagon/citologia , Glucagon/metabolismo , Células Secretoras de Insulina/citologia , Animais , Células Secretoras de Glucagon/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Transdução de Sinais
5.
Diabetes ; 64(7): 2409-19, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25858562

RESUMO

The prevalence of obesity-related diabetes is increasing worldwide. Here we report the identification of a pentapeptide, GLP-1(32-36)amide (LVKGRamide), derived from the glucoincretin hormone GLP-1, that increases basal energy expenditure and curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in diet-induced obese mice. The pentapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. Analyses of tissues from peptide-treated mice reveal increased expression of UCP-1 and UCP-3 in brown adipose tissue and increased UCP-3 and inhibition of acetyl-CoA carboxylase in skeletal muscle, findings consistent with increased fatty acid oxidation and thermogenesis. In palmitate-treated C2C12 skeletal myotubes, GLP-1(32-36)amide activated AMPK and inhibited acetyl-CoA carboxylase, suggesting activation of fat metabolism in response to energy depletion. By mass spectroscopy, the pentapeptide is rapidly formed from GLP-1(9-36)amide, the major form of GLP-1 in the circulation of mice. These findings suggest that the reported insulin-like actions of GLP-1 receptor agonists that occur independently of the GLP-1 receptor might be mediated by the pentapeptide, and the previously reported nonapeptide (FIAWLVKGRamide). We propose that by increasing basal energy expenditure, GLP-1(32-36)amide might be a useful treatment for human obesity and associated metabolic disorders.


Assuntos
Metabolismo Basal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Obesidade/tratamento farmacológico , Aumento de Peso/efeitos dos fármacos , Animais , Células Cultivadas , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Hiperinsulinismo/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/metabolismo , Obesidade/metabolismo
6.
Peptides ; 59: 20-4, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24937653

RESUMO

We have previously demonstrated in human subjects who under euglycemic clamp conditions GLP-1(9-36)amide infusions inhibit endogenous glucose production without substantial insulinotropic effects. An earlier report indicates that GLP-1(9-36)amide is cleaved to a nonapeptide, GLP-1(28-36)amide and a pentapeptide GLP-1(32-36)amide (LVKGR amide). Here we study the effects of the pentapeptide on whole body glucose disposal during hyperglycemic clamp studies. Five dogs underwent indwelling catheterizations. Following recovery, the dogs underwent a 180 min hyperglycemic clamp (basal glucose +98 mg/dl) in a cross-over design. Saline or pentapeptide (30 pmol kg(-1) min(-1)) was infused during the last 120 min after commencement of the hyperglycemic clamp in a primed continuous manner. During the last 30 min of the pentapeptide infusion, glucose utilization (M) significantly increased to 21.4±2.9 mg kg(-1) min(-1)compared to M of 14.3±1.1 mg kg(-1)min(-1) during the saline infusion (P=0.026, paired t-test; P=0.062, Mann-Whitney U test). During this interval, no significant differences in insulin (26.6±3.2 vs. 23.7±2.5 µU/ml, P=NS) or glucagon secretion (34.0±2.1 vs. 31.7±1.8 pg/ml, P=NS) were observed. These findings demonstrate that under hyperglycemic clamp studies the pentapeptide modulates glucose metabolism by a stimulation of whole-body glucose disposal. Further, the findings suggest that the metabolic benefits previously observed during GLP-1(9-36)amide infusions in humans might be due, at least in part, to the metabolic effects of the pentapeptide that is cleaved from the pro-peptide, GLP-1(9-36)amide in the circulation.


Assuntos
Glicemia/metabolismo , Peptídeo 1 Semelhante ao Glucagon/química , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Animais , Cães , Peptídeo 1 Semelhante ao Glucagon/metabolismo
8.
Trends Endocrinol Metab ; 24(3): 153-63, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23260869

RESUMO

The alpha cells that coinhabit the islets with the insulin-producing beta cells have recently captured the attention of diabetes researchers because of new breakthrough findings highlighting the importance of these cells in the maintenance of beta cell health and functions. In normal physiological conditions alpha cells produce glucagon but in conditions of beta cell injury they also produce glucagon-like peptide-1 (GLP-1), a growth and survival factor for beta cells. In this review we consider these new findings on the functions of alpha cells. Alpha cells remain somewhat enigmatic inasmuch as they now appear to be important in the maintenance of the health of beta cells, but their production of glucagon promotes diabetes. This circumstance prompts an examination of approaches to coax alpha cells to produce GLP-1 instead of glucagon.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Células Secretoras de Glucagon/fisiologia , Animais , Desdiferenciação Celular , Linhagem da Célula/fisiologia , Transdiferenciação Celular , Células Enteroendócrinas/fisiologia , Transição Epitelial-Mesenquimal , Glucagon/fisiologia , Peptídeo 1 Semelhante ao Glucagon/biossíntese , Células Secretoras de Glucagon/patologia , Proteínas de Homeodomínio/fisiologia , Humanos , Hiperplasia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/ultraestrutura , Camundongos , Fatores de Transcrição Box Pareados/fisiologia , Pró-Proteína Convertase 1/deficiência , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia
9.
Islets ; 4(3): 188-98, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22847495

RESUMO

This review considers the role of α-cells in ß-cell generation and regeneration. We present recent evidence obtained from lineage-tracing studies showing that α-cells can serve as progenitors of ß-cells and present a hypothetical model how injured ß-cells might activate α-cells in adult islets to promote ß-cell regeneration. ß-cells appear to arise by way of their trans-differentiation from undifferentiated α progenitor cells, pro-α-cells, both during embryonic development of the islets and in the adult pancreas in response to ß-cell injuries. Plasticity of α-cells is endowed by the expression of the gene encoding proglucagon, a prohormone that can give rise to glucagon and glucagon-like peptides (GLPs). The production of glucagon from proglucagon is characteristic of fully-differentiated α-cells whereas GLP-1 is a product of undifferentiated α-cells. GLP-1, a cell growth and survival factor, is proposed to promote the expansion of neurogenin3-expressing, undifferentiated pro-α-cells during development. ß-cells arise from pro-α-cells by a change in the relative amounts of the transcription factors Arx and Pax4, master regulators of the α- and ß-cell lineages, respectively. A paracrine/autocrine model is proposed whereby injuries of ß-cells in adult islets induce the production and release of factors, such as stromal cell-derived factor-1, that cause the de-differentiation of adjacent α-cells into pro-α-cells. Pro-α-cells produce GLP-1 and its receptor that renders them competent to trans-differentiate into ß-cells. The trans-differentiation of pro-α-cells into ß-cells provides a potentially exploitable mechanism for the regeneration of ß-cells in individuals with type 1 diabetes.


Assuntos
Células Secretoras de Glucagon/fisiologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/fisiologia , Regeneração/fisiologia , Animais , Diferenciação Celular/fisiologia , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células Secretoras de Glucagon/citologia , Células Secretoras de Glucagon/metabolismo , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Camundongos , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo
10.
J Endocrinol ; 213(2): 143-54, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22414687

RESUMO

Type 2 diabetes, often associated with obesity, results from a deficiency of insulin production and action manifested in increased blood levels of glucose and lipids that further promote insulin resistance and impair insulin secretion. Glucolipotoxicity caused by elevated plasma glucose and lipid levels is a major cause of impaired glucose-stimulated insulin secretion from pancreatic ß-cells, due to increased oxidative stress, and insulin resistance. Glucagon-like peptide-1 (GLP1), an insulinotropic glucoincretin hormone, is known to promote ß-cell survival via its actions on its G-protein-coupled receptor on ß-cells. Here, we report that a nonapeptide, GLP1(28-36)amide, derived from the C-terminal domain of the insulinotropic GLP1, exerts cytoprotective actions on INS-1 ß-cells and on dispersed human islet cells in vitro in conditions of glucolipotoxicity and increased oxidative stress independently of the GLP1 receptor. The nonapeptide appears to enter preferably stressed, glucolipotoxic cells compared with normal unstressed cells. It targets mitochondria and improves impaired mitochondrial membrane potential, increases cellular ATP levels, inhibits cytochrome c release, caspase activation, and apoptosis, and enhances the viability and survival of INS-1 ß-cells. We propose that GLP1(28-36)amide might be useful in alleviating ß-cell stress and might improve ß-cell functions and survival.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Trifosfato de Adenosina/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glucose/toxicidade , Humanos , Peróxido de Hidrogênio/toxicidade , Insulina/metabolismo , Secreção de Insulina , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácido Oleico/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Peptídeos/farmacologia , Receptores de Glucagon/agonistas , Receptores de Glucagon/efeitos dos fármacos , Peçonhas/farmacologia , terc-Butil Hidroperóxido/toxicidade
11.
Regul Pept ; 169(1-3): 43-8, 2011 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-21549160

RESUMO

BACKGROUND: The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28-36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1(28-36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome. METHODS AND RESULTS: Three- to 11-week infusions of GLP-1(28-36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28-36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP-1(28-36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25-70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight. CONCLUSIONS: GLP-1(28-36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28-36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome.


Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Fígado Gorduroso/prevenção & controle , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Obesidade/tratamento farmacológico , Fragmentos de Peptídeos/administração & dosagem , Aumento de Peso/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Gorduras na Dieta , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/etiologia , Fígado Gorduroso/fisiopatologia , Hiperglicemia/prevenção & controle , Hiperinsulinismo/prevenção & controle , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/fisiopatologia , Triglicerídeos/metabolismo
12.
Regul Pept ; 167(2-3): 177-84, 2011 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-21256872

RESUMO

BACKGROUND: Uncontrolled hepatic glucose production (gluconeogenesis), and glycogenolysis, is a major contributor to the fasting hyperglycemia associated with type 2 diabetes. Here we report the discovery of a C-terminal nonapeptide (FIAWLVKGRamide) derived from GLP-1 that suppresses glucose production and oxidative stress in isolated mouse hepatocytes. The nonapeptide, GLP-1(28-36)amide, was reported earlier to be a major product derived from the cleavage of GLP-1 by the endopeptidase NEP 24.11. METHODS AND RESULTS: Hepatocytes were isolated from the livers of normal and diet-induced obese mice. We find that the GLP-1(28-36)amide nonapeptide rapidly enters isolated mouse hepatocytes by GLP-1 receptor-independent mechanisms, and targets to mitochondria where it inhibits gluconeogenesis and oxidative stress. CONCLUSIONS: These findings suggest that GLP-1 not only acts on a cell surface G-protein coupled receptor activating kinase-regulated signaling pathways, but a small C-terminal peptide derived from GLP-1 also enters cells, targets mitochondria, and exerts insulin-like actions by modulating oxidative phosphorylation. GLP-1(28-36)amide, or a peptide mimetic derived there from, might prove to be a useful treatment for fasting hyperglycemia and metabolic syndrome in type 2 diabetes.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/farmacologia , Glucose/biossíntese , Hepatócitos/metabolismo , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Animais , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Fragmentos de Peptídeos/metabolismo , Receptores de Glucagon/metabolismo
13.
J Cell Sci ; 123(Pt 16): 2792-802, 2010 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-20663919

RESUMO

The adult pancreas has considerable capacity to regenerate in response to injury. We hypothesized that after partial pancreatectomy (Px) in adult rats, pancreatic-duct cells serve as a source of regeneration by undergoing a reproducible dedifferentiation and redifferentiation. We support this hypothesis by the detection of an early loss of the ductal differentiation marker Hnf6 in the mature ducts, followed by the transient appearance of areas composed of proliferating ductules, called foci of regeneration, which subsequently form new pancreatic lobes. In young foci, ductules express markers of the embryonic pancreatic epithelium - Pdx1, Tcf2 and Sox9 - suggesting that these cells act as progenitors of the regenerating pancreas. The endocrine-lineage-specific transcription factor Neurogenin3, which is found in the developing embryonic pancreas, was transiently detected in the foci. Islets in foci initially resemble embryonic islets in their lack of MafA expression and lower percentage of beta-cells, but with increasing maturation have increasing numbers of MafA(+) insulin(+) cells. Taken together, we provide a mechanism by which adult pancreatic duct cells recapitulate aspects of embryonic pancreas differentiation in response to injury, and contribute to regeneration of the pancreas. This mechanism of regeneration relies mainly on the plasticity of the differentiated cells within the pancreas.


Assuntos
Células-Tronco Embrionárias/fisiologia , Ilhotas Pancreáticas/fisiologia , Pâncreas/fisiologia , Ductos Pancreáticos/fisiologia , Regeneração/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Fator 6 Nuclear de Hepatócito/deficiência , Fator 6 Nuclear de Hepatócito/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Pâncreas/citologia , Pâncreas/metabolismo , Pancreatectomia , Ductos Pancreáticos/citologia , Ductos Pancreáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição/deficiência , Fatores de Transcrição/metabolismo
14.
Adv Exp Med Biol ; 654: 391-419, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20217507

RESUMO

The Wnt signaling pathway is critically important not only for stem cell amplification, differentiation, and migration, but also is important for organogenesis and the development of the body plan. Beta-catenin/TCF7L2-dependent Wnt signaling (the canonical pathway) is involved in pancreas development, islet function, and insulin production and secretion. The glucoincretin hormone glucagon-like peptide-1 and the chemokine stromal cell-derived factor-1 modulate canonical Wnt signaling in beta-cells which is obligatory for their mitogenic and cytoprotective actions. Genome-wide association studies have uncovered 19 gene loci that confer susceptibility for the development of type 2 diabetes. At least 14 of these diabetes risk alleles encode proteins that are implicated in islet growth and functioning. Seven of them are either components of, or known target genes for, Wnt signaling. The transcription factor TCF7L2 is particularly strongly associated with risk for diabetes and appears to be fundamentally important in both canonical Wnt signaling and beta-cell functioning. Experimental loss of TCF7L2 function in islets and polymorphisms in TCF7L2 alleles in humans impair glucose-stimulated insulin secretion, suggesting that perturbations in the Wnt signaling pathway may contribute substantially to the susceptibility for, and pathogenesis of, type 2 diabetes. This review focuses on considerations of the hormonal regulation of Wnt signaling in islets and implications for mutations in components of the Wnt signaling pathway as a source for risk-associated alleles for type 2 diabetes.


Assuntos
Ilhotas Pancreáticas/citologia , Proteínas Wnt/metabolismo , Alelos , Animais , Diabetes Mellitus Tipo 2/genética , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Camundongos , Modelos Biológicos , Mutação , Polimorfismo Genético , Transdução de Sinais , Fatores de Transcrição TCF/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição
15.
Trends Endocrinol Metab ; 21(2): 59-67, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20018525

RESUMO

GLP-1 (9-36)amide is the cleavage product of GLP-1(7-36) amide, formed by the action of diaminopeptidyl peptidase-4 (Dpp4), and is the major circulating form in plasma. Whereas GLP-1(7-36)amide stimulates glucose-dependent insulin secretion, GLP-1(9-36)amide has only weak partial insulinotropic agonist activities on the GLP-1 receptor, but suppresses hepatic glucose production, exerts antioxidant cardioprotective actions and reduces oxidative stress in vasculature tissues. These insulin-like activities suggest a role for GLP-1 (9-36)amide in the modulation of mitochondrial functions by mechanisms independent of the GLP-1 receptor. In this paper, we discuss the current literature suggesting that GLP-1(9-36)amide is an active peptide with important insulin-like actions. These findings have implications in nutrient assimilation, energy homeostasis, obesity, and the use of Dpp4 inhibitors for the treatment of diabetes.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Insulina/farmacologia , Receptor de Insulina/fisiologia , Receptores de Glucagon/fisiologia , Sequência de Aminoácidos , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Citoproteção/efeitos dos fármacos , Citoproteção/fisiologia , Peptídeo 1 Semelhante ao Glucagon/química , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Coração/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Modelos Biológicos , Modelos Teóricos , Dados de Sequência Molecular , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Processamento de Proteína Pós-Traducional/fisiologia , Receptor de Insulina/metabolismo , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo
16.
Cell ; 138(3): 424-6, 2009 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-19665963

RESUMO

Understanding the origins of insulin-producing beta cells of the pancreas could lead to new treatments for diabetes. Collombat et al. (2009) now show that in response to injury, a population of pancreatic progenitor cells can give rise to glucagon-expressing alpha cells that then transdifferentiate into beta cells.


Assuntos
Células Secretoras de Glucagon/citologia , Células Secretoras de Insulina/citologia , Pâncreas/citologia , Animais , Células Secretoras de Insulina/metabolismo , Camundongos , Células-Tronco/citologia
17.
Islets ; 1(3): 177-84, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-21099270

RESUMO

The basic helix-loop-helix transcription factor neurogenin-3 (Ngn3, Neurog3) is critical for the development of the endocrine cells of the islets. Either disrupted or forced expression of Ngn3 early in mouse pancreas development abrogates the formation of islets. The successive waves of Ngn3 expression that occur during the primary and secondary transitions of endocrine cell development temporally determine the four distinct endocrine cell lineages, α, ß, PP, and δ cells that express glucagon, insulin, pancreatic polypeptide, and somatostatin, respectively. During islet regeneration after injury of the adult mouse pancreas, such as by duct ligation or streptozotocin, Ngn3 is activated in duct-associated stem/progenitor cells that transform into alpha and/or beta cells (Xu et al, Collombat et al). The important role of Ngn3 as a master regulator of endocrine pancreas development directs attention to finding therapeutic approaches to enhance Ngn3 expression in diabetes as a means to increase beta cell mass and functions.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Diferenciação Celular/genética , Ilhotas Pancreáticas/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Sequência de Aminoácidos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Humanos , Ilhotas Pancreáticas/metabolismo , Camundongos , Modelos Biológicos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Regeneração/genética , Regeneração/fisiologia , Homologia de Sequência
18.
Obesity (Silver Spring) ; 16(7): 1501-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18421270

RESUMO

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) (7-36) amide is a glucoregulatory hormone with insulinotropic and insulinomimetic actions. We determined whether the insulinomimetic effects of GLP-1 are mediated through its principal metabolite, GLP-1 (9-36) amide (GLP-1m). METHODS AND PROCEDURES: Glucose turnover during two, 2-h, euglycemic clamps was measured in 12 lean and 12 obese (BMI <25 or >30 kg/m(2)) male and female subject volunteers with normal oral glucose tolerance test. Saline or GLP-1m were infused from 0 to 60 min in each study. Additionally, seven lean and six obese subjects underwent a third clamp in which the GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) amide was infused from -60 to 60 min with GLP-1m from 0 to 60 min. RESULTS: No glucose infusion was required in lean subjects to sustain euglycemia (glucose clamp) during saline or GLP-1m infusions. However, in obese subjects glucose infusion was necessary during GLP-1m infusion alone in order to compensate for a marked (>50%) inhibition of hepatic glucose production (HGP). Plasma insulin levels remained constant in lean subjects but rose significantly in obese subjects after termination of the peptide infusions. During GLP-1R blockade, infusion of glucose was immediately required upon starting GLP-1m infusions in all subjects due to a more dramatic reduction in HGP, as well as a delayed and modest insulinotropic response. DISCUSSION: We conclude that GLP-1m potently inhibits HGP and is a weak insulinotropic agent. These properties are particularly apparent and pronounced in obese but only become apparent in lean subjects during GLP-1 (7-36) receptor blockade. These previously unrecognized antidiabetogenic actions of GLP-1m may have therapeutic usefulness.


Assuntos
Glicemia/metabolismo , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/metabolismo , Insulina/sangue , Fígado/metabolismo , Obesidade/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo , Receptores de Glucagon/metabolismo , Adulto , Glicemia/efeitos dos fármacos , Feminino , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/administração & dosagem , Infusões Parenterais , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Peptídeos/administração & dosagem , Receptores de Glucagon/efeitos dos fármacos , Fatores de Tempo
19.
Biochem Biophys Res Commun ; 368(3): 614-9, 2008 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-18243136

RESUMO

The role of adenylate kinase (AK) as a determinant of K-ATP channel activity in human pancreatic beta-cells was investigated. We have identified that two cytosolic isoforms of AK, AK1 and AK5 are expressed in human islets and INS-1 cells. Elevated concentrations of glucose inhibit AK1 expression and AK1 immunoprecipitates with the Kir6.2 subunit of K-ATP. AK activation by ATP+AMP stimulates K-ATP channel activity and this stimulation is abolished by AK inhibitors. We propose that glucose stimulation of beta-cells inhibits AK through glycolysis and also through the elevation of diadenosine polyphosphate levels. Glucose-dependent inhibition of AK increases the ATP/ADP ratio in the microenvironment of the K-ATP channel promoting channel closure and insulin secretion. The down-regulation of AK1 expression by hyperglycemia may contribute to the defective coupling of glucose metabolism to K-ATP channel activity in type 2 diabetes.


Assuntos
Adenilato Quinase/metabolismo , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Ativação do Canal Iônico/fisiologia , Isoenzimas/metabolismo , Canais de Potássio/metabolismo , Adenilil Ciclases/metabolismo , Animais , Linhagem Celular , Citosol/metabolismo , Secreção de Insulina , Ratos
20.
J Biol Chem ; 283(13): 8723-35, 2008 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-18216022

RESUMO

The insulinotropic hormone GLP-1 (glucagon-like peptide-1) is a new therapeutic agent that preserves or restores pancreatic beta cell mass. We report that GLP-1 and its agonist, exendin-4 (Exd4), induce Wnt signaling in pancreatic beta cells, both isolated islets, and in INS-1 cells. Basal and GLP-1 agonist-induced proliferation of beta cells requires active Wnt signaling. Cyclin D1 and c-Myc, determinants of cell proliferation, are up-regulated by Exd4. Basal endogenous Wnt signaling activity depends on Wnt frizzled receptors and the protein kinases Akt and GSK3beta but not cAMP-dependent protein kinase. In contrast, GLP-1 agonists enhance Wnt signaling via GLP-1 receptor-mediated activation of Akt and beta cell independent of GSK3beta. Inhibition of Wnt signaling by small interfering RNAs to beta-catenin or a dominant-negative TCF7L2 decreases both basal and Exd4-induced beta cell proliferation. Wnt signaling appears to mediate GLP-1-induced beta cell proliferation raising possibilities for novel treatments of diabetes.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/farmacologia , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição TCF/metabolismo , Proteínas Wnt/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Separação Celular , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ciclina D1/genética , Ativação Enzimática , Exenatida , Receptores Frizzled/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Insulina/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Ligantes , Camundongos , Peptídeos/farmacologia , Ratos , Receptores de Glucagon/metabolismo , Fatores de Transcrição TCF/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição , Peçonhas/farmacologia , beta Catenina/metabolismo
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