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1.
J Neurochem ; 136(4): 859-870, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26603140

RESUMEN

Incretin-related therapy was found to be beneficial for experimental diabetic neuropathy, but its mechanism is obscure. The purpose of this study is to explore the mechanism through which dipeptidyl peptidase IV inhibitor, vildagliptin (VG), influences neuropathy in diabetic rodents. To this end, non-obese type 2 diabetic Goto-Kakizaki rats (GK) and streptozotocin (STZ)-induced diabetic mice were treated with VG orally. Neuropathy was evaluated by nerve conduction velocity (NCV) in both GK and STZ-diabetic mice, whereas calcitonin-gene-related peptide expressions, neuronal cell size of dorsal root ganglion (DRG) and intraepidermal nerve fiber density were examined in GK. DRG from GK and STZ-diabetic mice served for the analyses of GLP-1 and insulin signaling. As results, VG treatment improved glucose intolerance and increased serum insulin and GLP-1 in GK accompanied by the amelioration of delayed NCV and neuronal atrophy, reduced calcitonin-gene-related peptide expressions and intraepidermal nerve fiber density. Diet restriction alone did not significantly influence these measures. Impaired GLP-1 signals such as cAMP response element binding protein, protein kinase B/Akt (PKB/Akt) and S6RP in DRG of GK were restored in VG-treated group, but the effect was equivocal in diet-treated GK. Concurrently, decreased phosphorylation of insulin receptor substrate 2 in GK was corrected by VG treatment. Consistent with the effect on GK, VG treatment improved NCV in diabetic mice without influence on hyperglycemia. DRG of VG-treated diabetic mice were characterized by correction of GLP-1 signals and insulin receptor substrate 2 phosphorylation without effects on insulin receptor ß expression. The results suggest close association of neuropathy development with impaired signaling of insulin and GLP-1 in diabetic rodents. Diabetic neurons are resistant to insulin and such insulin resistance may contribute to development of neuropathy. DPP-IV inhibitor, vildagliptin, corrected insulin resistance and improved neuropathy irrespective of blood glucose via augmented action of GLP-1.

2.
J Diabetes Investig ; 5(1): 38-47, 2014 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-24843735

RESUMEN

AIMS/INTRODUCTION: Impaired growth and premature death of ß-cells are implicated in the progression of islet pathology in type 2 diabetes. It remains unclear, however, how aging affects islet cells, or whether the islet change in diabetes is an augmented process of aging. We studied age-related changes of the islet structure in Japanese non-diabetic subjects and explored the underlying mechanism of the changes. MATERIALS AND METHODS: A total of 115 non-diabetic autopsy cases were subjected to morphometric analysis for volume densities of islets, ß- and non-ß-cells, as well as their masses. Proliferation activity identified by Ki67, and expressions of pancreatic and duodenal homeobox (PDX)-1, cell cycle inhibitor P16, and oxidative stress marker γH2AX were also examined. RESULTS: There was a gradual and marginal decline of volume densities of islets, ß- and non-ß-cells with aging, while masses of these components were increased during maturation and slowly decreased after the 40s. Islet density was high in the young, but reduced after maturation. There was only a minimal influence of increased body mass index (BMI) on the increase in ß-cell mass, but not on the other variables. Ki67 positivity and PDX-1 expressions were high in the young, but low after maturation, whereas expressions of P16 and γH2AX were elevated in the aged. CONCLUSIONS: Age-associated decline of ß-cell mass is marginal after maturation, and the reduction of ß-cell mass could be a specific process in diabetes. The impact of BMI on the islet structure is limited in Japanese with normal glucose tolerance.

3.
Diabetes Care ; 37(7): 1966-74, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24705612

RESUMEN

OBJECTIVE: Deficits of ß-cells characterize the islet pathology in type 2 diabetes. It is yet to be clear how the ß-cell loss develops in type 2 diabetes. We explored the implication of oxidative stress, endoplasmic reticulum (ER)-induced stress, and autophagy deficit in the ß-cell decline in Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Pancreases from recent autopsy cases of 47 type 2 diabetic and 30 nondiabetic subjects were investigated on the islet structure with morphometric analysis. Volume densities of islet (Vi), ß-cell (Vß), and α-cell (Vα) were measured. To evaluate cell damage of endocrine cells, immunohistochemical expressions of oxidative stress-related DNA damage as expressed by γH2AX, ER stress-related cell damage as CCAAT/enhancer 1 binding protein-ß (C/EBP-ß), and autophagy deficit as P62 were semiquantified, and their correlations to islet changes were sought. RESULTS: Compared with nondiabetic subjects, Vß was reduced in diabetic subjects. Contrariwise, there was an increase in Vα. There was a significant link between reduced Vß and increased HbA1c levels (P < 0.01) and a trend of inverse correlation between Vß and duration of diabetes (P = 0.06). Expressions of γH2AX, P62, and C/EBP-ß were all enhanced in diabetic islets, and reduced Vß correlated with the intensity of γH2AX expression but not with C/EBP-ß or P62 expressions. Combined expressions of γH2AX, P62, and C/EBP-ß were associated with severe reduction of Vß. CONCLUSIONS: ß-Cell deficit in type 2 diabetes was associated with increased oxidative stress and may further be augmented by autophagic deficits and ER stress.


Asunto(s)
Daño del ADN/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Estrés del Retículo Endoplásmico/fisiología , Estrés Oxidativo/fisiología , Anciano , Pueblo Asiatico , Autofagia/fisiología , Autopsia , Femenino , Humanos , Células Secretoras de Insulina/metabolismo , Japón , Masculino , Persona de Mediana Edad , Páncreas/patología
4.
Amyloid ; 21(3): 191-201, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25007035

RESUMEN

AIMS: Islet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear. METHODS: From 118 autopsy cases with type 2 diabetes, 26 cases with islet amyloid deposition (DA+) were selected. Twenty diabetic subjects without obvious amyloid deposition (DA-) matched for the age and diabetes duration and 20 non-diabetic subjects (ND) served for comparison. We examined the severity of amyloid deposition and its relationships with population of endocrine cells, expression of cell damage markers or macrophage infiltration. Correlation of clinical profile with islet pathology was also sought on the subset of the investigated patients. RESULTS: ß-Cell volume density was nearly 40% less in DA+ and 20% less in DA- when compared to ND. Severity of amyloid deposition correlated with reduced volume densities of ß-cell and α-cell, and increased body mass index (BMI), but not with duration of diabetes, age or HbA1c. Amyloid-rich islets contained an increased number of macrophages mixed with ß-cells with oxidative stress-related DNA damage, characterized by γH2AX expression, and suppressed (pro)insulin mRNA expression. CONCLUSIONS: In Japanese type 2 diabetic patients, islet amyloid was more common with severe ß-cell loss and high BMI, associated with macrophage infiltration.


Asunto(s)
Diabetes Mellitus Tipo 2/patología , Células Secretoras de Glucagón/patología , Células Secretoras de Insulina/patología , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Macrófagos/patología , Anciano , Autopsia , Estudios de Casos y Controles , Movimiento Celular , Daño del ADN , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Expresión Génica , Células Secretoras de Glucagón/metabolismo , Hemoglobina Glucada/genética , Hemoglobina Glucada/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Japón , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Estrés Oxidativo , Proinsulina/deficiencia , Proinsulina/genética
5.
Pancreas ; 42(5): 786-94, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23774700

RESUMEN

OBJECTIVES: The risk of adverse effects of dipeptidyl peptidase-4 inhibitors on the exocrine pancreas, particularly the high risk of pancreatitis, is controversial. In this study, we examined the exocrine pancreatic function and structure in spontaneously diabetic Goto-Kakizaki (GK) rats treated with a dipeptidyl peptidase-4 inhibitor. METHODS: Male GK rats and normal Wistar rats 4 weeks of age were treated with vildagliptin (VG; 30 mg/kg/d) for 18 weeks. Subsequently, exocrine pancreatic pathology and function in treated animals were compared to those in untreated animals. RESULTS: In GK rats, VG treatment suppressed elevated serum concentrations of amylase and lipase, reduced lymphocytic infiltration around ducts, around vessels, and in acinar areas, and reduced the frequency of apoptotic acinar cells and ductule formation (both of which occurred more frequently in GK rats than Wistar rats). However, VG treatment had no effect on the proliferation rate of pancreatic duct glandular cells (which was low in GK rats) and of cells in the main ducts, peripheral ducts, and acini (which was similar in all groups). CONCLUSIONS: Perturbations of exocrine pancreatic function and structure in GK rats are ameliorated by long-term VG treatment.


Asunto(s)
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/fisiopatología , Nitrilos/farmacología , Páncreas Exocrino/efectos de los fármacos , Pirrolidinas/farmacología , Células Acinares/efectos de los fármacos , Células Acinares/patología , Adamantano/farmacología , Animales , Apoptosis/efectos de los fármacos , Glucemia/metabolismo , Proliferación Celular/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Ayuno/sangre , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/metabolismo , Inmunohistoquímica , Insulina/sangre , Antígeno Ki-67/análisis , Masculino , Páncreas Exocrino/patología , Páncreas Exocrino/fisiopatología , Conductos Pancreáticos/efectos de los fármacos , Conductos Pancreáticos/patología , Conductos Pancreáticos/fisiopatología , Ratas , Ratas Wistar , Especificidad de la Especie , Vildagliptina
6.
Eur J Pharmacol ; 691(1-3): 297-306, 2012 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-22820107

RESUMEN

Reduced ß cell mass is a characteristic feature of type 2 diabetes and incretin therapy is expected to prevent this condition. However, it is unknown whether dipeptidyl peptidase-4 inhibitors influence ß and α cell mass in animal models of diabetes that can be translated to humans. Therefore, we examined the long-term effects of treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin on islet morphology in Goto-Kakizaki (GK) rats, a spontaneous, non-obese model of type 2 diabetes, and explored the underlying mechanisms. Four-week-old GK rats were orally administered with vildagliptin (15 mg/kg) twice daily for 18 weeks. Glucose tolerance was monitored during the study. After 18 weeks, ß and α cell morphology and the expression of molecules involved in cell proliferation and cell death were examined by immunohistochemistry and morphometric analysis. We found that vildagliptin improved glucose tolerance and insulin secretion, and suppressed hyperglucagonemia by increasing plasma active glucagon-like peptide-1 concentrations. ß cell mass was reduced in GK rats to 40% of that in Wistar rats, but was restored to 80% by vildagliptin. Vildagliptin enhanced ß and α cell proliferation, and increased the number of small neogenetic islets. Vildagliptin also reduced the number of 8-hydroxy-2'-deoxyguanosine-positive cells and forkhead box protein O1 expression, inhibited macrophage infiltration, and enhanced S6 ribosomal protein, molecule of target of rapamycin, and pancreatic duodenal homeobox 1 expression. These results indicate that starting vildagliptin treatment from an early age improved glucose tolerance and preserved islet ß cell mass in GK rats by facilitating the proliferation of islet endocrine cells.


Asunto(s)
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/patología , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Nitrilos/farmacología , Pirrolidinas/farmacología , 8-Hidroxi-2'-Desoxicoguanosina , Adamantano/farmacología , Adamantano/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Ingestión de Alimentos/efectos de los fármacos , Glucagón/sangre , Péptido 1 Similar al Glucagón/sangre , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/tratamiento farmacológico , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Masculino , Nitrilos/uso terapéutico , Pirrolidinas/uso terapéutico , Ratas , Factores de Tiempo , Vildagliptina
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