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1.
Gen Physiol Biophys ; 30(1): 34-44, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21460410

RESUMO

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from intestinal L cells upon nutrients ingestion, and is currently used for treating diabetes mellitus. It plays an important role in receptor modulation and cross talk with insulin at the coronary endothelium (CE) and cardiomyocytes (CM) in diabetic type 1 rat heart model. We studied the effects of insulin, GLP-1 analogues (exendin-4), and dipeptidyl peptidase-IV (DPP-IV) inhibitor on GLP-1 cardiac receptor modulation. The binding affinity of GLP-1 to its receptor on CE and CM was calculated using a rat heart perfusion model with [(125)I]-GLP-1(7-36). Tissue samples from the heart were used for immunostaining and Western blot analyses. GLP-1 systemic blood levels were measured using ELISA. GLP-1 binding affinity (τ) increased on the CE (0.33 ± 0.01 vs. 0.25 ± 0.01 min; p < 0.001) and decreased on the CM (0.29 ± 0.02 vs. 0.43 ± 0.02 min; p < 0.001) in the diabetic non-treated rats when compared to normal. There was normalization of τ back to baseline on the CE and CM levels with insulin and DPP-IV inhibitor treatment, respectively. Histological sections and immunofluorescence showed receptor up-regulation in diabetic rats with significant decrease and even normalization with the different treatment strategies. Systemic GLP-1 levels increased after 14 days of diabetes induction (10 ± 3.7 vs. 103 ± 58 pM; p = 0.0005). In conclusion, there is a significant GLP-1 receptor affinity modulation on the CE and CM levels in rats with diabetes type 1, and a cross talk with GLP-1 analogues in early prevention of cardiac remodeling.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptores de Glucagon/metabolismo , Remodelação Ventricular , Animais , Glicemia/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Exenatida , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Receptor do Peptídeo Semelhante ao Glucagon 1 , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Insulina/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeos/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptor Cross-Talk , Receptores de Glucagon/efeitos dos fármacos , Peçonhas/farmacologia
2.
Can J Physiol Pharmacol ; 88(7): 753-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20651823

RESUMO

The aim of this study was to determine whether the jejunal oligopeptide transporter PepT1 is regulated by insulin and whether this regulation is sex-dependent in type 1 diabetic rats. PepT1 expression, real-time polymerase chain reaction, and Western blots were performed using jejunal segments from 4 groups of male and female rats: normal (nondiabetic), insulin-treated nondiabetic, streptozotocin (STZ)-induced diabetic (type 1 diabetes), and insulin-treated diabetic models. Furthermore, the same segments from all groups underwent perfusion to assess uptake of the dipeptide glycylsarcosine through PepT1. Our results showed that insulin treatment of nondiabetic female rats decreased blood glucose level but did not affect nondiabetic male rats. In both male and female diabetic rats, insulin did not completely decrease blood glucose level. Insulin treatment decreased PepT1 mRNA level in nondiabetic male rats and increased mRNA level in nondiabetic female rats without affecting the PepT1 protein level in either sex. Inducing diabetes with STZ increased PepT1 mRNA and protein levels in female rats; however, in diabetic male rats, the increase in mRNA level was accompanied by a decrease in PepT1 protein level. Treatment of diabetic male rats with insulin partially reversed the effect of diabetes on PepT1 mRNA and protein levels, whereas the same treatment completely restored both PepT1 mRNA and protein to control levels in insulin-treated diabetic female rats. In both nondiabetic male and female rats, insulin treatment had no effect on PepT1 influx rate, and STZ treatment decreased the transporter influx rate. Treatment of diabetic male and female rats with insulin significantly increased PepT1 influx rate; however, complete recovery was found only in diabetic female rats. These results clearly show that insulin and diabetes affected blood glucose level as well as PepT1 activity, expression, and protein levels in a sex-dependent manner. These results suggest that a factor, probably estrogen, could be responsible for the sex-dependent effects of diabetes and insulin in PepT1 level and activity.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Insulina/farmacologia , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Simportadores/genética , Simportadores/metabolismo , Animais , Sequência de Bases , Glicemia/metabolismo , Primers do DNA/genética , Diabetes Mellitus Experimental/genética , Dipeptídeos/metabolismo , Estrogênios/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Masculino , Transportador 1 de Peptídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais
3.
Can J Physiol Pharmacol ; 88(1): 54-63, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20130739

RESUMO

This study focused on the regulation and affinity modulation of the insulin receptor of coronary endothelium and cardiomyocytes in nondiabetic and STZ-induced type 1 diabetic rats. Male rats were divided into the following 9 groups: nondiabetic (N), nondiabetic treated with exendin-4 (NE), nondiabetic treated with dipeptidyl peptidase IV (DPP-IV) inhibitor (NDp), diabetic (D), diabetic treated with insulin (DI), diabetic treated with exendin-4 (DE), diabetic co-treated with insulin and exendin-4 (DIE), diabetic treated with DPP-IV inhibitor (DDp), and diabetic co-treated with insulin and DPP-IV inhibitor (DIDp). After the rats were treated for 1 month, a first-order Bessel function was employed to estimate the insulin binding affinity (with time constant tau = 1/k-n) to its receptors on the coronary endothelium and cardiomyocytes using CHAPS-untreated and CHAPS-treated heart perfusion, respectively. The results showed that diabetes (D) decreased the tau value on the coronary endothelium and increased it on cardiomyocytes compared with the nondiabetic group (N). Treatment with insulin and (or) exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, increased tau on the coronary endothelium only. On the coronary endothelium, tau values of DI and DIDp were normalized. Western blots of the insulin receptor showed upregulation in D, downregulation in DI, and normalization in DE and DDp. Immunohistochemistry and RT-PCR findings indicated atrial natriuretic factor (ANF) in all diabetic ventricles, thus ascertaining hypertrophy. Therefore, negative myocardial effects related to the insulin receptor were diminished in diabetic rats treated with DPP-IV inhibitor and, more efficiently, by exendin-4.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Receptor de Insulina/metabolismo , Animais , Glicemia/metabolismo , Bovinos , Diabetes Mellitus Experimental/tratamento farmacológico , Exenatida , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Masculino , Peptídeos/administração & dosagem , Peptídeos/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Peçonhas/administração & dosagem , Peçonhas/uso terapêutico
4.
Artigo em Inglês | MEDLINE | ID: mdl-17703431

RESUMO

This study focused on the regulation and affinity modulation of angiotensin II (Ang II) binding to its receptor subtypes (AT(1)- and AT(2)-receptor) in the coronary endothelium (CE) and cardiomyocytes (CM) of Sprague-Dawley male rats in normal (N), normal treated with losartan (NL), streptozotocin-induced diabetic (D), insulin-treated diabetic (DI), losartan-treated diabetic (DL), and diabetic co-treated with insulin and losartan (DIL). Heart perfusion was used to estimate Ang II binding affinity (tau=1/k-(n)) to its receptor subtypes on CE and CM. Diabetes decreased tau value on CE and increased it on CM as compared to normal. In DL group, the tau value decreased on CE but was normalised on CM. Insulin treatment alone (DI) or with losartan (DIL) restored t to normal on both CE and CM. Western blot results for AT(1)-receptor density showed an increase in diabetics compared to normal with no normalising effect with insulin treatment. The AT(1)-receptor density was normalised in the diabetic groups treated with losartan +/- insulin. Results for AT(2)-receptor regulation revealed a significant difference between untreated (D) and losartan-treated (DL, DIL) diabetic groups. All of these data show the interrelated pathway and cross-talk between insulin and Ang II system indicating potentially negative effects on the diabetic heart.


Assuntos
Angiotensina II/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Coração/fisiopatologia , Insulina/metabolismo , Losartan/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Receptor Cross-Talk/fisiologia , Animais , Antiarrítmicos/uso terapêutico , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Coração/anatomia & histologia , Insulina/uso terapêutico , Tamanho do Órgão/efeitos dos fármacos , Ratos , Receptor de Insulina/fisiologia , Receptores de Angiotensina/fisiologia , Valores de Referência
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