Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner

Mukai, Eri; Fujimoto, Shimpei; Sato, Hiroki; Oneyama, Chitose; Kominato, Rieko; Sato, Yuichi; Sasaki, Michihito; Nishi, Yuichi; Okada, Masato; Inagaki, Nobuya

doi:10.2337/db10-0021

Cited by 86 publications

(80 citation statements)

References 49 publications

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“…The mechanism for how exendin-4 mitigates ROS remains unknown. However, in line with our observations, a previous report indicated that exendin-4 decreases endogenous ROS production and increases ATP production in diabetic Goto Kakizaki rat islets through suppression of Src activation (26). It is reported that the reduced rate of mitochondrial respiration capacity contributes to impairment of mitochondrial function and cardiac function (5).…”

Section: Discussionsupporting

confidence: 81%

Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium

DeNicola

Wang

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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. Two weeks later, cardiac function was assessed by echocardiography and an isovolumetrically perfused heart. Compared with control MI hearts, stimulation of GLP-1R improved cardiac function, which was associated with attenuation of myocardial hypertrophy, the mitigation of interstitial fibrosis, and an increase in survival rate in post-MI hearts. Furthermore, H9c2 cardiomyoblasts were preconditioned with exendin-4 at a dose of 100 nmol/l and then subjected to hydrogen peroxide exposure at concentrations of 50 and 100 mol/l. The exendin-4 treatment decreased lactate dehydrogenase leakage and increased cell survival. Notably, this event was also associated with the reduction of cleaved caspase-3 and caspase-9 and attenuation of reactive oxygen species production. Exendin-4 treatments improved mitochondrial respiration and suppressed the opening of mitochondrial permeability transition pore and protected mitochondria function. Our results indicate that GLP-1R serves as a novel approach to eliciting cardioprotection and mitigating oxidative stress-induced injury.glucagon-like peptide-1 receptor; exendin-4; heart; infarction; oxidant stress

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Section: Discussionsupporting

confidence: 81%

Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium

DeNicola

Wang

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Among the two known mammalian EPAC isoforms, EPAC1 is ubiquitously expressed in all major tissues, whereas EPAC2 is mainly restricted to the brain, pancreas, and adrenal gland (1,2). Consistent with this tissue-specific expression pattern of EPAC isoforms, EPAC1 has been implicated in cardiac hypertrophy (3,4), fibrosis (5-7), and cancers (8-10), as well as leptin resistance (11), whereas EPAC2 is involved in diabetes/insulin secretion (12)(13)(14)(15)(16)(17)(18) and autism/depression (19)(20)(21).…”

mentioning

confidence: 75%

Isoform-specific antagonists of exchange proteins directly activated by cAMP

Tsalkova

Mei

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

128

148

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The major physiological effects of cAMP in mammalian cells are transduced by two ubiquitously expressed intracellular cAMP receptors, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), as well as cyclic nucleotide-gated ion channels in certain tissues. Although a large number of PKA inhibitors are available, there are no reported EPAC-specific antagonists, despite extensive research efforts. Here we report the identification and characterization of noncyclic nucleotide EPAC antagonists that are exclusively specific for the EPAC2 isoform. These EAPC2-specific antagonists, designated as ESI-05 and ESI-07, inhibit Rap1 activation mediated by EAPC2, but not EPAC1, with high potency in vitro. Moreover, ESI-05 and ESI-07 are capable of suppressing the cAMP-mediated activation of EPAC2, but not EPAC1 and PKA, as monitored in living cells through the use of EPAC-and PKA-based FRET reporters, or by the use of Rap1-GTP pull-down assays. Deuterium exchange mass spectroscopy analysis further reveals that EPAC2-specific inhibitors exert their isoform selectivity through a unique mechanism by binding to a previously undescribed allosteric site: the interface of the two cAMP binding domains, which is not present in the EPAC1 isoform. Isoform-specific EPAC pharmacological probes are highly desired and will be valuable tools for dissecting the biological functions of EPAC proteins and their roles in various disease states.cAMP-regulated guanine nucleotide exchange factor | high-throughput screening | hydrogen/deuterium exchange mass spectrometry

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“…These results suggest that β‐cell function is actually well activated with combined use of sulfonylurea drugs and DPP‐4 inhibitors, although the effect of sitagliptin to lower glucagon 4 might also contribute to the reduced sulfonylurea doses. It is coming to be understood that incretin not only promotes the insulin release reaction in β‐cells 5,23 , but it also stimulates the insulin secretion response through multiple actions 24 , such as promoting adenosine triphosphate generation in mitochondria 25 , and both sulfonylurea and incretin act on exchange protein directly activated by cyclic adenosine monophosphate 2A in β‐cells 26,27 . Therefore, incretin and sulfonylurea are supposed to stimulate insulin secretion in coordinated and synergistic manners, and the present results appear to reflect these stimulatory effects of incretin and sulfonylureas on pancreatic β‐cells.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

Kubota

Maeda

Kanamori

et al. 2012

J of Diabetes Invest

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(J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00221.x, 2012) Aims/Introduction: To determine the efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients after 3 months’ therapy.Materials and Methods: A retrospective, observational study of 741 type 2 diabetes patients was carried out; 110 received sitagliptin monotherapy, and 631 received combination therapy with sitagliptin when other oral medications were insufficient. The primary outcome measure was glycated hemoglobin (HbA1c) measured at 0, 4 and 12 weeks of sitagliptin therapy.Results: In the monotherapy and combination therapy groups, HbA1c decreased significantly after 12 weeks. Target HbA1c (<7%) was achieved in 39.1% overall. On logistic regression analysis, baseline HbA1c was the strongest contributing factor for achieving target HbA1c; baseline body mass index and duration of diabetes were also significant factors. A total of 82 patients (11%) were unresponsive to sitagliptin. These patients’ baseline body mass index was significantly higher and their baseline HbA1c was significantly lower than those of patients who responded to sitagliptin. The most commonly co‐administered drugs were sulfonylureas (508 patients). In these patients, the dose of sulfonylurea decreased with time. In 66 patients whose sulfonylurea dosage was reduced when sitagliptin was started, HbA1c and bodyweight decreased significantly after 12 weeks. A total of 24 patients receiving sulfonylureas had mild hypoglycemia, but none discontinued sitagliptin.Conclusions: Sitagliptin was effective and safe as both monotherapy and combination therapy in Japanese type 2 diabetes patients. When sulfonylureas were ineffective, sitagliptin improved glycemic control. In patients whose sulfonylurea dose was reduced at the start of sitagliptin, blood glucose improved and bodyweight decreased after 12 weeks.

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Exendin-4 Suppresses Src Activation and Reactive Oxygen Species Production in Diabetic Goto-Kakizaki Rat Islets in an Epac-Dependent Manner

Cited by 86 publications

References 49 publications

Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium

Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium

Isoform-specific antagonists of exchange proteins directly activated by cAMP

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients

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