Incretin-based therapy: renal effects

Korbut, Anton I.; Климонтов, В. В.

doi:10.14341/dm7727

Cited by 12 publications

(13 citation statements)

References 93 publications

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“…A growing body of evidence indicates that DPP4 inhibitors could produce multiple pleiotropic effects independent of lowering glucose levels[19,20]. In this study, we demonstrated the beneficial effects of the DPP4 inhibitor linagliptin on both parenchymal and non-parenchymal hepatic cells in T2D db/db mice (BKS.Cg- Dockm м +/+ Lepr db /J).…”

Section: Discussionmentioning

confidence: 53%

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Мичурина¹,

Ishenko²,

Климонтов³

et al. 2016

WJD

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AIMTo study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease (NAFLD) in db/db mice.METHODSMale diabetic db/db mice (BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin (10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) was assessed by immunohistochemistry.RESULTSIn 18-wk-old diabetic mice, liver steatosis (predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets (92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets (20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels.CONCLUSIONThe DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.

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Section: Discussionmentioning

confidence: 53%

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Мичурина¹,

Ishenko²,

Климонтов³

et al. 2016

WJD

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“…It is well known that both SGLT2 and DPP4 inhibitors generate glucose-dependent and glucose-independent effects in the targeted organs [14][15][16][17][18][19]. In our study, autophagy was reactivated by both empagliflozin and linagliptin, while glucose levels were reduced, but not to the normal range, only under empagliflozin administration.…”

Section: Reactivation Of Autophagy: a Missing Link In The Mechanism Omentioning

confidence: 44%

“…SGLT2 inhibitors have been shown to enhance sodium excretion and suppress glomerulosclerosis and interstitial fibrosis, inflammation and oxidative stress in diabetic kidney [14][15][16]. In addition, DPP4 inhibitors have been showed to reduce glomerular hypertension and hyperfiltration [17][18][19]. Moreover, empagliflozin has been shown to activate autophagy in tubular cells [20,21].…”

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confidence: 99%

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

Korbut

Taskaeva

Bgatova

et al. 2020

IJMS

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Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old male db/db mice were randomly assigned to treatment with empagliflozin, linagliptin, empagliflozin-linagliptin or vehicle for 8 weeks. Age-matched non-diabetic db/+ mice acted as controls. To estimate glomerular autophagy, immunohistochemistry for beclin-1 and LAMP-1 was performed. Podocyte autophagy was assessed by counting the volume density (Vv) of autophagosomes, lysosomes and autolysosomes by transmission electron microscopy. LC3B and LAMP-1, autophagy markers, and caspase-3 and Bcl-2, apoptotic markers, were evaluated in renal cortex by western blot. Vehicle-treated db/db mice had weak glomerular staining for beclin-1 and LAMP-1 and reduced Vv of autophagosomes, autolysosomes and lysosomes in podocytes. Empagliflozin and linagliptin, both as monotherapy and in combination, enhanced the areas of glomerular staining for beclin-1 and LAMP-1 and increased Vv of autophagosomes and autolysosomes in podocytes. Renal LC3B and Bcl-2 were restored in actively treated animals. LAMP-1 expression was enhanced in the empagliflozin group; caspase-3 expression decreased in the empagliflozin-linagliptin group only. Mesangial expansion, podocyte foot process effacement and urinary albumin excretion were mitigated by both agents. The data provide further explanation for the mechanism of the renoprotective effect of SGLT2 inhibitors and DPP4 inhibitors in diabetes.Int. J. Mol. Sci. 2020, 21, 2987 2 of 22 dedifferentiation. In its turn, the loss or damage of podocytes causes dysfunction of the filtration barrier and increases albuminuria [2]. Some recent studies have indicated an emerging role of autophagy downregulation in diabetic podocytopathy [4][5][6]. Autophagy is a cellular recycling process involving self-degradation and reconstruction of damaged organelles and proteins [6]. The process is vital for highly differentiated post-mitotic cells, such as neurons and podocytes [7]. A growing body of evidence indicates a critical role of autophagy in maintaining podocyte integrity and renal function [6]. Mice with podocyte-specific deletion of autophagic regulators, such as class III PI3K vacuolar protein sorting 34 (Vps34) and the Atg5 gene, develop early proteinuria, progressive glomerulosclerosis, and renal failure [6]. Accordingly, autophagy is considered a potential therapeutic target for renal protection [8,9].Sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidylpeptidase-4 (DPP4) inhibitors are promising antidiabetic agents introduced into clinical practice in the last decade. The antihyperglycemic effect of SGLT2 inhibitors is mediated by increment of glucosuria, while DPP4 inhibitors realize their activity through an increase in the half-life of incretin hormones. Both SGLT2 and DPP4 inhibitors demonstrated renal protective...

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“…Возможно, в торможение развития ХБП внесло вклад снижение систолического АД и массы тела [44]. Известно, что некоторые сахароснижающие препа-раты, в частности, агонисты глюкагоноподобного пеп-тида-1 и ингибиторы дипептидилпептидазы-4, могут оказывать антиальбуминурический эффект за счет пря-мого действия на почки [47,48]. Очевидно, в основе нефропротективного действия эмпаглифлозина также могут лежать внутрипочечные эффекты.…”

Section: сахарный диабет Diabetes Mellitusunclassified

Empagliflozin: a new strategy for nephroprotection in diabetes

Korbut¹,

Климонтов²

2017

Diabetes mellitus

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Диагностика, контроль, лечение Diagnosis, control, treatment нгибиторы глюкозо-натриевого симпортера 2 (SGLT2) -новый класс сахароснижающих препаратов с многочисленными негликеми-ческими эффектами. Применение препаратов данного класса открывает большие перспективы не только в плане контроля гликемии, но и в профилактике осложне-ний сахарного диабета (СД). В данном обзоре обобщены результаты экспериментальных и клинических иссле-дований эффектов ингибитора SGLT2 эмпаглифлозина на структурно-функциональные изменения в почках при СД и динамику развития диабетической нефропа-тии (ДН). Поиск источников проведен в базах данных Medline/PubMed, Scopus, Web of Science, ClinicalTrials.gov, eLibrary. Представлены результаты оригинальных иссле-дований и мета-анализов, опубликованных преимуще-ственно в период 2012-2016 гг. Эмпаглифлозин

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Incretin-based therapy: renal effects

Cited by 12 publications

References 93 publications

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Linagliptin alleviates fatty liver disease in diabetic db/db mice

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

Empagliflozin: a new strategy for nephroprotection in diabetes

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