Combination effects of alogliptin and pioglitazone on steatosis and hepatic fibrosis formation in a mouse model of non-alcoholic steatohepatitis

Amano, Yuichiro; Tsuchiya, Shuntarou; Imai, Masaru; Tohyama, Kimio; Matsukawa, Jun; Isono, Osamu; Yasuno, Hironobu; Enya, Kazuaki; Koumura, Emiko; Nagabukuro, Hiroshi

doi:10.1016/j.bbrc.2018.02.055

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…Each treatment was administered daily by oral gavage for 10 weeks. Voglibose and pioglitazone doses were 1.0 mg/kg/day and 10 mg/kg/day, respectively, given human doses and the results of previous experiments 43 – 46 . The mice were maintained at a temperature of 23 °C ± 2 °C and a humidity level of 60% ± 10% under a 12-h light/dark cycle.…”

Section: Methodsmentioning

confidence: 99%

The effects of the voglibose on non-alcoholic fatty liver disease in mice model

Bae

Lee

Shin

et al. 2022

Sci Rep

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The α-glucosidase inhibitor (α-GI) delays the intestinal absorption of glucose, which reduces postprandial hepatic glucose intake. This mechanism is considered to be effective in treating non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effect of voglibose, an α-glucosidase inhibitor, on high-fat, high-fructose (HFHFr) diet-induced NAFLD models. Seven-week-old male C57BL/6J mice were randomly placed in a chow diet group or an HFHFr diet group. After 10 weeks, mice in the HFHFr group were randomly assigned to one of three groups: HFHFr diet with vehicle, HFHFr with voglibose, or HFHFr with pioglitazone. Each diet and treatment was continued for 10 weeks. The HFHFr diet induced severe NAFLD in terms of steatosis, hepatitis, and fibrosis. Administration of voglibose improved all aspects of NAFLD, comparable to those of pioglitazone, a positive control. In voglibose-treated mice, gene expressions of hepatic lipogenesis markers were significantly downregulated. In the in vitro experiment, reducing the influx of glucose into hepatocytes significantly reduced steatosis and de novo lipogenesis even in the presence of sufficient fructose and fat, demonstrating that the mechanism of voglibose could be effective in treating HFHFr diet-induced NAFLD. These results indicate that voglibose improves HFHFr diet-induced NAFLD by suppressing hepatic de novo lipogenesis.

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Section: Methodsmentioning

confidence: 99%

The effects of the voglibose on non-alcoholic fatty liver disease in mice model

Bae

Lee

Shin

et al. 2022

Sci Rep

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“…Особый интерес представляют метаболические эффекты пиоглитазона. Так, проведенные исследования продемонстрировали, что назначение как отдельно пиоглитазона, так и в комбинации с алоглиптином улучшает гистологическую картину печени при неалкогольной жировой болезни печени (НАЖБП) за счет повышения концентрации адипонектина плазмы [8] и профилактирует развитие стеатоза и фиброза печени у данных групп пациентов [15]. Изложенные данные позволяют рассматривать комбинацию пиоглитазона и алоглиптина как препарат выбора в приведенном клиническом случае у пациентки с СД2 и НАЖБП.…”

Section: Discussionunclassified

Long-term results of transferring the patient from therapy with glucagon-like peptide-1 receptor agonists in combination with metformin to a dipeptidyl peptidase-4 inhibitor in combination with pioglitazone and inhibitor of type 2 sodium-glucose cotransporter in type 2 diabetes

Salukhov,

Shipilova,

Minakov

2024

Diabetes mellitus

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The pioglitazone belongs to the class of antidiabetic medications and has various pleiotropic effects. The evidence base for this medication, based on the results of randomized clinical trials, demonstrates convincing cardio- and cerebroprotective efficacy of pioglitazone, comparable to innovative glucose-lowering drugs from the classes of GLP-1 agonists and SGLT-2 inhibitors. Currently, in Russia, a fixed combination of pioglitazone and alogliptin is available. However, it should be noted that there has been a recent lack of GLP-1 agonists on the domestic pharmaceutical market, which raises questions about the choice of further tactics for patients who have been taking them until recently.This clinical case presents an example of the transformation of glucose-lowering therapy from a combined treatment regimen with semaglutide and metformin to the combined use of a fixed combination of alogliptin and pioglitazone with empagliflozin. Against the background of therapy change, a stable and pronounced glucose-lowering effect was obtained and confirmed after six months, comparable to GLP-1 receptor agonists without the effect of escape and hypoglycemia. No edema or weight gain was observed, and no other adverse events were detected, which allowed continuing the chosen glucose-lowering therapy. Strategic perspectives of the prescribed therapy were determined — reducing cardio- and cerebrovascular risk and improving the patient’s prognosis.

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“…Multiple compounds that failed in phase 3 trials (elafibrinor, 37 firsocostat, 38 cilofexor, 39 aramchol, 40 cenicrivoroc 41 ) all showed efficacy in rodent models, but were not tested (or reported to be) in NHP models of NASH. A switch from either a high fat 42 or a high sucrose/high fat diet 43 to a chow diet, or alternative approaches to reduce body weight such as Roux‐en‐Y gastric bypass (inducing 25% weight loss 44 ), and treatment with pioglitazone, 45‐47 have all been shown to improve histology in mouse models of NASH. However, 25% CR resulting in 10% weight loss did not improve NASH in the genetic foz/foz mouse model 48 .…”

Section: Discussionmentioning

confidence: 99%

“…32 The data for humans and monkeys were fit using the equation ΔLiver fat(%) = β 1 (1 À exp(Àβ 2 *ΔBW(%)), with similar estimates of β 1 = 100 ± 40 in humans versus 89 ± 15 in monkeys and β 2 = 0.09 ± 0.06 in humans versus 0.11 ± 0.03 in monkeys. ANOVA, analysis of variance; NHP, non-human primate diet 43 to a chow diet, or alternative approaches to reduce body weight such as Roux-en-Y gastric bypass (inducing 25% weight loss 44 ), and treatment with pioglitazone, [45][46][47] have all been shown to improve histology in mouse models of NASH. However, 25% CR resulting in 10% weight loss did not improve NASH in the genetic foz/foz mouse model.…”

Section: Pioglitazone Improves Nash In Cynomolgus Monkeysmentioning

confidence: 99%

Validation of a diet‐induced Macaca fascicularis model of non‐alcoholic steatohepatitis with dietary and pioglitazone interventions

Camacho

Polidori

Chen³

et al. 2023

Diabetes Obesity Metabolism

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Aim To develop an obese, insulin‐resistant cynomolgus monkey model of non‐alcoholic steatohepatitis (NASH) with fibrosis with a high fat/high cholesterol (HFHC) diet (with or without high fructose) and test its responsiveness to caloric restriction or pioglitazone. Methods First, two groups of monkeys (n = 24/group) with histologically proven NASH and fibrosis were fed the HFHC diet for 17 weeks. The treatment group was subjected to a 40% caloric restriction (CR) and had their diet switched from the HFHC diet to a chow diet (DSCR). Paired liver biopsies were taken before and 17 weeks after DSCR. Subsets of monkeys (nine/group) had whole liver fat content assessed by MRI. Next, two groups of monkeys with histologically proven NASH and fibrosis were treated with vehicle (n = 9) or pioglitazone (n = 20) over 24 weeks. Results The HFHC and DSCR groups lost 0.9% and 11.4% of body weight, respectively. After 17 weeks, non‐alcoholic fatty liver disease activity score (NAS) improvement was observed in 66.7% of the DSCR group versus 12.5% of the HFHC group (P < .001). Hepatic fat was reduced to 5.2% in the DSCR group versus 23.0% in the HFHC group (P = .0001). After 24 weeks, NAS improvement was seen in 30% of the pioglitazone group versus 0% of the vehicle group (P = .08). Conclusions Both weight loss induced by DSCR and treatment with pioglitazone improve the histological features of NASH in a diet‐induced cynomolgus monkey model. This model provides a translational preclinical model for testing novel NASH therapies.

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Combination effects of alogliptin and pioglitazone on steatosis and hepatic fibrosis formation in a mouse model of non-alcoholic steatohepatitis

Cited by 5 publications

References 31 publications

The effects of the voglibose on non-alcoholic fatty liver disease in mice model

The effects of the voglibose on non-alcoholic fatty liver disease in mice model

Long-term results of transferring the patient from therapy with glucagon-like peptide-1 receptor agonists in combination with metformin to a dipeptidyl peptidase-4 inhibitor in combination with pioglitazone and inhibitor of type 2 sodium-glucose cotransporter in type 2 diabetes

Validation of a diet‐induced Macaca fascicularis model of non‐alcoholic steatohepatitis with dietary and pioglitazone interventions

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