Dataset Information

Oleanolic acid derivative DKS26 exerts antidiabetic and hepatoprotective effects in diabetic mice and promotes glucagon-like peptide-1 secretion and expression in intestinal cells.

ABSTRACT:

Background and purpose

Glucagon-like peptide-1 (GLP-1) is an important target for diabetes therapy based on its key role in maintaining glucose and lipid homeostasis. This study was designed to investigate antidiabetic and hepatoprotective effects of a novel oleanolic acid derivative DKS26 in diabetic mice and elucidate its underlying GLP-1 related antidiabetic mechanisms in vitro and in vivo.

Experimental approach

The therapeutic effects of DKS26 were investigated in streptozotocin (STZ)-induced and db/db diabetic mouse models. Levels of plasma glucose, glycosylated serum protein (GSP), lipid profiles, insulin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), oral glucose tolerance (OGT), pancreatic islets and hepatic histopathological morphology, liver lipid levels and expression of pro-inflammatory cytokines were assessed. Intestinal NCI-H716 cells and diabetic models were used to further validate its potential GLP-1-related antidiabetic mechanisms.

Key results

DKS26 treatment (100 mg·kg^-1 ·day^-1 ) decreased plasma levels of glucose, GSP, ALT and AST; ameliorated OGT and plasma lipid profiles; augmented plasma insulin levels; alleviated islets and hepatic pathological morphology; and reduced liver lipid accumulation, inflammation and necrosis in vivo. Furthermore, DKS26 enhanced GLP-1 release and expression, accompanied by elevated levels of cAMP and phosphorylated PKA in vitro and in vivo.

Conclusion and implications

DKS26 exerted hypoglycaemic, hypolipidaemic and islets protective effects, which were associated with an enhanced release and expression of GLP-1 mediated by the activation of the cAMP/PKA signalling pathway, and alleviated hepatic damage by reducing liver lipid levels and inflammation. These findings firmly identified DKS26 as a new viable therapeutic option for diabetes control.

SUBMITTER: Chen FF

PROVIDER: S-EPMC5554319 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Oleanolic acid derivative DKS26 exerts antidiabetic and hepatoprotective effects in diabetic mice and promotes glucagon-like peptide-1 secretion and expression in intestinal cells.

Chen Fei-Fei FF Wang Jian-Ta JT Zhang Li-Xia LX Xing Shu-Fang SF Wang Yun-Xia YX Wang Kai K Deng Shu-Li SL Zhang Ji-Quan JQ Tang Lei L Wu Hao-Shu HS

British journal of pharmacology 20170726 17

<h4>Background and purpose</h4>Glucagon-like peptide-1 (GLP-1) is an important target for diabetes therapy based on its key role in maintaining glucose and lipid homeostasis. This study was designed to investigate antidiabetic and hepatoprotective effects of a novel oleanolic acid derivative DKS26 in diabetic mice and elucidate its underlying GLP-1 related antidiabetic mechanisms in vitro and in vivo.<h4>Experimental approach</h4>The therapeutic effects of DKS26 were investigated in streptozotoc ...[more]

PMID: 28627773

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Project description:BackgroundBerberine is a plant alkaloid that has multiple beneficial effects against intestine inflammation. In our previous study, we have found that berberine also possesses an antidiabetic effect. However, whether berberine is useful in the prevention of type 2 diabetes mellitus (T2DM) through its effect on intestine endocrine function and gut microbiota is unclear.AimTo investigate the effects of berberine in the prevention of T2DM, as well as its effects on intestine GLP-2 secretion and gut microbiota in ZDF rats.MethodsTwenty Zucker Diabetic Fatty (ZDF) rats were fed a high-energy diet until they exhibited impaired glucose tolerance (IGT). The rats were then divided into two groups to receive berberine (100 mg/kg/d; berberine group) or vehicle (IGT group) by gavage for 3 weeks. Five Zucker Lean (ZL) rats were used as controls. Fasting blood glucose (FBG) was measured, an oral glucose tolerance test was performed, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. Intestinal expression of TLR-4, NF-κB, TNF-α, mucin, zona occludens-1 (ZO-1) and occludin were assessed (immunohistochemistry). Plasma levels and glutamine-induced intestinal secretion of glucagon-like peptide-1 (GLP-1) and GLP-2 were measured (enzyme-linked immunosorbent assay). The plasma lipopolysaccharide (LPS) level was measured. Fecal DNA extraction, pyrosequencing, and bioinformatics analysis were performed.ResultsAfter 3 weeks of intervention, diabetes developed in all rats in the IGT group, but only 30% of rats in the berberine group. Treatment with berberine was associated with reductions in food intake, FBG level, insulin resistance, and plasma LPS level, as well as increases in fasting plasma GLP-2 level and glutamine-induced intestinal GLP-2 secretion. Berberine could increase the goblet cell number and villi length, and also reverse the suppressed expressions of mucin, occludin, ZO-1 and the upregulated expressions of TLR-4, NF-κB and TNF-α induced in IGT rats (P<0.05). Berberine also improved the structure of the gut microbiota and restored species diversity.ConclusionBerberine may slow the progression of prediabetes to T2DM in ZDF rats by improving GLP-2 secretion, intestinal permeability, and the structure of the gut microbiota.

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Dataset Information

Oleanolic acid derivative DKS26 exerts antidiabetic and hepatoprotective effects in diabetic mice and promotes glucagon-like peptide-1 secretion and expression in intestinal cells.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Oleanolic acid derivative DKS26 exerts antidiabetic and hepatoprotective effects in diabetic mice and promotes glucagon-like peptide-1 secretion and expression in intestinal cells.

Similar Datasets

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