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Endocrine. 2018 Dec;62(3):576-587. doi: 10.1007/s12020-018-1689-y. Epub 2018 Aug 16.

Berberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting deacetylase SIRT3.

Author information

1
Department of Gastroenterology, Drum Tower hospital affiliated to Nanjing University Medical School, Nanjing University, Nanjing, China.
2
Department of Endocrinology, Drum Tower hospital affiliated to Nanjing University Medical School, Nanjing University, Nanjing, China.
3
Department of Digestive Diseases of Huashan Hospital, Fudan University, Shanghai, China.
4
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
5
School of Life Sciences, Fudan University, Shanghai, China.
6
Key laboratory of Reproduction Regulation of NPFPC (SIPPR, IRD), Fudan University, Shanghai, China.
7
Department of Gastroenterology, Drum Tower hospital affiliated to Nanjing University Medical School, Nanjing University, Nanjing, China. 867152094@qq.com.
8
Department of Gastroenterology, Drum Tower hospital affiliated to Nanjing University Medical School, Nanjing University, Nanjing, China. doczmm@126.com.
9
School of Life Sciences, Fudan University, Shanghai, China. doczmm@126.com.
10
Key laboratory of Reproduction Regulation of NPFPC (SIPPR, IRD), Fudan University, Shanghai, China. doczmm@126.com.

Abstract

OBJECTIVE:

Many studies have confirmed the glucose-lowering effect of berberine in type 2 diabetes patients. Although the mechanism of action of berberine involves the improvement of insulin sensitivity, its hypoglycemic mechanism remains elusive. Here we show a new mechanism by which berberine antagonizes glucagon signaling and find that SIRT3 is involved in the hypoglycemic effect of berberine.

METHODS:

Gene knockout and overexpression were used to assess the inhibitory effect of berberine on SIRT3. Downstream signaling pathways and the hypoglycemic effect of SIRT3 were evaluated by immunoblotting and metabolic monitoring.

RESULTS:

We found that berberine led to mitochondrial dysfunction and AMP accumulation by inhibiting deacetylase SIRT3. We confirmed that AMP accumulation activated the AMPK signaling pathway and further promoted glucose uptake. Simultaneously, AMP accumulation reduced cyclic AMP (cAMP) levels and abrogated the phosphorylation of critical protein targets of protein kinase A (PKA). Furthermore, we found that phosphoenolpyruvate carboxykinase 1 (PEPCK1) is a key gluconeogenesis enzyme that can be stabilized by glucagon. Berberine caused significant PEPCK1 ubiquitination and degradation by antagonizing glucagon and was accompanied by high levels of PEPCK1 acetylation. Interestingly, berberine-induced glucagon inhibition is independent of AMPK activation. The in vivo data from sirt3 knockout mice were further confirmed by the in vitro experiments.

CONCLUSIONS:

Berberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting SIRT3, and regulating mitochondria-related pathways may provide a novel approach to the development of antidiabetic drugs.

KEYWORDS:

AMP; Berberine; Glucose; PEPCK1; SIRT3

PMID:
30117113
DOI:
10.1007/s12020-018-1689-y
[Indexed for MEDLINE]

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