title: Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression.
abstract: Natural product berberine (BBR) has been reported to have hypoglycemic and insulin-sensitizing activities; however, its mechanism remains unclear. This study was designed to investigate the molecular mechanism of BBR against insulin resistance. Here, we identify insulin receptor (InsR) as a target of BBR to increase insulin sensitivity. In cultured human liver cells, BBR increased InsR messenger RNA (mRNA) and protein expression in a dose- and time-dependent manner. Berberine increased InsR expression in the L6 rat skeletal muscle cells as well. Berberine-enhanced InsR expression improved cellular glucose consumption only in the presence of insulin. Silencing InsR gene with small interfering RNA or blocking the phosphoinositol-3-kinase diminished this effect. Berberine induced InsR gene expression through a protein kinase C (PKC)-dependent activation of its promoter. Inhibition of PKC abolished BBR-caused InsR promoter activation and InsR mRNA transcription. In animal models, treatment of type 2 diabetes mellitus rats with BBR lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver. In addition, BBR lowered blood glucose in KK-Ay type 2 but not in NOD/LtJ type 1 diabetes mellitus mice that were insulin deficient. Our results suggest that BBR is a unique natural medicine against insulin resistance in type 2 diabetes mellitus and metabolic syndrome.
authors.affiliation: Department of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
authors.forename: Wei-Jia
authors.initials: WJ
authors.lastname: Kong
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
authors.forename: Rong
authors.initials: R
authors.lastname: Xue
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Shan
authors.forename: Zhen-Xian
authors.initials: ZX
authors.lastname: Zhou
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Xue-Fu
authors.initials: XF
authors.lastname: You
authors.forename: Zhuo-Rong
authors.initials: ZR
authors.lastname: Li
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Si
authors.forename: Li-Xun
authors.initials: LX
authors.lastname: Zhao
authors.forename: Huai-Ning
authors.initials: HN
authors.lastname: Pan
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D001599:Berberine; D012313:RNA; D011972:Receptor, Insulin; D011493:Protein Kinase C; C093642:SB 203580