Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression
Introduction
The insulin receptor (InsR) is a membrane-spanning glycoprotein that is essential for the action of insulin. Binding of insulin to InsR in the liver, muscles, or adipose tissues triggers multiple intracellular pathways that cause glycogen synthesis and glucose uptake increase, as well as hepatic/muscle glucose output reduction. The blood glucose level is thus lowered [1], [2]. This is one of the major mechanisms for the human body to keep glucose homeostasis. Disruption of the expression of InsR generates a hyperglycemic phenotype in mice [3]. Type 2 diabetes mellitus (T2DM) is a human hyperglycemic state characterized by insulin resistance in peripheral tissues, particularly the liver, muscles, adipocytes, and pancreatic β-cells [1], [4], [5]. About 92% of the patients with T2DM show insulin resistance [6]. Individuals with insulin resistance have either decreased levels or absence of InsR expression [7], [8], [9]. Thus, InsR is considered as a potential target to treat T2DM and insulin resistance, in which the intrinsic tyrosine kinase could be activated for insulin signaling. At the present time, small–molecular weight compounds that mimic insulin action are under development aiming for the discovery of hypoglycemic insulin mimetics [8], [10], [11]. With similar concept, novel InsR up-regulators may also have clinical benefit on improving insulin sensitivity and lowering blood glucose in T2DM. With the adverse effect reports for the thiazolidinediones (TZDs) [12], [13], hypoglycemic drugs with new targets are highly desirable.
Berberine (BBR) is a natural compound and has been a nonprescription medicine for diarrhea in China since the 1950s [14], [15], [16]. In 2004, we found that BBR is a promising cholesterol-lowering drug that increases the expression of the low-density lipoprotein receptor through an extracellular signal–regulated kinase–dependent mechanism [17], [18], [19], [20], [21]. Our recent study revealed that BBR also up-regulates the expression of the InsR gene in the liver and muscle cells [22]. Different from its action on low-density lipoprotein receptor, BBR increases InsR expression at the transcriptional level by stimulating InsR promoter; protein kinase C activation is essential for its activity [22]. Our results support the hypoglycemic effect of BBR observed in patients with T2DM [23]. The present study bridges our mechanism research with the clinical observations.
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Cell culture
CEM, HCT-116, SW1990, HT1080, 293T cells, and the hepatitis B virus (HBV) full genome–transfected human liver cells (HepG2.2.15 cells) were maintained in minimum essential medium (Gibco-Invitrogen, Grand Island, NY) containing 10% fetal bovine serum and antibiotics. Cells were cultured in an atmosphere of 5% CO2 at 37°C. One day before treatment, cells were trypsinized and allowed to grow to about 80% confluence. Afterward, fresh media supplemented with vehicle (dimethyl sulfoxide [DMSO]) or
BBR increases InsR expression and enhances insulin signaling in human cell lines
Our previous study demonstrated that BBR increases InsR mRNA and protein expression in human liver cells in a dose- and time-dependent manner [22]. To determine if BBR can up-regulate InsR in other types of human cells, we used BBR to treat a variety of human cell lines, including CEM T-lymphocytes, HCT-116 colon cancer cells, SW1990 pancreatic cells, HT1080 fibrosarcoma cells, and 293T fibroblast cells. The InsR mRNA expression levels in these cells were assayed by real-time reverse
Discussion
Type 2 diabetes mellitus is a sugar-related metabolic disorder with complicated mechanisms, in which InsR is one of the major factors responsible for the state of insulin resistance [25], [26], [27]. Defects in InsR expression or function will cause insulin resistance and diabetes mellitus [26], [27]. Our previous studies demonstrated that BBR increases InsR expression both in vitro and in animal models [22]. In the present study, we verify that BBR indeed up-regulates InsR in the peripheral
Acknowledgment
This study was supported by the 10th 5-year Program/Key Project from the Ministry of Sciences and Technology of China (JD Jiang) and the National Natural Sciences Foundation of China (39925037, 39870889 & 39930190; JD Jiang).
References (41)
New perspectives into the molecular pathogenesis and treatment of type 2 diabetes
Cell
(2001)- et al.
Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction
Mol Cell
(2000) Pathogenesis of non–insulin-dependent diabetes mellitus
Lancet
(1994)Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review
Drug Metab Pharmacokinet
(2006)- et al.
Combination of simvastatin with berberine improves the lipid-lowering efficacy
Metabolism
(2008) - et al.
Synthesis and structure-activity relationships of berberine analogues as a novel class of low-density-lipoprotein receptor up-regulators
Bioorg Med Chem Lett
(2008) - et al.
Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression
Metabolism
(2009) - et al.
Reduction of blood lipid by berberine in hyperlipidemic patients with chronic hepatitis or liver cirrhosis
Biomed Pharmacother
(2008) - et al.
Type 2 diabetes: principles of pathogenesis and therapy
Lancet
(2005) - et al.
Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARgamma pathway
Biochem Biophys Res Commun
(2006)
Clinical review 125: the insulin receptor and its cellular targets
J Clin Endocrinol Metab
Insulin resistance versus insulin deficiency in non–insulin-dependent diabetes mellitus: problems and prospects
Endocr Rev
Insulin sensitivity in subjects with type 2 diabetes. Relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study
Diabetes Care
Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM?
Diabetes
Discovery of a small molecule insulin mimetic with antidiabetic activity in mice
Science
Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice
Nat Med
Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity
Nat Med
Insulin-mimetic and anti-diabetic effects of vanadium compounds
Diabet Med
Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs
Semin Liver Dis
Experience of berberine in the treatment of diarrhea
Chin J Med
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There is no conflict of interest in this work.
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These authors contributed equally to this work.