Elsevier

Metabolism

Volume 59, Issue 2, February 2010, Pages 285-292
Metabolism

Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression

https://doi.org/10.1016/j.metabol.2009.07.029Get rights and content

Abstract

Our previous work demonstrated that berberine (BBR) increases insulin receptor (InsR) expression and improves glucose utility both in vitro and in animal models. Here, we study the InsR–up-regulating and glucose-lowering activities of BBR in humans. Our results showed that BBR increased InsR messenger RNA and protein expression in a variety of human cell lines, including CEM, HCT-116, SW1990, HT1080, 293T, and hepatitis B virus–transfected human liver cells. Accordingly, insulin-stimulated phosphorylations of InsR β-subunit and Akt were increased after BBR treatment in cultured cells. In the clinical study, BBR significantly lowered fasting blood glucose (FBG), hemoglobin A1c, triglyceride, and insulin levels in patients with type 2 diabetes mellitus (T2DM). The FBG- and hemoglobin A1c–lowering efficacies of BBR were similar to those of metformin and rosiglitazone. In the BBR-treated patients, the percentages of peripheral blood lymphocytes that express InsR were significantly elevated after therapy. Berberine also lowered FBG effectively in chronic hepatitis B and hepatitis C patients with T2DM or impaired fasting glucose. Liver function was improved greatly in these patients by showing reduction of liver enzymes. Our results confirmed the activity of BBR on InsR in humans and its relationship with the glucose-lowering effect. Together with our previous report, we strongly suggest BBR as an ideal medicine for T2DM with a mechanism different from metformin and rosiglitazone.

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.

Section snippets

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).

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    There is no conflict of interest in this work.

    1

    These authors contributed equally to this work.

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