Antidiabetic properties of berberine: from cellular pharmacology to clinical effects.

Berberine is an alkaloid highly concentrated in the roots, rhizomes and stem bark of various plants. It affects glucose metabolism increasing insulin secretion, stimulating glycolysis, suppressing adipogenesis, inhibiting mitochondrial function, activating the adenosine monophosphate-activated protein kinase (AMPK) pathway, and increasing glycokinase activity. Berberine also increases glucose transporter-4 (GLUT-4) and glucagon like peptide-1 (GLP-1) levels. Upon GLP-1 receptors activation, adenylyl cyclase is activated and cyclic adenosine monophosphate (cAMP) generated, leading to activation of second messenger pathways and closure of adenosine triphosphate-dependent potassium channels. Increased intracellular potassium causes depolarisation, and calcium influx through the voltage dependent calcium channels occurs. This intracellular calcium increase stimulates the migration and exocytosis of the insulin granules. In glucose consuming tissues, such as adipose, liver or muscle cells, berberine affects both GLUT-4 and retinol binding protein-4 (RBP-4) in favour of glucose uptake into cells, stimulates glycolysis by AMPK activation and has effects on the peroxisome proliferator-activated receptor  (PPAR) molecular targets and on the phosphorylation of insulin receptor substrate 1 (IRS-1), finally resulting in decreased insulin resistance. Moreover, recent studies suggest that berberine could have a direct action on carbohydrate metabolism in the intestine. The antidiabetic and insulin-sensitizing effect of berberine has also been confirmed in a few relatively small short-term clinical trials. The tolerability is high for low dosages, with some gastrointestinal complaints appearing with the use of high dosages.