How does berberine reduce blood sugar?

Broadly speaking, berberine supplementation results in the activation of enzymes responsible for regulating (among other things) energy usage in the body. Most notably, berberine activates AMPK, PKC, and SIRT 1.^[1]

In animal models, berberine supplementation results in the activation of AMPK.^[2] When active, AMPK interacts with a variety of enzymes to suppress anabolic processes (i.e., storing energy and building tissue) and promote catabolism (i.e., breaking down the aforementioned tissue and utilizing glucose for energy).^[3] As well as increasing the activity of the glycolytic pathway, AMPK also improves glucose uptake by cells by encouraging glucose transport proteins to migrate to the cell membrane, which increases the rate at which glucose exits the blood and enters the cells (where it is broken down).^[4]

Relatedly, berberine also results in the activation of PKC. Like AMPK, PKC has a variety of regulatory functions, but most importantly (in this case) it regulates the expression of insulin receptor genes. When activated, PKC increases the rate at which these genes are transcribed and translated into proteins, thereby increasing the number of insulin receptors on cell membranes.^[5] Insulin is required to transport glucose into muscle and fat cells, so this PKC-dependent upregulation of insulin receptors can be said to make these cells more “insulin-sensitive”, meaning that less insulin must be released by the pancreas to effectively move glucose from the blood into cells.

Berberine can also improve insulin sensitivity through its effects on another regulatory enzyme, SIRT1. SIRT1 is one of several sirtuins present in mammals and helps regulate apoptosis (programmed cell death), mitochondrial function, and inflammation. One animal study found that berberine’s activation of SIRT1 helps improve mitochondrial function (in part by increasing the synthesis of mitochondria) and consequently lowers blood sugar and reduces obesity in rats fed a high-fat diet.^[6]