|Fighting Diabetes with Curcumin||Curcumin|
Curcumin is an active component of turmeric which has been commonly used as food additive and herbal medicine in Asia since ancient times. Numerous studies have demonstrated its efficacy in fighting a wide variety of diseases, including diabetes [1, 2]. Curcumin is a direct and potent inhibitor of glycogen synthase kinase-3 (GSK-3)  which plays critical roles in various diseases. The beneficial effects of curcumin may depend largely on this biochemical function. In diabetes, GSK-3 has been proposed as a therapeutic target more than a decade ago . This article will show how hyperactive GSK-3 may lead to diabetes.
Causes of Diabetes
Diabetes is characterized by high level of glucose (a type of sugar) in the blood. Most of the food we eat is broken down into glucose which then passes into the bloodstream and circulates throughout the body. Glucose can enter cells via specific transporters such as GLUT2 in liver cells and the beta cells of pancreas or GLUT4 in muscle cells (myocytes) and fat cells (adipocytes). Insulin is a hormone produced by the pancreatic beta cells. Under normal conditions, the entry of glucose into beta cells stimulates the production of insulin. In diabetes, this function is impaired, resulting in insulin deficiency.
The entry of glucose into beta cells also stimulates the release of insulin into bloodstream to facilitate the entry of glucose into other cells such as myocytes and adipocytes. In the absence of insulin, glucose cannot enter myocytes/adipocytes because GLUT4 is located inside the cell, not on the cell membrane. Insulin, upon binding to its receptor, stimulates the translocation of GLUT4 to cell membrane (Figure 1), allowing glucose to enter the cell for the generation of energy. In diabetes, insulin fails to stimulate GLUT4 translocation - a condition known as "insulin resistance".
GSK-3 Regulates Glucose Level
Glucose can be converted into glycogen by the enzyme, glycogen synthase. Glycogen synthase kinase-3 (GSK-3), as the name implies, is a direct regulator of glycogen synthase. Activation of GSK-3 inhibits glycogen synthase, thus preventing conversion of glucose into glycogen. Therefore, hyperactive GSK-3 may elevate glucose level.
As mentioned above, insulin resistance refers to the condition that insulin fails to facilitate glucose entry into cells via GLUT4. Insulin signaling is mediate by insulin receptor substrate (IRS). It has been demonstrated that hyperactive GSK-3 can induce excessive degradation of IRS (particularly its subtype IRS-1) . Without the crucial IRS, insulin signaling to stimulate GLUT4 translocation to the cell membrane is disrupted.
Remarkably, GSK-3 also plays a crucial role in the production of insulin in beta cells. The production (in technical term, the "expression") of a protein from its gene requires binding of a specific transcription factor (a protein) to the gene. The transcription factor that regulates the expression of insulin is called PDX1. Activation of GSK-3 has been shown to inhibit the function of PDX1 . Hence, hyperactive GSK-3 may cause insulin deficiency.
Recent studies have provided compelling evidence that GSK-3 is the central player in diabetes through three mechanisms as summarized in Figure 2. Since curcumin is a potent GSK-3 inhibitor, it should be a promising dietary supplement for the prevention and treatment of diabetes.
1. Pivari F et al. (2019) Curcumin and Type 2 Diabetes Mellitus: Prevention and Treatment.
2. Chuengsamarn S et al. (2012) Curcumin extract for prevention of type 2 diabetes.
3. Bustanji Y et al. (2009) Inhibition of glycogen synthase kinase by curcumin.
4. MacAulay K and Woodgett JR. (2008) Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes.
6. Sacco F et al. (2019) Phosphoproteomics Reveals the GSK3-PDX1 Axis as a Key Pathogenic Signaling Node in Diabetic Islets.
Author: Frank Lee