A therapeutic for type 2 diabetes
The development of type 2 diabetes is associated with gene mutation, obesity, inherited genetic issues from parents as well as some other sources which interfere with insulin resistance.
Diabetics have difficulty regulating their blood sugar leading to potential problems in the heart, kidneys, nerves, and brain if the level of blood sugar becomes too high. Many diabetics use insulin to help control this condition. The dysfunction of β cells from the pancreas is the primary hallmark of this condition. In the body β cells secrete insulin to help regulate glucose homeostasis via a complex signalling network. Insulin binds to a surface receptor in muscle and fat cells triggering the removal of sugar from the blood.
Honokiol has in recent years become the focus of diabetes research. One in-vitro study demonstrated that honokiol and magnolol (a related compound found in magnolia) could promote the glucose uptake of adipocytes derived from both humans or mice in a concentration dependent manner via the insulin signaling pathway (1). Honokiol was also reported to improve the basal glucose uptake in mouse 3T3-L1 cells (2). The same study also reported that treatment with honokiol could prevent hyperglycemia in KKAy mice (a diabetic mouse model) even in relatively low doses.
Honokiol and its potential for T2 Diabetes
Today we are going to take a look at an interesting type 2 diabetes study from 2015 where oral supplementation with honokiol yielded some interesting results (3).
Researchers tested diabetes mellitus mice (T2DM mice) supplementing them with 200 mg/kg of honokiol for a total of 8 weeks during the study. The research team noted a significant decrease in the fasting blood glucose levels of the type 2 diabetic mice. The study results suggest that honokiol not only increases the level of insulin signalling factors improving the regulation of blood sugar levels but is also able to inhibit protein tyrosine phosphatase 1B (PTP1B). So without further ado let us dive into the study results and see what they discovered.
Honokiol improves insulin sensitivity
The researchers found that T2DM mice supplemented with honokiol showed improved phosphorylation of the insulin receptor beta (IRβ) as seen here in section A from the study. In fact the level of tyrosine phosphorylations in adipose, skeletal muscle and liver tissues were significantly higher than that of the diabetic control mice and were actually higher than that of normal mice. This means that supplementation with honokiol was able to help improve insulin receptor function and thus increase insulin sensitivity.
A. Effect of honokiol on insulin signaling in T2DM mice.
Next the researchers looked at the effect of honokiol on the associated downstream signalling factors They observed an increase of the downstream signalling factors AKT (Akt/protein kinase B) and ERK1/2 (Extracellular signal–regulated kinases) in adipose, liver, and skeletal muscle tissues in mice treated with honokiol as seen in B and C below from the study. As observed with p-IRβ in section A, honokiol enhanced the tyrosine phosphorylation of ERK and the serine phosphorylation of AKT.
B/C. Effect of honokiol on AKT and ERK1/2 signaling in T2DM mice.
Based on the discovery that honokiol lowers blood glucose levels via improved insulin signalling in T2DM mice, the researchers tested honokiol on C2C12 myotubes (a mouse myoblast cell line) to see if similar effects were observed. It was shown that honokiol enhanced insulin-stimulated phosphorylations of IRβ, AKT, and ERK1/2 in a dose-dependent manner consistent with the results seen in T2DM mice.
The researchers then investigated the effects of honokiol on Glucose transporter type 4 (GLUT4). GLUT4 is an insulin-regulated glucose transporter found primarily in adipose and muscle tissues. GLUT4 facilitates glucose transport in response to insulin and thus regulates homeostasis. AKT plays a key role in GLUT4 translocation and given that honokiol enhances insulin-stimulated IR and AKT phosphorylation they investigated if it affected the translocation of GLUT4 to the plasma membrane. They found that honokiol increased the insulin induced level of GLUT4 in the plasma membrane but the levels in the whole cell lysates remained unaffected. They concluded that the hypoglycemic effect of honokiol is via its insulin sensitivity enhancing activity.
Potent PTP1B inhibitory activity
Protein tyrosine phosphatase 1B is a negative regulator of the leptin and insulin signaling pathways. The connection between PTP1B, obesity and diabetes has been confirmed by the deletion of the PTP1B gene in mice in previous studies. PTP1B affects the regulation of blood sugar by dephosphorylating the insulin receptor thus reducing its activity. As PTP1B removes the phosphate group from the insulin receptor, inhibiting it can potentially help to reduce the rate of phosphate removal from the insulin receptor. Thus, as PTP1B normally reduces insulin receptor activity, inhibiting it could help to increase insulin sensitivity.
The research team tested both in-vitro and in-vivo and confirmed that treatment with honokiol had a powerful inhibiting effect on Protein tyrosine phosphatase (PTP1B). They conclude that by inhibiting PTP1B, honokiol increases the protein tyrosine phosphorylation both in-vitro and very likely in-vivo based on the measurements taken.
The targeting of PTP1B is of great interest to researchers looking for ways to treat diabetes and improve blood sugar regulation. Whilst further study is required to ascertain the effects of honokiol on the other elements of the insulin signalling pathway the results here are nonetheless exciting. In closing, honokiol is a promising insulin sensitizer for the potential treatment of type 2 diabetes.
(1) Alonso-Castro, A. J., Zapata-Bustos, R., Domínguez, F., García-Carrancá, A., & Salazar-Olivo, L. A. (2011). Magnolia dealbata Zucc and its active principles honokiol and magnolol stimulate glucose uptake in murine and human adipocytes using the insulin-signaling pathway. Phytomedicine, 18(11), 926-933.
(2) Atanasov, A. G., Wang, J. N., Gu, S. P., Bu, J., Kramer, M. P., Baumgartner, L., … & Noha, S. M. (2013). Honokiol: a non-adipogenic PPARγ agonist from nature. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(10), 4813-4819.
(3) Sun, J., Fu, X., Liu, Y., Wang, Y., Huo, B., Guo, Y., … & Hu, X. (2014). Hypoglycemic effect and mechanism of honokiol on type 2 diabetic mice. Drug design, development and therapy, 9, 6327-6342.