Diabetes is a common metabolic disorder that leads to hyperglycemic conditions. If not managed properly, it leads to heart and kidney failure, nerve damage, eye problems and dementia. According to WHO statistics, more than 830 million people are living with diabetes (WHO, 2022).
T1DM Vs. T2DM
Type 1 diabetes mellitus (T1DM) is an autoimmune disease associated with the destruction of insulin-producing pancreatic β cells. This destruction of β cells impaired insulin secretion leads to hyperglycemia. T1DM is managed with insulin supplementation and lifestyle changes. T2DM, also known as insulin-independent, is characterized by insulin resistance. It can be managed with metformin, meglitinides, sulfonylureas and other drugs, along with lifestyle changes1.
Although T2DM respond well to currently available medicines, their side effects can’t be neglected. Continuous use of sulfonylureas puts an individual at increased risk of developing cardiovascular diseases2. Metformin downregulates the expression of pyruvate dehydrogenase, which can lead to lactic acidosis2,3. The increased risk associated with conventional anti-diabetic therapy demands an alternative approach to managing T2DM. In this article, we will focus on the anti-diabetic action of berberine.
Berberine and blood sugar regulation: A mechanistic insight
Berberine is a benzylisoquinoline alkaloid naturally present in many medicinal plants, including Berberis aristata, Berberis vulgaris and Berberis aquifolium. It is reported to possess antibacterial, neuroprotective, antioxidant, anti-inflammatory, anti-cancer, hypolipidemic and antihyperglycemic properties4. This article will explore the mechanism behind the antihyperglycemic activity of berberine.
Berberine is reported to exert its hypoglycemic action by regulating various enzymes and pathways involved in glucose metabolism.
One mechanism of the hypoglycemic effect of berberine is via activating the AMPK pathway. Berberine activates AMPK by phosphorylating Thr172 on the α-subunit. AMPK activation increases glucose uptake via transporting GLUT-4 to the cytoplasm, ultimately reducing the extracellular glucose levels. A group of researchers reported that berberine could exhibit its hypoglycemic effect independently of AMPK activation. They reported that berberine can suppress ATP synthesis by inhibiting mitochondrial respiratory chain complex I, which led to elevated glycolytic activity5.
α-amylase and β-glucosidase are two important enzymes that control the digestion and absorption of glucose. Berberine is reported to have a great inhibitory effect on these enzymes6. Inhibition of these enzymes by berberine is another possible mechanism behind its anti-diabetic properties.
Another mechanism of the anti-hyperglycemic activity of berberine is inducing the secretion of GLPs. There are various reports that berberine lowers blood glucose by inducing GLP-1 secretion7. Recently, one report highlighted the effect of berberine on GLP-2. They observed that berberine supplementation reduces insulin resistance, induces intestinal GLP-2 secretion, modulates gut microbiota and reduces the progression of prediabetes to diabetes in a mice model8.
To conclude, berberine exerts its hypoglycaemic activity by activating AMPK, inhibiting α-amylase and β-glucosidase, secretion of GLP-1 and increasing glucose uptake. Berberine could be employed in the management of T2DM.
References
(1) Ozougwu, O. The Pathogenesis and Pathophysiology of Type 1 and Type 2 Diabetes Mellitus. Journal of Physiology and Pathophysiology 2013, 4 (4), 46–57. https://doi.org/10.5897/jpap2013.0001.
(2) Taneja, N.; Mani, S.; Kalsi, A.; Singh, S.; Kukal, S. Current Treatments for Type 2 Diabetes, Their Side Effects and Possible Complementary Treatments; 2015; Vol. 7. https://innovareacademics.in/journals/index.php/ijpps/rt/printerFriendly/3962/8416.
(3) Feng, J.; Wang, X.; Ye, X.; Ares, I.; Lopez-Torres, B.; Martínez, M.; Martínez-Larrañaga, M. R.; Wang, X.; Anadón, A.; Martínez, M. A. Mitochondria as an Important Target of Metformin: The Mechanism of Action, Toxic and Side Effects, and New Therapeutic Applications. Pharmacological Research. Academic Press March 1, 2022. https://doi.org/10.1016/j.phrs.2022.106114.
(4) Kumar, A.; Ekavali; Chopra, K.; Mukherjee, M.; Pottabathini, R.; Dhull, D. K. Current Knowledge and Pharmacological Profile of Berberine: An Update. European Journal of Pharmacology. Elsevier June 26, 2015, pp 288–297. https://doi.org/10.1016/j.ejphar.2015.05.068.
(5) Xu, M.; Xiao, Y.; Yin, J.; Hou, W.; Yu, X.; Shen, L.; Liu, F.; Wei, L.; Jia, W. Berberine Promotes Glucose Consumption Independently of AMP-Activated Protein Kinase Activation. PLoS One 2014, 9 (7). https://doi.org/10.1371/journal.pone.0103702.
(6) Zhao, J.; Wang, Z.; Karrar, E.; Xu, D.; Sun, X. Inhibition Mechanism of Berberine on α-Amylase and α-Glucosidase in Vitro. Starch/Staerke 2022, 74 (3–4). https://doi.org/10.1002/star.202100231.
(7) Araj-Khodaei, M.; Ayati, M. H.; Azizi Zeinalhajlou, A.; Novinbahador, T.; Yousefi, M.; Shiri, M.; Mahmoodpoor, A.; Shamekh, A.; Namazi, N.; Sanaie, S. Berberine-Induced Glucagon-like Peptide-1 and Its Mechanism for Controlling Type 2 Diabetes Mellitus: A Comprehensive Pathway Review. Arch Physiol Biochem 1–8. https://doi.org/10.1080/13813455.2023.2258559.
(8) Wang, Y.; Liu, H.; Zheng, M.; Yang, Y.; Ren, H.; Kong, Y.; Wang, S.; Wang, J.; Jiang, Y.; Yang, J.; Shan, C. Berberine Slows the Progression of Prediabetes to Diabetes in Zucker Diabetic Fatty Rats by Enhancing Intestinal Secretion of Glucagon-Like Peptide-2 and Improving the Gut Microbiota. Front Endocrinol (Lausanne) 2021, 12. https://doi.org/10.3389/fendo.2021.609134.
