Charting New Paths in T2DM: From Liver Glucose to Therapeutic Targets
Type 2 diabetes mellitus (T2DM) is a common chronic disease that often causes high fasting glucose levels, puzzling many patients. This problem mainly stems from the liver, where insulin resistance triggers glucose production. Despite ongoing research, this mechanism remains complex.
The World Health Organization (WHO) calls T2DM one of the big health problems of the 21st century. In T2DM, the liver produces excessive glucose, which medications like metformin aim to control. The review explores recent discoveries, such as the role of growth differentiation factor 15 (GDF15) in reducing proteins involved in glucose production. Understanding pathways like TGF-β, associated with conditions like fatty liver disease, could improve strategies for managing blood sugar levels.
Unravelling Metformin’s Mechanisms
Combination therapies targeting different aspects of glucose production are recommended for more effective T2DM management. Potential therapeutic targets discussed include molecules such as TGF-β, TOX3, and TOX4. TGF-β, which is involved in the progression of metabolic dysfunction-associated fatty liver disease (MASLD), a very prevalent pathology that often coexists with type 2 diabetes mellitus. TGF-β plays a very relevant role in the progression of liver fibrosis and has become one of the most important factors that may contribute to increased hepatic gluconeogenesis and, therefore, to type 2 diabetes mellitus. Studying the involvement of the TGF-β pathway in the regulation of hepatic gluconeogenesis could help to achieve better glycaemic control. Patients hospitalized with COVID-19 often have high blood sugar levels, likely due to the virus triggering proteins that increase how much glucose the liver makes.
Hyperglycaemia was very prevalent in patients hospitalised with COVID-19, which seems to be related to the ability of SARS-CoV-2 to induce the activity of proteins involved in hepatic gluconeogenesis. Metformin is the main drug for T2DM. It works in ways that researchers are still studying. Recent studies found that metformin lowers how much glucose the liver makes by affecting complex IV of the mitochondria, which is independent of the classical effects known until now through activation of the AMPK protein, a sensor of the cell's energy metabolism. This change reduces the materials the liver needs to make glucose. Metformin also helps in the gut by making it easier to take in glucose and creating substances that stop the liver from making glucose. Finally, metformin also stimulates the secretion of GLP-1 in the intestine, a hepatic gluconeogenesis inhibitory peptide that contributes to its anti-diabetic effect.
REFERENCE:
Emma Barroso, Javier Jurado-Aguilar, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera. Increased hepatic gluconeogenesis and type 2 diabetes mellitus. Trends in Endocrinology & Metabolism, 2024.
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https://medicalxpress.com/news/2024-06-therapeutic-diabetes.html
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