One of the most confusing aspects for individuals with type 2 diabetes is their elevated fasting glucose levels. This condition arises because in people who are resistant to insulin then the liver continues to produce glucose. This phenomenon still poses many questions for scientists.
New Insights into Glucose Production
A recent review article published in the journal “Trends in Endocrinology & Metabolism”, sheds light on the latest advances in understanding this mechanism. The review highlights crucial findings that may lead to new therapeutic targets for treating type 2 diabetes. According to the World Health Organization (WHO), type 2 diabetes is one of the major pandemics of the 21st century by making these discoveries particularly significant.
Collaborative Research Efforts
The study was led by a team of researchers from various prestigious institutions including the UB Institute of Biomedicine (UBIB), the Sant Joan de Deu Research Institute (SJDRI) and the Faculty of Pharmacy and Food Sciences at the University of Barcelona. Additionally, the Centre for Biomedical Research Network on Diabetes and Associated Metabolic Diseases (CBRNDMED) played a crucial role with Professor Manuel Vazquez-Carrera as the key person of the research.
Key Contributors
The research involved notable experts such as Emma Barroso, Javier Jurado-Aguilar and Xavier Palomer from UB-IBUB-IRJSJD-CIBERDEM. Moreover, Professor Walter Wahli from the University of Lausanne in Switzerland contributed significantly to the work. Their combined efforts have provided deeper insights into the liver’s role in glucose production in insulin-resistant individuals and paving the way for potential new treatments for type 2 diabetes. Understanding why individuals with type 2 diabetes have raised fasting glucose levels is complex, but recent research is bringing us closer to answering these critical questions and developing effective therapies.
Understanding Type 2 Diabetes Mellitus: A Growing Concern
Type 2 diabetes mellitus is a chronic disease that is becoming increasingly common. It leads to high blood sugar levels because the body doesn't respond properly to insulin which is crucial for regulating blood glucose and a primary energy source for cells. If not managed well, this condition can cause significant damage to various organs and remains under-diagnosed in a large portion of the global population.
The Role of Gluconeogenesis in Type 2 Diabetes
In individuals with type 2 diabetes, the liver's process of producing glucose known as gluconeogenesis is overly active. Medications like metformin are used to control this process. Recent research has highlighted new factors that influence hepatic gluconeogenesis. Professor Manuel Vazquez-Carrera from the University of Barcelona's Department of Pharmacology, Toxicology and Therapeutic Chemistry shared that their team discovered the growth differentiation factor (GDF15) can lower the levels of proteins involved in this liver function.
The Importance of TGF-b Pathway in Diabetes and Liver Disease
To combat type 2 diabetes effectively, further exploration of pathways like TGF-b is essential. This pathway is linked to the development of metabolic dysfunction-associated fatty liver disease (MASLD) which is commonly seen in conjunction with type 2 diabetes. TGF-b is crucial in the progression of liver fibrosis and is believed to increase hepatic gluconeogenesis thus aggravating type 2 diabetes. Professor Vazquez-Carrera emphasizes that understanding the TGF-b pathway's role in regulating liver glucose production could lead to improved blood sugar management in patients with type 2 diabetes.
Challenges in Regulating Gluconeogenesis in Type 2 Diabetes
Focusing on a single factor to regulate gluconeogenesis as a process where the liver produces glucose—doesn't seem sufficient to effectively manage type 2 diabetes. According to Professor Manuel Vazquez-Carrera, it's crucial to design combination therapies that address multiple factors involved in the disease to enhance treatment strategies.
Potential Therapeutic Targets
Today, various molecules such as TGF-b, TOX3, and TOX4 are being considered as potential therapeutic targets for future treatment strategies. The success of these therapies will depend on their effectiveness and safety. Controlling the excessive activation of hepatic gluconeogenesis in type 2 diabetes is particularly challenging because this pathway is essential for producing glucose during fasting and is regulated by numerous factors.
The Complexity of Regulation
Regulating gluconeogenesis is complex due to its critical role in glucose production during fasting. This pathway is influenced by many factors by making its regulation difficult. Ensuring precise control is necessary to avoid disrupting glucose availability during fasting.
COVID-19 and Hyperglycemia
Interestingly, new factors influencing gluconeogenesis have been identified in patients hospitalized with COVID-19 who exhibited high glucose levels. Hyperglycemia was common among these patients, likely due to the SARS-CoV-2 virus's ability to increase the activity of proteins involved in hepatic gluconeogenesis as noted by Vazquez-Carrera. This connection underlines the importance of understanding and addressing various factors that impact glucose regulation in type 2 diabetes.
Unravelling the Mechanisms of Metformin in Diabetes Treatment
Metformin is the most frequently prescribed medication for managing type 2 diabetes primarily due to its ability to reduce glucose production in the liver. However, the precise ways it achieves this effect remain only partially understood. Recent findings shed light on new mechanisms through which metformin operates by expanding our understanding beyond its well-known pathways.
A New Pathway: Inhibition of Mitochondrial Complex IV
Recent research has revealed that metformin decreases gluconeogenesis by inhibiting complex IV of the mitochondrial electron transport chain. This mechanism is distinct from the previously established pathway involving the activation of the AMPK protein which is a key sensor in the cell's energy regulation. According to Vazquez-Carrera, "Inhibition of mitochondrial complex IV activity by metformin—not complex I as previously thought—reduces the availability of substrates required for hepatic glucose synthesis." This means that by blocking complex IV, metformin limits the materials necessary for producing glucose in the liver.
The Role of the Gut in Gluconeogenesis
In addition to its effects on the liver, metformin also influences glucose production through actions on the gut. These gut-related effects lead to changes that further decrease glucose synthesis in the liver. Metformin enhances glucose uptake and utilization in the gut by resulting in the creation of metabolites that inhibit gluconeogenesis when they reach the liver through the portal vein.
GLP-1 Secretion and Its Impact
Furthermore, metformin promotes the secretion of GLP-1, a peptide hormone that plays central role in inhibiting hepatic gluconeogenesis. GLP-1, secreted in the intestine then contributes significantly to metformin's anti-diabetic effects by curbing the liver's glucose production. These new insights into metformin's mechanisms highlight its multifaceted role in managing type 2 diabetes. By inhibiting mitochondrial complex IV and influencing gut-derived processes, metformin reduces hepatic glucose production through several pathways. Understanding these mechanisms not only enhances our knowledge of metformin's action but also opens potential avenues for improving diabetes treatments in the future.
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