Pathophysiology of type 2 diabetes
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Pathophysiology of Type 2 Diabetes
Insulin Resistance and Beta-Cell Dysfunction
Type 2 Diabetes Mellitus (T2DM) is primarily characterized by two major defects: insulin resistance in peripheral tissues and impaired insulin secretion by pancreatic β-cells. Insulin resistance forces β-cells to produce more insulin, leading to β-cell exhaustion and dysfunction over time . This dysfunction is often due to a combination of disrupted insulin secretory machinery and a decrease in β-cell volume, which can be exacerbated by islet amyloid deposits.
Genetic and Environmental Factors
The pathophysiology of T2DM is influenced by both genetic and environmental factors. Large-scale genetic studies have identified numerous susceptibility loci associated with T2DM, implicating processes such as CREBBP-related transcription, adipocytokine signaling, and cell cycle regulation . Environmental factors, including obesity, unhealthy diet, and physical inactivity, also play significant roles in the development of insulin resistance and β-cell dysfunction .
Metabolic Interorgan Crosstalk
Recent research highlights the importance of metabolic interorgan crosstalk in T2DM. Dysregulated blood glucose and long-lasting hyperglycemia are associated with changes in metabolism, where metabolites from different tissues contribute to the disease's progression. Lipids, free fatty acids, and amino acids are crucial in this interorgan signaling, affecting physiological homeostasis and promoting T2DM development.
Epigenetic and Early Life Influences
Emerging evidence suggests that a significant portion of diabetes susceptibility is acquired early in life through fetal or neonatal programming via epigenetic mechanisms. Maternal and early childhood health are thus critical in the development of effective prevention strategies. This early-life programming can lead to inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, resulting in nutrient spillover, insulin resistance, and metabolic stress.
Pathophysiological Heterogeneity
T2DM is a heterogeneous disease with varying pathophysiological mechanisms among individuals. Subphenotyping based on clinical and genetic differences has identified distinct clusters of individuals with different risks of developing T2DM and its complications. This heterogeneity underscores the need for personalized treatment approaches .
Conclusion
The pathophysiology of T2DM is complex and multifactorial, involving insulin resistance, β-cell dysfunction, genetic predisposition, environmental influences, and metabolic interorgan crosstalk. Understanding these diverse mechanisms is crucial for developing targeted prevention and treatment strategies to manage and mitigate the impact of this pervasive disease.
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