Abstract
Type 2 diabetes is a major global health burden, causing approximately 2 million deaths annually. Recent studies have revealed a strong positive correlation between elevated triglyceride levels and plasma glucose, as well as increased prevalence, incidence, and mortality of type 2 diabetes, suggesting a potential causal link. This review explores the metabolic interconversion between triglycerides and glucose, emphasizing how excess carbohydrate intake leads to ectopic triglyceride accumulation, which in turn enhances hepatic gluconeogenesis. It highlights key signaling pathways through which ectopic triglyceride deposition drives insulin resistance, hyperinsulinemia, β-cell dysfunction and apoptosis, and increased glucose production-central mechanisms in diabetes pathogenesis. Evidence from clinical interventions, such as the reversal of type 2 diabetes through bariatric surgery and dietary energy restriction, supports the hypothesis that ectopic triglyceride accumulation is a driving factor. Furthermore, this review explains why omega-3 fatty acids and niacin, in contrast to fibrates, do not protect against type 2 diabetes, despite lowering triglycerides. Overall, this review emphasizes the contribution of ectopic triglyceride accumulation-driven by obesity, hypertriglyceridemia, excessive consumption of carbohydrates and fats, and physical inactivity-to the onset and progression of type 2 diabetes, offering valuable insights into potential therapeutic strategies.