Unraveling metabolic health and diabetes: insights into Placental mitochondrial programming, O-GlcNAc/mTORC1 dynamics, and pancreatic Beta-cell function

Abstract

Type 2 diabetes (T2D) is a condition characterized by impaired blood glucose regulation and is associated with comorbidities such as cardiovascular disease, nerve and kidney damage, and vision loss. The etiology of T2D is complex, involving both genetic predispositions and environmental factors, which can exert influence as early as pregnancy and extend into adulthood. Despite significant advances in T2D treatment since the discovery of insulin nearly a century ago, the disease continues to rise in prevalence. Pancreatic β-cells, responsible for insulin production, play a crucial role in T2D progression, as their dysfunction directly contributes to the disease. Understanding the timing of metabolic health programming and the mechanisms underlying β-cell failure is essential for advancing T2D therapies. This study aims to elucidate mechanisms behind the development of T2D and metabolic disorders, focusing on the role of in utero programming during critical developmental windows and nutrient sensor crosstalk in regulating pancreatic β-cell mass and function. Key findings include: 1) Placental mitochondrial dysfunction leads to fetal growth restriction, specifically in the females and alter offspring metabolic responses to stressors; 2) Disruptions in nutrient-driven O-GlcNAc and mTORC1 signaling contribute to β-cell failure through distinct and overlapping effects on glucose-stimulus coupling and β-cell proliferation; and 3) O-GlcNAc-dependent autophagy is essential for maintaining β-cell function and glucose homeostasis. This work suggests that metabolic trajectories are shaped as early as during pregnancy, through placenta, with distinct differences between males and females. Stressors in both early and later life can disrupt nutrient sensor pathways, such as O-GlcNAc and mTORC1 signaling, contributing to β-cell dysfunction and the progression of T2D. We emphasize that chronic disturbances, whether an increase or decrease, in these signaling pathways are detrimental to β-cell survival and function. Mechanistically, the findings highlight autophagy as a key downstream regulator of insulin secretion, controlled by nutrient sensor pathways.