1762-P: The Dynamic Role of PPAR-γ and Related Pathways in Beta Cells during Type 2 Diabetes Mellitus Progression

Type 2 Diabetes (T2D) is characterized by peripheral insulin resistance, deteriorating beta-cell function and eventual beta-cell failure. The role of Peroxisome proliferator-activated receptor γ (PPAR-γ) in beta-cells, as opposed to its role in peripheral cells in glucose metabolism, is not well understood during T2D progression. Here, we utilized S961, a specific insulin receptor inhibitor, to induce glucose intolerance and hyperglycemia in mice, thereby simulating the stages of T2D progression. Using beta-cell-specific knockouts of PPAR-γ, WNT5A and SMAD7, we explored the molecular mechanisms through which PPAR-γ and related signaling pathways affect beta-cell proliferation, insulin secretion, and dysfunction in T2D. Our results indicated an initial increase in PPAR-γ expression in beta-cells of pre-diabetic patients, followed by a reduction in diabetic patients. In mice, PPAR-γ expression in beta-cells rose after 7 days of S961 treatment (paralleling pre-diabetic conditions) but fell after 14 days (reflecting diabetic conditions). Conversely, SMAD7 levels in beta-cells were stably minimal initially but increased in later stages in both mice and diabetic patients. Assisted with single-cell RNA sequencing, we found that S961-treated mice experienced an upregulation in the TGF-β signaling cascade in beta-cells, leading to the activation of pSMAD3, which subsequently upregulated PPAR-γ, enhancing beta-cell proliferation and secretion. However, prolonged S961 exposure and the direct effects of hyperglycemia augmented SMAD7 levels, which inhibited SMAD signaling, resulting in reduced PPAR-γ, compromised beta-cell functionality and the onset of diabetes. This late upregulation of SMAD7 was likely mediated through WNT5A/Smarf2/ubiquitin signaling, which was progressively altered during T2D progression. Our findings underscore the intricate interplay of PPAR-γ and related pathways in beta-cells during T2D pathogenesis.