ALDOB Modulates Beta-Cell Insulin Secretion in Diabetes Through Insulin Receptor Pathways 

Description

Diabetes Mellitus is one of the most common chronic metabolic diseases, characterized by elevated levels of blood glucose caused by insulin resistance, insufficient insulin secretion from pancreaticbcells or both. As the major threat to global public health, Diabetes is projected to affect up to 690 million people in year 2045 with a global healthcare cost around US $850 billion. In Hong Kong, prevalence of Type 2 Diabetes (T2D) accounts for 8.5% of the total population. Understanding the mechanisms ofb cell insulin secretion is important for developing effective therapies for T2D.Emerging data have linked a classic glycolytic enzyme fructose-1,6-bisphosphate B (ALDOB) to T2D but the underlying mechanisms remain elusive. We previously found that hepatic ALDOB exerts non-enzymatic functions by interacting with insulin receptor (IR) in insulin signaling pathways. We observed a decreased insulin secretion in global ALDOB knockout mice. In preliminary study, we found an upregulation of ALDOB in islets of db/db mice, and ALDOB knockdown (KD) impaired insulin secretion in human islets derived from iPSC. We constructed β cell-specific ALDOB KO mice (ALDOBIns2-/-) and discovered that ALDOB depletion impaired glucose tolerance and insulin secretion without significantly affecting glucose metabolism. In a T2D mouse model, HFHS feeding further exacerbated impaired insulin secretion. Transcriptomics and proteomics in islets of ALDOBIns2-/- mice identified that cAMP and insulin signaling pathways are among the most significantly altered pathways. Interestingly, insulin secretion in ALDOBIns2-/- islets attenuated responses to GLP1 receptor agonist Liraglutide, a common T2D drug. In this application, we will test the hypothesize that ALDOB functions non-enzymatically for insulin secretion through modulating cAMP and insulin signaling pathways in b cells, presumably via protein-protein interaction with IR and Gnai2 (Guanine nucleotide-binding protein Gi subunit a2), while the major aldolase isoform ALDOA acts as a classic glycolytic enzyme for glucose sensing and metabolism to generate ATP for insulin secretion. Consistent with the preliminary observations that ALDOBIns2-/- mice exhibited impairs insulin secretion, upregulated ALDOB in diabetic islets may promote insulin secretion to compensate insulin resistance through blocking IR/Gnai2 interactions, leading to activated GPCR-cAMP-PKA pathways. We will utilize multi-omics techniques, including transcriptomics, proteomics, metabolomics, and metabolic flux analysis to investigate the mechanisms, in combination withbcell-specific ALDOB KO or overexpression, conditional KO of ALDOA mice, and pointmutations of ALDOB with varying interactions with IR. This project will have significant impact on our understanding of the pathogenesis of T2D and exploring potential therapeutic strategies.