Wednesday, January 15, 2025
1/15/2025
Project Summary Diabetes is among the fastest growing health challenges of the 21st century, affecting >30 million people, with ≥80,000 deaths annually, and involving ~15% of U.S. national health expenditures. Type 2 diabetes (T2D) is the most common form of diabetes, which is linked to an insufficient amount of circulating insulin because of the body’s insensitivity to the hormone. Maintenance of the insulin storage pool requires synthesis of ~6000 proinsulin (PI) molecules/ß-cell/second, each delivered to the endoplasmic reticulum (ER) for folding. Even more molecules are needed in states of insulin resistance. Significantly, we discovered that PI enters aberrant disulfide-linked intermolecular complexes, even in healthy (human and murine) islets. Under conditions that demand increased insulin production (even prediabetes), these complexes dramatically increase, thus limiting insulin production. We show new key evidence that these aberrantly folded PI complexes can be resolved to monomeric PI within the ER. We recently elucidated the first map of the human PI interactome identifying PI folding modifiers. The most significant PI interactor in human islets is the ER chaperone BiP and we present new evidence (both gain of function, and loss of function) that this interaction, supported by BiP co- chaperones, is absolutely required for productive proinsulin folding (and limiting misfolding), leading to successful anterograde transport. For our studies we generated a novel BiP-tagged mouse that can for the first time identify fundamental steps in PI folding essential for insulin production. Moreover, we show that increased expression of BiP and its co-chaperone P58IPK dramatically reduces accumulation of the high molecular weight PI complexes. Thus, our discoveries open the possibility that pharmacologic intervention may improve chaperone-dependent PI folding, and this may attenuate T2D. As we begin to elucidate the human PI folding pathway, we are developing parallel animal models to determine how PI folds/misfolds. Here we propose to: 1) Mechanistically dissect how BiP and additional PI interactors in the ER orchestrate successful PI folding and determine which step(s) of PI folding go awry in T2D; 2) Identify how the PI interactome changes in human T2D; determine the function of altered PI interactions in islets from patients with T2D; and utilize novel assays to measure productive PI folding/trafficking in ß-cells. We will integrate physiologic studies of human islets with novel genetic and biochemical approaches to generate a comprehensive understanding of how PI folding homeostasis impacts ß-cell function in health and disease. We believe that this hypothesis is a high-impact idea essential to the mission of the NIDDK, and we now bring tools, assays, and approaches that are not currently available anywhere else.
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