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Introduction Glucose uptake and metabolism are the most physiologically important driver of insulin release from pancreatic islet [beta] cells, a highly specialized class of endocrine cells that secrete this hormone [...], Glucose plays a key role in shaping pancreatic [beta] cell function. Thus, deciphering the mechanisms by which this nutrient stimulates [beta] cells holds therapeutic promise for combating [beta] cell failure in type 2 diabetes (T2D). [beta] cells respond to hyperglycemia in part by rewiring their mRNA metabolism, yet the mechanisms governing these changes remain poorly understood. Here, we identify a requirement for the RNA-binding protein PCBP2 in maintaining [beta] cell function basally and during sustained hyperglycemic challenge. PCBP2 was induced in primary mouse islets incubated with elevated glucose and was required to adapt insulin secretion. Transcriptomic analysis of primary Pcbp2-deficient [beta] cells revealed impacts on basal and glucose-regulated mRNAs encoding core components of the insulin secretory pathway. Accordingly, Pcbp2-deficient [beta] cells exhibited defects in calcium flux, insulin granule ultrastructure and exocytosis, and the amplification pathway of insulin secretion. Further, PCBP2 was induced by glucose in primary human islets, was downregulated in islets from T2D donors, and impacted genes commonly altered in islets from donors with T2D and linked to single-nucleotide polymorphisms associated with T2D. Thus, these findings establish a paradigm for PCBP2 in governing basal and glucose-adaptive gene programs critical for shaping the functional state of [beta] cells.

Introduction Longitudinal studies have shown that individuals who are at high genetic risk for or have a family history of type 1 diabetes (T1D), who later develop diabetes, progress through [...], BACKGROUND. Multiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single [GADA.sup.+] state may represent an early stage of T1D. METHODS. Here, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic [GADA.sup.+] and T1D donors. RESULTS. Similar to the few remaining [beta] cells in the T1D islets, [GADA.sup.+] donor islets demonstrated a preserved insulin secretory response. By contrast, [alpha] cell glucagon secretion was dysregulated in both [GADA.sup.+] and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of [GADA.sup.+] [alpha] cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor p (PKIB), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in [GADA.sup.+] donor islets. CONCLUSION. We found that [alpha] cell dysfunction was present during the early stages of islet autoimmunity at a time when p cell mass was still normal, raising important questions about the role of early [alpha] cell dysfunction in the progression of T1D. FUNDING. This work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).

The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain ( Spop βKO ) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α-XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation., (© 2025 Oguh et al.; Published by Cold Spring Harbor Laboratory Press.)