Baricitinib and β-Cell Function in Patients with New-Onset Type 1 Diabetes

Waibel, Michaela; Wentworth, John M.; So, Michelle; Couper, Jennifer J.; Cameron, Fergus J.; MacIsaac, Richard J.; Atlas, Gabby; Gorelik, Alexandra; Litwak, Sara; Sanz-Villanueva, Laura; Trivedi, Prerak; Ahmed, Simi; Martin, Francis J.; Doyle, Madeleine E.; Harbison, Jessica E.; Hall, Candice; Krishnamurthy, Balasubramanian; Colman, Peter G.; Harrison, Leonard C.; Thomas, Helen E.; Kay, Thomas W.H.

doi:10.1056/nejmoa2306691

Cited by 61 publications

(9 citation statements)

References 41 publications

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“…Cases of hypoglycemia have been reported among diabetic patients with rheumatoid arthritis who have been treated with JAK inhibitors [ 12 ]. Recently, a phase 2 randomized controlled trial suggested that treatment with baricitinib preserves β-cell function in type 1 diabetes mellitus patients [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…The activation of the JAK2-STAT1 pathway is associated with the impairment of pancreatic β-cells, promoting the development of diabetes mellitus [ 3 , 5 ]. Recently, a randomized controlled trial suggested that baricitinib could preserve β-cell function in type 1 diabetes mellitus patients [ 6 ]. JAK2 is also involved in leptin signaling, the recognition of which activates the JAK2-STAT3 pathway, contributing to appetite suppression and increased energy expenditure [ 5 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Tofacitinib and Baricitinib in Type 2 Diabetic Patients with Rheumatoid Arthritis

Martinez-Molina,

Diaz-Torne,

Park

et al. 2024

Medicina

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Background and Objectives: Recently, a randomized controlled trial suggested a potential benefit of baricitinib in patients with diabetes mellitus, preserving β-cell function. However, the clinical evidence currently available is limited. We aimed to assess the potential impact of tofacitinib and baricitinib on type 2 diabetes mellitus (T2DM) patients with rheumatoid arthritis. Materials and Methods: The candidates for this observational, retrospective, single-center study were selected from a cohort of 120 rheumatoid arthritis patients treated with tofacitinib or baricitinib between September 2017 and September 2023. The eligibility criteria included patients with T2DM who were receiving oral antidiabetic drugs (OADs). The primary outcome was the glycosylated hemoglobin (HbA1c) value after 6 months of a JAK inhibitor treatment. Secondary outcomes included body mass index (BMI) and rheumatoid arthritis disease activity. Differences were evaluated using Fisher’s exact test, as well as the Mann–Whitney test or the Wilcoxon test. Results: Thirteen patients were included; 46.2% (6/13) underwent treatment with tofacitinib, while 53.8% (7/13) were treated with baricitinib. At 6 months, baricitinib treatment resulted in a reduction in HbA1c (p = 0.035), with 57.1% (4/7) of patients achieving values <7%, and 28.6% (2/7) of patients requiring a reduction in OAD dosage. Concerning BMI, an increase (p = 0.022) was observed at 6 months following baricitinib administration. All the patients treated with either tofacitinib or baricitinib achieved remission or low disease activity, without requiring statistically significant changes in concomitant rheumatoid arthritis treatment. Conclusions: In T2DM patients with rheumatoid arthritis, baricitinib can improve insulin sensitivity and glucose uptake, enabling the optimization of T2DM management.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tofacitinib and Baricitinib in Type 2 Diabetic Patients with Rheumatoid Arthritis

Martinez-Molina,

Diaz-Torne,

Park

et al. 2024

Medicina

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“…Preclinical studies on these stress pathways support their involvement in the pathogenesis and onset of symptomatic diabetes in the gold standard T1D mouse model, the nonobese diabetic (NOD) mouse [ 3 , 4 ]. Recent phase II clinical trials have shown promising results in slowing beta cell decline after diagnosis using agents to modulate these pathways [ 5 , 6 , 7 ]. Thus, beta cell stress pathways have emerged as important therapeutic targets for T1D and a better understanding of their molecular mechanisms will improve efforts to develop new treatments.…”

Section: Introductionmentioning

confidence: 99%

Exploring Transcriptional Regulation of Beta Cell SASP by Brd4-Associated Proteins and Cell Cycle Control Protein p21

Manji,

Pipella,

Brawerman

et al. 2024

Epigenomes

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Type 1 diabetes (T1D) is a metabolic disease resulting from progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the majority of beta cells are lost in T1D, a small subset undergoes senescence, a stress response involving growth arrest, DNA damage response, and activation of a senescence-associated secretory phenotype (SASP). SASP in beta cells of the nonobese diabetic (NOD) mouse model of T1D and primary human islets is regulated at the level of transcription by bromodomain extra-terminal (BET) proteins, but the mechanisms remain unclear. To explore how SASP is transcriptionally regulated in beta cells, we used the NOD beta cell line NIT-1 to model beta cell SASP and identified binding partners of BET protein Brd4 and explored the role of the cyclin-dependent kinase inhibitor p21. Brd4 interacted with a variety of proteins in senescent NIT-1 cells including subunits of the Ino80 chromatin remodeling complex, which was expressed in beta cells during T1D progression in NOD mice and in human beta cells of control, autoantibody-positive, and T1D donors as determined from single-cell RNA-seq data. RNAi knockdown of p21 during senescence in NIT-1 cells did not significantly impact viability or SASP. Taken together, these results suggest that Brd4 interacts with several protein partners during senescence in NIT-1 cells, some of which may play roles in SASP gene activation and that p21 is dispensable for the SASP in this beta cell model.

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“…Clinical trials targeting the tumor necrosis factor alpha (TNF-a) pathway using golimumab 6,7 or etanercept 8 demonstrated improved clinical indicators in recently diagnosed patients. An initial trial of baricitinib, which blocks Janus Kinase 1 (JAK1) and JAK2 required for cytokines signal transduction, also showed improved beta-cell function in newly diagnosed individuals 9 .…”

Section: Introductionmentioning

confidence: 99%

Aberrant TNF signaling in pancreatic lymph nodes of patients with Type 1 Diabetes

Abedi,

Rai,

Zhou

et al. 2024

Preprint

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The therapeutic landscape for Type 1 Diabetes (T1D) is rapidly changing as ongoing clinical trials aim to delay beta-cell loss by inhibiting proinflammatory cytokines. However, the precise timing and cellular contexts of cytokine dysregulation remains unknown. We generated the largest existing measurement of gene expression and chromatin accessibility in ∼1 million immune cells from the pancreatic lymph nodes and spleens of 34 T1D and non-diabetic organ donors. Our study revealed heightened gene activity of the tumor necrosis factor (TNF) pathway and subsequent chromatin remodeling in central memory CD4+T cells residing in the pancreatic lymph nodes of T1D and non-diabetic islet-autoantibody positive donors. These findings, validated in mice, offer a mechanism underlying the efficacy of TNF inhibitors, currently undergoing clinical trials to delay T1D onset.

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Baricitinib and β-Cell Function in Patients with New-Onset Type 1 Diabetes

Cited by 61 publications

References 41 publications

Tofacitinib and Baricitinib in Type 2 Diabetic Patients with Rheumatoid Arthritis

Tofacitinib and Baricitinib in Type 2 Diabetic Patients with Rheumatoid Arthritis

Exploring Transcriptional Regulation of Beta Cell SASP by Brd4-Associated Proteins and Cell Cycle Control Protein p21

Aberrant TNF signaling in pancreatic lymph nodes of patients with Type 1 Diabetes

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