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Inhibition of RIPK1 kinase does not affect diabetes development: β-Cells survive RIPK1 activation

Tatiana Takiishi1, Peng Xiao1, Marie Franchimont1

  • 1Inflammation and Cell Death Signalling Group, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles (ULB), Brussels, Belgium.

Molecular Metabolism
|January 27, 2023
PubMed
Abstract

Insights

Receptor interacting serine/threonine protein kinase 1 (RIPK1) kinase activity is not essential for developing type 1 diabetes or obesity. Mouse models lacking RIPK1 kinase activity showed normal glucose metabolism and no increased susceptibility to diabetes or diet-induced obesity.

Area of Science:

  • Immunology
  • Endocrinology
  • Cell Biology

Background:

  • Type 1 diabetes (T1D) involves immune-mediated destruction of insulin-producing beta-cells, with inflammation, apoptosis, and necrosis contributing to beta-cell loss.
  • Receptor interacting serine/threonine protein kinase 1 (RIPK1) is a key regulator of inflammation and cell death pathways, including apoptosis and necroptosis.
  • The specific role of RIPK1 kinase activity in T1D pathogenesis and metabolic disease remains unclear.

Purpose of the Study:

  • To investigate the in vivo role of RIPK1 kinase activity in the development of immune-mediated diabetes and diet-induced obesity (DIO).
  • To assess beta-cell death and RIPK1 kinase activity in vitro under conditions known to induce RIPK1-dependent cell death.

Main Methods:

  • Utilized a RIPK1 knockin mouse line (Ripk1S25D/S25D) with abrogated RIPK1 kinase activity.
  • Assessed in vivo susceptibility to immune-mediated diabetes and DIO.
  • Analyzed in vitro beta-cell death and RIPK1 kinase activity upon stimulation with TNF+BV6+zVAD.

Main Results:

  • Mice lacking RIPK1 kinase activity (Ripk1S25D/S25D) exhibited normal glucose metabolism and beta-cell function.
  • No significant differences in susceptibility to immune-mediated diabetes or DIO were observed between Ripk1S25D/S25D and wild-type (Ripk1+/+) mice.
  • Mouse islets and human beta-cells did not undergo cell death despite strong activation of RIPK1 kinase and necroptosis effectors (RIPK3, MLKL).

Conclusions:

  • RIPK1 kinase activity is not required for beta-cell death in response to inflammatory stimuli.
  • Beta-cells may possess a unique resistance to RIPK1-dependent necroptosis, potentially due to their limited proliferative capacity.
  • These findings challenge the generalizability of RIPK1's role in necroptosis across all cell types, particularly in the context of T1D.
Keywords:
ApoptosisNecroptosisObesityRIPK1Type 1 diabetes

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