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Inceptor binds and directs insulin to lysosomal degradation in -cells

ABSTRACT: Blunted first-phase insulin secretion and insulin deficiency are early signs of -cell dysfunction and diabetes manifestation. Thus, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore -cell function. Here, we identified the insulin inhibitory receptor (short: inceptor; encoded by the gene IIR) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (iPSC)-derived islets, we show that IIR knockout (KO) results in enhanced stem cell (SC)--cell differentiation, maturation, and survival. Strikingly, extended in vitro culture of IIR KO SC--cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find inceptor localized to clathrin-coated vesicles close to the plasma membrane (PM) and in the trans-Golgi network (TGN), as well as in secretory granules (SGs), where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases insulin content and improves SC--cell function. Altogether, our findings revealed basic mechanisms of -cell insulin turnover and identified inceptor as a druggable insulin degradation receptor.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Richard Scheltema

LAB HEAD: Richard Scheltema

PROVIDER: PXD040758 | Pride | 2024-09-09

REPOSITORIES: Pride

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			Action	DRS
	20211028_F1_UM4_alban001_SA_EXT00_Inceptor_NQ_cys1.raw	Raw
	20211028_F1_UM4_alban001_SA_EXT00_Inceptor_NQ_cys2.raw	Raw
	20211028_F1_UM4_alban001_SA_EXT00_Inceptor_NQ_cys3.raw	Raw
	20211028_F1_UM4_alban001_SA_EXT00_Inceptor_WT_cys1.raw	Raw
	20211028_F1_UM4_alban001_SA_EXT00_Inceptor_WT_cys2.raw	Raw

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Inceptor binds to and directs insulin towards lysosomal degradation in beta-cells

Project description:Blunted first-phase insulin secretion and insulin deficiency are indicators of β-cell dysfunction and diabetes manifestation. Thus, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β-cell function. Here, we identify the insulin inhibitory receptor (short: inceptor; encoded by the gene IIR) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (iPSC)-derived islets, we show that IIR knockout (KO) results in enhanced stem cell (SC)-β-cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC-β-cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localises to clathrin-coated vesicles (CCVs) close to the plasma membrane (PM) and in the trans-Golgi network (TGN), as well as in secretory granules (SGs), where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody (mAB) increases proinsulin and insulin content and improves SC-β-cell GSIS.

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Insulin deficiency distorts human pancreatic endocrine cell composition during development

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Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men

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2018-10-04 | PXD010212 | Pride

Comprehensive analysis of different in vitro insulin resistance models

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