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The pancreas is a mixed gland primarily composed of exocrine tissue, which secretes digestive enzymes into the digestive tract, and an endocrine component organized into small clusters known as islets of Langerhans, constituting approximately 1% of the pancreatic mass. Each adult islet contains an average of 1,500 cells, including beta-, alpha- and delta-cells, which produce and secrete insulin (INS), glucagon (GCG), and somatostatin (SST) respectively. The destruction of insulin-producing beta-cells or the defective insulin secretion give rise to type 1 and type 2 diabetes mellitus, respectively. These chronic metabolic disorders are characterized by the dysregulation of glucose homeostasis.
Current Issue
Apolipoprotein E receptor 2 in endothelium promote glucose tolerance by mediating insulin delivery to skeletal muscle
Apolipoprotein E receptor 2 in endothelium promote glucose tolerance by mediating insulin delivery to skeletal muscle
Objective
The delivery of circulating insulin to skeletal muscle myocytes is a rate-limiting step in peripheral insulin action, and there is minimal understanding of the underlying mechanisms in endothelial cells. Recognizing that the LDL receptor family member apolipoprotein E receptor 2 (ApoER2, also known as LRP8) mediates apolipoprotein E (ApoE)-induced signaling in endothelial cells, the present project determined if endothelial ApoER2 influences glucose homeostasis in mice.
Methods
Mice were generated deficient in ApoER2 selectively in endothelial cells, and glucose homeostasis was studied. Insulin-stimulated recruitment of the skeletal muscle microvasculature was assessed using contrast-enhanced ultrasound imaging. Endothelial cell insulin uptake and transcytosis were evaluated in culture. The ApoER2 interactome in endothelial cells was interrogated using immunoprecipitation and liquid chromatography/tandem mass spectrometry. ApoER2 structure–function was studied by mutagenesis.
Results
Mice deficient in endothelial cell ApoER2 are glucose intolerant and insulin resistant due to a blunting of skeletal muscle glucose disposal that is related to a decrease in muscle insulin delivery. Endothelial ApoER2 manipulation does not alter direct insulin action on skeletal muscle or insulin-stimulated recruitment of the skeletal muscle microvasculature. Instead, ApoER2 stimulation by apolipoprotein E3 (ApoE3) increases endothelial cell insulin uptake and transcytosis. ApoE3 and ApoER2 stimulation of endothelial insulin transport require the ApoER2 adaptor protein Dab2 and the scaffolding protein IQGAP1, which is known to mediate insulin secretion by pancreatic β cells. IQGAP1 is not required for ApoE3/ApoER2-induced insulin uptake by endothelial cells; alternatively it is necessary for insulin transcytosis. ApoE3 prompts IQGAP1 recruitment to the exocyst complex, and ApoER2 interaction with IQGAP1 is necessary for the recruitment.
Conclusions
In endothelial cells the ApoE3 and ApoER2 tandem co-opts the role of IQGAP1 in pancreatic β cell insulin secretion to enhance endothelial insulin transport. In this manner endothelial ApoER2 promotes glucose disposal in skeletal muscle and supports normal glucose homeostasis.
Articles in Press
Apolipoprotein E receptor 2 in endothelium promote glucose tolerance by mediating insulin delivery to skeletal muscle
Apolipoprotein E receptor 2 in endothelium promote glucose tolerance by mediating insulin delivery to skeletal muscle
Objective
The delivery of circulating insulin to skeletal muscle myocytes is a rate-limiting step in peripheral insulin action, and there is minimal understanding of the underlying mechanisms in endothelial cells. Recognizing that the LDL receptor family member apolipoprotein E receptor 2 (ApoER2, also known as LRP8) mediates apolipoprotein E (ApoE)-induced signaling in endothelial cells, the present project determined if endothelial ApoER2 influences glucose homeostasis in mice.
Methods
Mice were generated deficient in ApoER2 selectively in endothelial cells, and glucose homeostasis was studied. Insulin-stimulated recruitment of the skeletal muscle microvasculature was assessed using contrast-enhanced ultrasound imaging. Endothelial cell insulin uptake and transcytosis were evaluated in culture. The ApoER2 interactome in endothelial cells was interrogated using immunoprecipitation and liquid chromatography/tandem mass spectrometry. ApoER2 structure–function was studied by mutagenesis.
Results
Mice deficient in endothelial cell ApoER2 are glucose intolerant and insulin resistant due to a blunting of skeletal muscle glucose disposal that is related to a decrease in muscle insulin delivery. Endothelial ApoER2 manipulation does not alter direct insulin action on skeletal muscle or insulin-stimulated recruitment of the skeletal muscle microvasculature. Instead, ApoER2 stimulation by apolipoprotein E3 (ApoE3) increases endothelial cell insulin uptake and transcytosis. ApoE3 and ApoER2 stimulation of endothelial insulin transport require the ApoER2 adaptor protein Dab2 and the scaffolding protein IQGAP1, which is known to mediate insulin secretion by pancreatic β cells. IQGAP1 is not required for ApoE3/ApoER2-induced insulin uptake by endothelial cells; alternatively it is necessary for insulin transcytosis. ApoE3 prompts IQGAP1 recruitment to the exocyst complex, and ApoER2 interaction with IQGAP1 is necessary for the recruitment.
Conclusions
In endothelial cells the ApoE3 and ApoER2 tandem co-opts the role of IQGAP1 in pancreatic β cell insulin secretion to enhance endothelial insulin transport. In this manner endothelial ApoER2 promotes glucose disposal in skeletal muscle and supports normal glucose homeostasis.
2022 impact factor: 6.6
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