Cover Story Current Issue
Postpartum (PP) maternal mortality remains alarmingly high, with a rate of 32.9 per 100,000 live births in 2021 in the United States. Cardiovascular diseases, including peripartum/postpartum cardiomyopathy (PPCM) and coronary heart disease, are among the leading causes of PP morbidity and mortality. Although socioeconomic status and the level of PP care can influence the mortality rate, the underlying mechanisms leading to PPCM are not well understood. PPCM is clinically defined as (1) the development of the disease in the last month of pregnancy or within 5 months of delivery, (2) absence of pre-existing heart disease prior to the last month of pregnancy, (3) unknown cause of heart failure, and (4) left ventricular systolic dysfunction. Prognosis remains poor, with full recovery reported in only 23% of affected individuals and 50% experiencing heart failure-related mortality due to limited therapeutic options. Limited studies in both humans and mouse models of PPCM have proposed several potential mechanisms, including inflammation, viral myocarditis, autoimmune reactions, oxidative stress, and apoptosis, resulting from environmental as well as genetic factors. Studying these mechanisms in animal models, particularly those involving genetic causes, has been difficult due to the lack of severity or relevance of existing mouse models of PPCM to the human disease.
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.
Opening Abstract Submission & Registration
13th
Helmholtz Diabetes Conference
Munich, 21-23. Sep 2026
2024 impact factor: 6.6
You are what you eat
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