Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes.

Abstract

Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression.

• Authors: Qian Li, Jialin Fu, Yu Xia, Weier Qi, Atsushi Ishikado, Kyoungmin Park, Hisashi Yokomizo, Qian Huang, Weikang Cai, Christian Rask-Madsen, C Ronald Kahn, George L King
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 4427 (09 27 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31562314 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Igf1r protein, mouse
• Insulin
• Insulin-Like Growth Factor I
• Has2 protein, mouse
• Hyaluronan Synthases
• Receptor, IGF Type 1
• Receptor, Insulin

Topics

• Animals
• Diabetes Mellitus (metabolism)
• Disease Models, Animal
• Femoral Artery (injuries, metabolism, pathology)
• Homozygote
• Hyaluronan Synthases (metabolism)
• Hyperplasia (metabolism)
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Insulin-Like Growth Factor I (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Smooth, Vascular (metabolism)
• Receptor, IGF Type 1 (chemistry, metabolism)
• Receptor, Insulin (chemistry, metabolism)
• Signal Transduction