α3(V) Collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues
Guorui Huang, Gaoxiang Ge, Dingyan Wang, Bagavathi Gopalakrishnan, Delana H. Butz, Ricki J. Colman, Andras Nagy, Daniel S. Greenspan
Guorui Huang, Gaoxiang Ge, Dingyan Wang, Bagavathi Gopalakrishnan, Delana H. Butz, Ricki J. Colman, Andras Nagy, Daniel S. Greenspan
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Research Article Metabolism

α3(V) Collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues

Abstract

Collagen V, broadly expressed as α1(V)2α2(V) heterotrimers that regulate collagen fibril geometry and strength, also occurs in some tissues, such as white adipose tissue (WAT), pancreatic islets, and skeletal muscle, as the poorly characterized α1(V) α2(V) α3(V) heterotrimer. Here, we investigate the role of α3(V) collagen chains by generating mice with a null allele of the α3(V) gene Col5a3 (Col5a3–/– mice). Female Col5a3–/– mice had reduced dermal fat and were resistant to high-fat diet–induced weight gain. Male and female mutant mice were glucose intolerant, insulin-resistant, and hyperglycemic, and these metabolic defects worsened with age. Col5a3–/– mice demonstrated decreased numbers of pancreatic islets, which were more susceptible to streptozotocin-induced apoptosis, and islets isolated from mutant mice displayed blunted glucose-stimulated insulin secretion. Moreover, Col5a3–/– WAT and skeletal muscle were defective in glucose uptake and mobilization of intracellular GLUT4 glucose transporter to the plasma membrane in response to insulin. Our results underscore the emerging view of the importance of ECM to the microenvironments that inform proper development/functioning of specialized cells, such as adipocytes, β cells, and skeletal muscle.

Authors

Guorui Huang, Gaoxiang Ge, Dingyan Wang, Bagavathi Gopalakrishnan, Delana H. Butz, Ricki J. Colman, Andras Nagy, Daniel S. Greenspan

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Figure 6

Aberrations in Col5a3–/– islet insulin/IGF-1 signaling pathway components and Pdx1 levels, and increased susceptibility to STZ.

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Aberrations in Col5a3–/– islet insulin/IGF-1 signaling pathway component...
(A) Representative immunoblots are shown of extracts of isolated islets stained with IRS2, IRS1, phospho-Erk1/Erk2 (p-Erk1, p-Erk2), Erk1/Erk2, phospho-Akt (p-Akt), Pdx1, and α-tubulin antibodies. The latter was a loading control. All blots are from the same SDS-PAGE gel, with the exception of the blot for Pdx1 and an associated α-tubulin control. (B) Immunoblots for IRS2, IRS1, phospho-Akt, Akt, and Pdx1 were repeated 3 times, from 3 independent preps of isolated islets (from different mice). Films were scanned, and results were quantified using NIH ImageJ software. In each histogram, results are normalized to wild-type values, and Col5a3–/– values are given ± SEM. (C) Immunofluorescent staining for Pdx1 in pancreas sections from 12-week-old wild-type and Col5a3–/– mice. Sections were counterstained with DAPI, and islets are outlined in red. Original magnification, ×10. (D) A comparison is shown of 3H-thymidine incorporation in response to serum-induced proliferation in wild-type and Col5a3–/– islets. (E) An approximately 7-fold increase in apoptosis was observed in islets of Col5a3–/– pancreases compared with that in wild-type pancreases from STZ-treated mice. Numbers are of TUNEL-positive cells/mm2 of total insulin-positive area in pancreas sections. Differences are shown in (F) plasma insulin levels and (G) body weight between STZ-treated Col5a3–/– and wild-type mice. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.