α3(V) Collagen is critical for glucose homeostasis in mice due to effects in pancreatic islets and peripheral tissues
Guorui Huang, … , Andras Nagy, Daniel S. Greenspan
Guorui Huang, … , Andras Nagy, Daniel S. Greenspan
Published January 10, 2011
Citation Information: J Clin Invest. 2011;121(2):769-783. https://doi.org/10.1172/JCI45096.
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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 5

Col5a3–/– mice have reduced β cell relative area, numbers of pancreatic islets, β cell mass, and β cell function.

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Col5a3–/– mice have reduced β cell relative area, numbers of pancreatic...
Eight- to twelve-week-old Col5a3–/– mice had highly significant decreases (A) in β cell area relative to total pancreas area, (B) in absolute numbers of pancreatic islets (islet density), (C) in pancreas weight, and, consequently, (D) in β cell mass (fractional cross-sectional area of β cells × pancreas weight) (n = 6–8 mice, per combination of gender and genotype). Islets isolated from (E) female or (F) male Col5a3–/– and wild-type pancreases (7–8 mice for each combination of genotype and gender) were incubated in the presence of 5.5 or 25 mM glucose, followed by ELISA quantification of insulin secretion. Eighteen islets were assayed per mouse (3 islets per tube, 3 tubes per each concentration of glucose, so that each assay was performed in triplicate). (G) ELISA was also used to quantify whole pancreas insulin content. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.