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 3

Col5a3–/– mice have impaired glucose tolerance and insulin sensitivity and are hypoinsulinemic.

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Col5a3–/– mice have impaired glucose tolerance and insulin sensitivity ...
(A) Serum glucose levels are shown in mg/dl for 3-month-old female and male wild-type and Col5a3–/– (KO) mice (n = 6 for each combination of gender and genotype) after glucose administration for glucose tolerance tests (GTTs) or after insulin administration for insulin tolerance tests (ITTs). Areas under glucose tolerance test glucose curves for wild-type and Col5a3–/– females were 22,428 and 34,074 mg/dl per 120 minutes, respectively, demonstrating a significant (P < 0.001) 1.52-fold difference. Areas under the glucose tolerance test glucose curves for wild-type and Col5a3–/– males were 25,884 and 36,882 mg/dl per 120 minutes, respectively, demonstrating a significant (P < 0.002) 1.42-fold difference. Plasma insulin levels (insulin) were measured for aliquots of glucose tolerance test samples from 0, 30, and 60 minutes time points. (B) Glucose tolerance test and insulin tolerance test glucose levels are shown in mg/dl for 1-year-old wild-type (n = 12) and Col5a3–/– (n = 10) mice (genders were not tested separately for these assays). Areas under glucose tolerance test glucose curves for wild-type and Col5a3–/– mice were 19,926 and 38,772 mg/dl per 120 minutes, respectively, demonstrating a significant (P < 0.0002) 1.95-fold difference. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.