Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes.
<h4>Background/objective</h4>The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in...
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oai:doaj.org-article:300ce441f73e4252bb1dfceb572b92202021-11-18T08:08:22ZDeletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes.1932-620310.1371/journal.pone.0049055https://doaj.org/article/300ce441f73e4252bb1dfceb572b92202012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23173044/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background/objective</h4>The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects.<h4>Methods</h4>In Cdkal1-deficient (Cdkal1⁻/⁻) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese.<h4>Principal findings</h4>On a standard diet, Cdkal1⁻/⁻ mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1⁻/⁻ mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1⁻/⁻ mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1⁻/⁻ mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1⁻/⁻ mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI.<h4>Conclusions</h4>Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet.Tadashi OkamuraRieko Yanobu-TakanashiFumihiko TakeuchiMasato IsonoKoichi AkiyamaYukiko ShimizuMotohito GotoYi-Qiang LiangKen YamamotoTomohiro KatsuyaAkihiro FujiokaKeizo OhnakaRyoichi TakayanagiToshio OgiharaYukio YamoriNorihiro KatoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e49055 (2012) |
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Medicine R Science Q Tadashi Okamura Rieko Yanobu-Takanashi Fumihiko Takeuchi Masato Isono Koichi Akiyama Yukiko Shimizu Motohito Goto Yi-Qiang Liang Ken Yamamoto Tomohiro Katsuya Akihiro Fujioka Keizo Ohnaka Ryoichi Takayanagi Toshio Ogihara Yukio Yamori Norihiro Kato Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes. |
| description |
<h4>Background/objective</h4>The CDKAL1 gene is among the best-replicated susceptibility loci for type 2 diabetes, originally identified by genome-wide association studies in humans. To clarify a physiological importance of CDKAL1, we examined effects of a global Cdkal1-null mutation in mice and also evaluated the influence of a CDKAL1 risk allele on body mass index (BMI) in Japanese subjects.<h4>Methods</h4>In Cdkal1-deficient (Cdkal1⁻/⁻) mice, we performed oral glucose tolerance test, insulin tolerance test, and perfusion experiments with and without high-fat feeding. Based on the findings in mice, we tested genetic association of CDKAL1 variants with BMI, as a measure of adiposity, and type 2 diabetes in Japanese.<h4>Principal findings</h4>On a standard diet, Cdkal1⁻/⁻ mice were modestly lighter in weight than wild-type littermates without major alterations in glucose metabolism. On a high fat diet, Cdkal1⁻/⁻ mice showed significant reduction in fat accumulation (17% reduction in %intraabdominal fat, P = 0.023 vs. wild-type littermates) with less impaired insulin sensitivity at an early stage. High fat feeding did not potentiate insulin secretion in Cdkal1⁻/⁻ mice (1.0-fold), contrary to the results in wild-type littermates (1.6-fold, P<0.01). Inversely, at a later stage, Cdkal1⁻/⁻ mice showed more prominent impairment of insulin sensitivity and glucose tolerance. mRNA expression analysis indicated that Scd1 might function as a critical mediator of the altered metabolism in Cdkal1⁻/⁻ mice. In accordance with the findings in mice, a nominally significant (P<0.05) association between CDKAL1 rs4712523 and BMI was replicated in 2 Japanese general populations comprising 5,695 and 12,569 samples; the risk allele for type 2 diabetes was also associated with decreased BMI.<h4>Conclusions</h4>Cdkal1 gene deletion is accompanied by modestly impaired insulin secretion and longitudinal fluctuations in insulin sensitivity during high-fat feeding in mice. CDKAL1 may affect such compensatory mechanisms regulating glucose homeostasis through interaction with diet. |
| format |
article |
| author |
Tadashi Okamura Rieko Yanobu-Takanashi Fumihiko Takeuchi Masato Isono Koichi Akiyama Yukiko Shimizu Motohito Goto Yi-Qiang Liang Ken Yamamoto Tomohiro Katsuya Akihiro Fujioka Keizo Ohnaka Ryoichi Takayanagi Toshio Ogihara Yukio Yamori Norihiro Kato |
| author_facet |
Tadashi Okamura Rieko Yanobu-Takanashi Fumihiko Takeuchi Masato Isono Koichi Akiyama Yukiko Shimizu Motohito Goto Yi-Qiang Liang Ken Yamamoto Tomohiro Katsuya Akihiro Fujioka Keizo Ohnaka Ryoichi Takayanagi Toshio Ogihara Yukio Yamori Norihiro Kato |
| author_sort |
Tadashi Okamura |
| title |
Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes. |
| title_short |
Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes. |
| title_full |
Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes. |
| title_fullStr |
Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes. |
| title_full_unstemmed |
Deletion of CDKAL1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes. |
| title_sort |
deletion of cdkal1 affects high-fat diet-induced fat accumulation and glucose-stimulated insulin secretion in mice, indicating relevance to diabetes. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/300ce441f73e4252bb1dfceb572b9220 |
| work_keys_str_mv |
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