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Muscle-specific knockout of PKC-λ impairs glucose transport and induces metabolic and diabetic syndromes
Robert V. Farese, … , Ursula Braun, Michael Leitges
Robert V. Farese, … , Ursula Braun, Michael Leitges
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2289-2301. https://doi.org/10.1172/JCI31408.
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Research Article Metabolism Article has an altmetric score of 10

Muscle-specific knockout of PKC-λ impairs glucose transport and induces metabolic and diabetic syndromes

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Abstract

Obesity, the metabolic syndrome, and type 2 diabetes mellitus (T2DM) are major global health problems. Insulin resistance is frequently present in these disorders, but the causes and effects of such resistance are unknown. Here, we generated mice with muscle-specific knockout of the major murine atypical PKC (aPKC), PKC-λ, a postulated mediator for insulin-stimulated glucose transport. Glucose transport and translocation of glucose transporter 4 (GLUT4) to the plasma membrane were diminished in muscles of both homozygous and heterozygous PKC-λ knockout mice and were accompanied by systemic insulin resistance; impaired glucose tolerance or diabetes; islet β cell hyperplasia; abdominal adiposity; hepatosteatosis; elevated serum triglycerides, FFAs, and LDL-cholesterol; and diminished HDL-cholesterol. In contrast to the defective activation of muscle aPKC, insulin signaling and actions were intact in muscle, liver, and adipocytes. These findings demonstrate the importance of aPKC in insulin-stimulated glucose transport in muscles of intact mice and show that insulin resistance and resultant hyperinsulinemia owing to a specific defect in muscle aPKC is sufficient to induce abdominal obesity and other lipid abnormalities of the metabolic syndrome and T2DM. These findings are particularly relevant because humans who have obesity, impaired glucose tolerance, and T2DM reportedly have defective activation and/or diminished levels of muscle aPKC.

Authors

Robert V. Farese, Mini P. Sajan, Hong Yang, Pengfei Li, Steven Mastorides, William R. Gower Jr., Sonali Nimal, Cheol Soo Choi, Sheene Kim, Gerald I. Shulman, C. Ronald Kahn, Ursula Braun, Michael Leitges

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Figure 10

Effects of homozygous and heterozygous muscle-specific KO of PKC-λ on basal and insulin-stimulated glucose uptake and transport in whole adipose tissue, isolated adipocytes, and serum adipokines.

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Effects of homozygous and heterozygous muscle-specific KO of PKC-λ on ba...
(A) Glucose transport was measured in adipose tissues obtained from WT, homozygous KO, and heterozygous KO mice treated with or without insulin in vivo, as described in Figure 1. Insets show aPKC levels in indicated groups with or without insulin. (B) Adipocytes isolated from male mice were incubated with increasing concentrations of insulin. (C) Results in ad libitum–fed male mice. Values are mean ± SEM. n for each group is shown in parentheses. #P < 0.05 versus non–insulin-stimulated group of the same genotype (ANOVA). *P < 0.05; **P < 0.01 (ANOVA).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 14 patents
Mentioned by 1 peer review sites
123 readers on Mendeley
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