The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain
Open accessAbstract
Low-carbohydrate, high-fat ketogenic diets (KD) have been suggested to be more effective in promoting weight loss than conventional caloric restriction, whereas their effect on hepatic glucose and lipid metabolism and the mechanisms by which they may promote weight loss remain controversial. The aim of this study was to explore the role of KD on liver and muscle insulin sensitivity, hepatic lipid metabolism, energy expenditure, and food intake. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in mice fed a KD or regular chow (RC). Body composition was assessed by 1 H magnetic resonance spectroscopy. Despite being 15% lighter ( P < 0.001) than RC-fed mice because of a 17% increase in energy expenditure ( P < 0.001), KD-fed mice manifested severe hepatic insulin resistance, as reflected by decreased suppression (0% vs. 100% in RC-fed mice, P < 0.01) of endogenous glucose production during the clamp. Hepatic insulin resistance could be attributed to a 350% increase in hepatic diacylglycerol content ( P < 0.001), resulting in increased activation of PKCε ( P < 0.05) and decreased insulin receptor substrate-2 tyrosine phosphorylation ( P < 0.01). Food intake was 56% ( P < 0.001) lower in KD-fed mice, despite similar caloric intake, and could partly be attributed to a more than threefold increase ( P < 0.05) in plasma N-acylphosphatidylethanolamine concentrations. In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications.
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Cites
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Use and Abuse of HOMA Modeling
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“However, in these studies, insulin sensitivity was assessed by intraperitoneal glucose tolerance tests; one of these studies (2) reported improvement in QUICKI in KD-fed wild-type mice compared with RC-fed wild-type mice but no correlation with the insulin sensitivity.”
MethodInfluentialCold-Activated Brown Adipose Tissue in Healthy Men
van Marken Lichtenbelt, W. D., Vanhommerig, J. W., Smulders, N. M., Drossaerts, J. M. A. F. L., Kemerink, G. J., Bouvy, N. D., Schrauwen, P., & Teule, G. J. J. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808718 · Cited by 3,452
FGF-21 as a novel metabolic regulator
Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23606 · Cited by 2,125
A Randomized Trial of a Low-Carbohydrate Diet for Obesity
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“DAG and ceramide were extracted as previously described (46).”
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Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., & Shulman, G. I. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m313478200 · Cited by 1,322
Self-citationA Low-Carbohydrate as Compared with a Low-Fat Diet in Severe Obesity
Samaha, F. F., Iqbal, N., Seshadri, P., Chicano, K. L., Daily, D. A., McGrory, J., Williams, T., Williams, M., Gracely, E. J., & Stern, L. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa022637 · Cited by 1,267 · cited 3×
“Although some human studies have found KD to be effective in short-term weight loss (16, 43, 45), the effect of KD on glucose metabolism remains controversial (5, 8, 23, 30, 37).”
Background
Cited by
Ketone bodies as signaling metabolites
Newman, J. C., & Verdin, E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2013.09.002 · Cited by 966
Roles of diacylglycerols and ceramides in hepatic insulin resistance
Petersen, M. C., & Shulman, G. I. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.04.004 · Cited by 373
Self-citationβ-hydroxybutyrate: Much more than a metabolite
Newman, J. C., & Verdin, E. (2014) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2014.08.009 · Cited by 326
DAG tales: the multiple faces of diacylglycerol—stereochemistry, metabolism, and signaling
Eichmann, T. O., & Lass, A. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1982-3 · Cited by 314
Haufe, S., Engeli, S., Kast, P., Böhnke, J., Utz, W., Haas, V., Hermsdorf, M., Mähler, A., Wiesner, S., Birkenfeld, A. L., et al. (2011) · Hepatology · doi:10.1002/hep.24242 · Cited by 307
Self-citation
Metadata
- Authors
- Jornayvaz, F. R., Jurczak, M. J., Lee, H.-Y., Birkenfeld, A. L., Frederick, D. W., Zhang, D., Zhang, X.-M., Samuel, V. T., & Shulman, G. I.
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2010-11
- Volume
- 299
- Issue
- 5
- Pages
- E808-E815
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2165028825
- Cited by
- 211
- References
- 25
- FWCI
- 7.42
- Type
- journal article
- Language
- en
- Open access
- green
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- Jornayvaz, F. R., Jurczak, M. J., Lee, H.-Y., Birkenfeld, A. L., Frederick, D. W., Zhang, D., Zhang, X.-M., Samuel, V. T., & Shulman, G. I. (2010). A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. American Journal of Physiology-Endocrinology and Metabolism. https://doi.org/10.1152/ajpendo.00361.2010
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