Carnitine revisited: potential use as adjunctive treatment in diabetes
Open accessAbstract
Aims/hypothesis This study examined the efficacy of supplemental L: -carnitine as an adjunctive diabetes therapy in mouse models of metabolic disease. We hypothesised that carnitine would facilitate fatty acid export from tissues in the form of acyl-carnitines, thereby alleviating lipid-induced insulin resistance.Materials and methods Obese mice with genetic or diet-induced forms of insulin resistance were fed rodent chow +/- 0.5% L: -carnitine for a period of 1-8 weeks. Metabolic outcomes included insulin tolerance tests, indirect calorimetry and mass spectrometry-based profiling of acyl-carnitine esters in tissues and plasma.Results Carnitine supplementation improved insulin-stimulated glucose disposal in genetically diabetic mice and wild-type mice fed a high-fat diet, without altering body weight or food intake. In severely diabetic mice, carnitine supplementation increased average daily respiratory exchange ratio from 0.886 +/- 0.01 to 0.914 +/- 0.01 (p < 0.01), reflecting a marked increase in systemic carbohydrate oxidation. Similarly, under insulin-stimulated conditions, carbohydrate oxidation was higher and total energy expenditure increased from 172 +/- 10 to 210 +/- 9 kJ kg fat-free mass(-1) h(-1) in the carnitine-supplemented compared with control animals. These metabolic improvements corresponded with a 2.3-fold rise in circulating levels of acetyl-carnitine, which accounts for 86 and 88% of the total acyl-carnitine pool in plasma and skeletal muscle, respectively. Carnitine supplementation also increased several medium- and long-chain acyl-carnitine species in both plasma and tissues.Conclusions/interpretation These findings suggest that carnitine supplementation relieves lipid overload and glucose intolerance in obese rodents by enhancing mitochondrial efflux of excess acyl groups from insulin-responsive tissues. Carefully controlled clinical trials should be considered.
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Lowering mitochondrial acyl-CoAs, resulting in increased PDH activity and improved metabolic flexibility, can be achieved via dietary L-carnitine supplementation.
“Moreover, recent evidence suggests that lowering of mitochondrial acyl CoAs, resulting in increased PDH activity and improved metabolic flexibility, can be achieved via dietary supplementation with L-carnitine (Noland et al., 2009; Power et al., 2007).”
From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Power et al., 2007
Oral carnitine supplementation improves insulin sensitivity in diabetic mice, in parallel with a marked rise in plasma acylcarnitines.
“In another recent investigation we found that oral carnitine supplementation improved insulin sensitivity in diabetic mice, in parallel with a marked rise in plasma acylcarnitines (8).”
From Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control (2009) · cites this paper as [8]
The antidiabetic actions of carnitine are accompanied by an increase in whole body glucose oxidation.
“The antidiabetic actions of carnitine were accompanied by an increase in whole body glucose oxidation, a surprising result given that carnitine is best known for its essential role in permitting mitochondrial translocation and oxidation of long chain acyl-CoAs.”
From Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control (2009) · cites this paper as [8]
Previous work suggested that tissue export of acetylcarnitine lowers local concentrations of acetyl-CoA, which in turn favors increased pyruvate dehydrogenase activity and higher rates of glucose oxidation.
“Previous work suggested that tissue export of acetylcarnitine lowers local concentrations of acetyl-CoA, which in turn favors increased pyruvate dehydrogenase activity and higher rates of glucose oxidation (8,20).”
From Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control (2009) · cites this paper as [8]
We previously reported that carnitine supplementation effectively restored insulin responsiveness in multiple mouse models of glucose intolerance.
“We previously reported that carnitine supplementation effectively restored insulin responsiveness in multiple mouse models of glucose intolerance (8).”
From Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control (2009) · cites this paper as [8]
Carnitine therapy improves glucose tolerance and insulin responsiveness in rodent models of aging, genetic diabetes, and high-fat feeding, and reverses obesity-related mitochondrial fuel-selection defects.
“carnitine therapy improved glucose tolerance and insulin responsiveness in rodent models of aging, genetic diabetes and high fat feeding [65,71], while also reversing obesity-related derangements in mitochondrial fuel selection [65].”
From Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? (2010) · cites this paper as [71]
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“L-C may enhance glucose oxidation by enhancing mitochondrial efflux of excess acyl groups [50] and stimulate CRAT [11], thus causing a feedback inhibition of fatty acid oxidation by relieving inhibition of the pyruvate dehydrogenase complex (PDH) [10,12]; the rate limiting enzyme in mitochondrial glucose oxidation [51…”
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“L-carnitine supplementation has previously been shown to relieve lipid overload and increase glucose sensitivity in obese mice [27].”
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“Short-chain acyl carnitines (C6 or less) were the most abundant acylcarnitines constituting 99% of the total acyl-carnitines in skeletal muscle, 95% in plasma, 96% in white fat, and 93% in liver [27].”
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“Acute carnitine administration is able to improve peripheral insulin sensitivity in non-insulin-dependent diabetic patients [54] and to relieve glucose intolerance in obese rodents [55].”
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“L-carnitine is reported to control hyperglycemia and improve insulin sensitivity [34] and also increase the peripheral glucose utilization in the insulin resistance patients [35].”
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“Thus, it has been hypothesised that increasing carnitine availability might contribute to the improvement in glucose tolerance or insulin sensitivity (Power et al. 2007; Mynatt 2009).”
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“However, L-carnitine itself has also demonstrated some beneficial effects in insulin resistance without necessarily decreasing body weight [23], leading to the opening of extra hypothesis explaining the effects of L-carnitine and PLC on insulin resistance.”
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“carnitine status due to carnitine supplementation reverses mitochondrial dysfunction under these conditions [4,9,10,12,13].”
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“Besides its role in permitting mitochondrial oxidation of long-chain fatty acids, more recent studies showed that carnitine also stimulates whole body glucose oxidation and improves insulin sensitivity in distinct models of glucose intolerance including high-fat (HF) feeding and genetic diabetes [2].”
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“In experimental research, oral L-carnitine supplementation was proved to increase total energy expenditure in obese rats with insulin resistance [28].”
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l-Carnitine intake prevents irregular feeding-induced obesity and lipid metabolism disorder
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“and accounts for the fact that carnitine, a metabolite devoted to the transport of long chain acyl-CoA from cytosol to mitochondria for oxidation [ , , ,”
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“These and previous((28)) outcomes support the necessity of clinical trials showing the effect of L-carnitine supplements on insulin-resistant and obesity states.”
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“Specifically, treatment with l-carnitine has been associated with improvement in insulin sensitivity and endothelial function [33], as well as reductions in oxidative stress and blood pressure [34].”
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Diabetic Cardiac Autonomic Neuropathy
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“Moreover, carnitine supplementation may relieve overload of lipid [46].”
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Alterations in the carnitine cycle in a mouse model of Rett syndrome
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Highlights of the 2012 Research Workshop
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“Moreover, carnitine supplementation has been shown to improve whole-body 78 glucose tolerance in insulin-resistant human subjects and rodent models of 79 metabolic disease (34, 37, 38).”
BackgroundLiao, D., Liu, X., Yuan, X., Feng, P., Ouyang, Z., Liu, Y., & Li, C. (2021) · Gynecological Endocrinology · doi:10.1080/09513590.2021.1988559 · Cited by 15 · see citing works
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“In contrast, supplementation with carnitine improves carnitine status, which was also demonstrated in the present study, and reverses to a great part these metabolic disturbances, like elevated blood levels of triacylglycerides and non-esterified fatty acids, glucose intolerance and insulin resistance [30-32,34].”
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“Nevertheless, additional intake of L-carnitine is recommended for diabetic patients with late complications (Poorabbas et al., 2007; Power et al., 2007).”
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“Carnitine supplementation promotes CrAT-mediated acetylcarnitine efflux and improves metabolic outcome in obese rodents [12,13].”
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“of fatty acid oxidation in skeletal muscle has been proposed to affect insulin sensitivity in this tissue [30,32,46-50].”
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“Skeletal muscles constitute the main reservoir of carnitine in the body and have a carnitine concentration at least 200 times higher than blood plasma [13].”
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“…concentrations are reported in obese insulin-resistant mice, along with blunted metabolic flexibility and elevated plasma glucose levels, 5 where metabolic flexibility is defined as the ability to switch from predominantly fat oxidation while fasted to carbohydrate oxidation upon…”
L-carnitine ameliorated weight loss in fasting therapy: A propensity score-matched study
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“L-carnitine supplementation resulted in increased average daily respiratory exchange ratio, which reflected systemic carbohydrate oxidation, among mice with obesity and insulin resistance [46].”
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“Power et al.27 reported that supplementing obese mice with L-carnitine reduced lipid overload and glucose intolerance by enhancing the mitochondrial efflux of excess acyl groups in insulin-responsive tissues.”
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“of pyruvate dehydrogenase, which facilitates glucose oxidation (Power et al., 2007).”
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- Authors
- Power, R. A., Hulver, M. W., Zhang, J. Y., Dubois, J., Marchand, R. M., Ilkayeva, O., Muoio, D. M., & Mynatt, R. L.
- Affiliations
- Pennington Biomedical Research Center (US)
- Virginia Tech (US)
- Duke University (US)
- Corresponding author
- Mynatt, R. L.
- Venue
- Diabetologia
- Published
- 2007-02-20
- Volume
- 50
- Issue
- 4
- Pages
- 824-832
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC5682624
- OpenAlex
- W2069095858
- Cited by
- 113
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 9 · 2015: 5 · 2014: 15 · 2013: 7 · 2012: 11
- FWCI
- 3.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK072476, P30DK072476)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- carnitine supplementation, insulin resistance, type 2 diabetes, acylcarnitines, acetyl-L-carnitine, fatty acid export, lipid overload, impaired glucose tolerance, carbohydrate oxidation, energy expenditure, respiratory exchange ratio, skeletal muscle, high-fat diet, obesity, adjunctive therapy
- MeSH terms
- Animals, Calorimetry, Carnitine, Diabetes Mellitus, Experimental, Fatty Acids, Glucose Tolerance Test, Glycerol, Insulin Resistance, Male, Mice, Obese, Mass Spectrometry, Vitamin B Complex, Pyruvate Dehydrogenase (Lipoamide), Mice
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