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L-carnitine and insulin sensitivity

L-carnitine and insulin sensitivity

Carnitine improves L-carnitine and insulin sensitivity glucose disposal in anx diabetic patients. Restful practices E, Steffes MW, L-carnitime H, Matsushita L-carnitine and insulin sensitivity, Wagenknecht L, Pankow J, et al. Ruggenenti PCattaneo DLoriga GLedda FMotterlini NGherardi GOrisio SRemuzzi G. Carnitine is present in the body as free and esterified form acylcarnitines.

L-carnitine and insulin sensitivity -

Because doses of L-carnitine have mostly had significant effects for more than 12 weeks It seems that L-carnitine can have optimal and significant effects on human health when it is accompanied by increased physical activity, modification of lifestyle, and compliance with a healthy diet — The non-linear dose-response analysis revealed a significant negative relationship between FBG levels and L-carnitine intervention duration for 4 weeks and more.

But it was not significant for insulin levels. It can be said that the optimal duration for effective reduction of FBG, HOMA-IR, and HbA1c was 50 weeks. Although unlike the other three indices insulin changes were significant with the increase of L-carnitine in highest vs.

Of course, our study has some limitations, including that most of the included articles showed high bias and heterogeneity which makes it difficult to reach a definitive conclusion about the effects of carnitine.

Although we tried to find the source of the heterogeneity by performing subgroup analysis. Moreover, we did not evaluate the effects of other glycemic indices such as 2-h post-prandial glucose due to the lack of examination of this outcome in clinical trials.

Although all studies used randomization; information on allocation concealment, randomization efficiency, and withdrawal was not consistently disclosed. Moreover, there are differences in laboratory assessment methods in different trials, as well as differences in intra assay coefficient of variation intra-assay CV and inter-assay coefficient of variation inter-assay CV.

Although adverse events were mentioned in some trials, most of them were not reported. There are also strengths in the present study. To our knowledge, the present study is one of the first comprehensive dose-response meta-analyses to evaluate the L-carnitine effects on glycemic markers in diabetes and non-diabetic adults and we considered all published RCTs that were conducted on the effect of L-carnitine sapplementation on glycemic indices.

Furthermore, we performed a dose-response analysis and considered different subgroups to evaluate the effects of L-carnitine on glycemic indices. All trials were included based on inclusion criteria, with varying individuals, which provides the possibility of subgroup analysis.

The randomized and placebo-controlled design of all included trials and the double-blind design of most of them can also be other strengths and due to the RCT nature of the studies, the drugs used by the patients especially in diabetic patients , the diet and the level of physical activity of the participants were controlled and in fact their effects were considered and it can be said that the pure effects of L-carnitine was evaluated.

In the current meta-analysis, there were no time and language restrictions for inclusion of studies. In addition, GRADE assessment, sensitivity tests, and subgroup analysis were used to assess quality of studies, detect publication bias and identify potential sources of heterogeneity among trials, respectively.

The findings of our systematic review and dose-response meta-analysis showed a significant reductions for FBG, HbA1c, and HOMA-IR levels. However, based on our analysis, L-carnitine failed to significantly affect serum insulin.

On the other hand; 50 weeks of intervention has beneficial effects on decreasing HOMA-IR, HbA1c, and FBG. Larger, well-designed trials are still required to further evaluation of this association.

MZ designed the study. MZ and OA developed the search strategy and assessed the risk of bias of the meta-analyses. MZ, MN-S, and OA extracted the data and conducted the analyses.

NP, RG-E, NR, and SR drafted the manuscript. FS, OA, and MN-S interpreted the results. FS, OA, and SR revised manuscript. All authors read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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J Gastroenterol Hepatol Res. Odo S, Tanabe K, Yamauchi M. This suggests that the nuclear receptor PPARα, which plays a crucial role in the adaptive response to fasting, is a regulator of acyl carnitine metabolism The plasmalemmal carrier OCTN2 is responsible for cellular carnitine uptake in various organs, including reabsorption from urine in the kidney.

As is the case for BBD, OCTN2 expression in liver is regulated by PPARα. A synthetic PPARα agonist increased OCTN2 expression in wild-type mice and caused a rise in carnitine levels in plasma, liver, kidney, and heart Once inside the cell, FAs are activated by esterification to CoA.

Then, the carnitine shuttle transports long-chain acyl-CoAs into mitochondria via their corresponding carnitine ester Fig. Long-chain acyl-CoAs are converted to acylcarnitines by carnitine palmitoyltransferase 1 CPT1 , which exchanges the CoA moiety for carnitine.

CPT1 is located at the outer mitochondrial membrane, and three isoforms are known: CPT1a, 1b, and 1c are encoded by separate genes CPT1a is expressed in liver and most other abdominal organs, as well as human fibroblasts.

CPT1b is selectively expressed in heart, skeletal muscle, adipose tissue, and testes CPT1c is only expressed in the endoplasmic reticulum and not the mitochondria of neurons in the brain The carnitine shuttle.

After transportation into the cell by FA transporters FAT , FA are activated by esterification to CoA. Subsequently, CPT1 exchanges the CoA moiety for carnitine C. The resulting acylcarnitine AC is transported across the inner mitochondrial membrane into the mitochondrion by CACT.

Once inside, CPT2 reconverts the acylcarnitine back into free carnitine and a long-chain acyl-CoA that can undergo FAO for ATP production via the TCA and respiratory chain RC. CPT1 is an important regulator of FAO flux.

Glucose oxidation after a meal leads to inhibition of CPT1 activity via the FA-biosynthetic intermediate malonyl-CoA 23 , which is produced by acetyl-CoA carboxylase ACC There are two ACC isoforms. ACC1 plays a role in FA biosynthesis.

ACC2 has been implicated in the regulation of FAO mainly because of its localization to the outer mitochondrial membrane Conversely, in the fasting state, activated AMP-activated protein kinase inhibits ACC resulting in falling malonyl-CoA levels, thereby permitting CPT1 activity and thus FAO.

CPT1a is limiting for hepatic FAO and ketogenesis Although the inhibition of malonyl-CoA on CPT1b is more potent than on CPT1a, no unequivocal evidence exists showing its control over muscle FAO FAO is also regulated at the transcriptional level.

There is ample evidence that both PPARs participate in the transcriptional regulation of CPT1b 28 — Regulation of CPT1a by PPAR is less prominent After production of acylcarnitines by CPT1, the mitochondrial inner membrane transporter carnitine acylcarnitine translocase CACT, or SLC25A20 transports the acylcarnitines into the mitochondrial matrix.

The FA transporter CD36 possibly facilitates transfer of acylcarnitines from CPT1 to CACT Finally, the enzyme CPT2 reconverts acylcarnitines back into free carnitine and long-chain acyl-CoAs, which can then be oxidized 21 Fig.

With the introduction of tandem mass spectrometry MS in clinical chemistry in the s, it became relatively easy to measure acylcarnitine profiles. In these profiles, the mass-to-charge ratio reflects the length and composition of the acyl chain This technique rapidly became the preferred screening test to diagnose inherited disorders in FAO, which lead to prominent changes in the acylcarnitine profile, with a pattern specific for the deficient enzyme.

More recently, acylcarnitine analysis is used to investigate more common metabolic derangements such as insulin resistance. Although most acylcarnitines are derived from FAO, they can be formed from almost any CoA ester Other intermediates that yield acylcarnitines are ketone bodies [COH-carnitine 33 ], degradation products of lysine, tryptophan, valine, leucine, and isoleucine C3- and C5-carnitine and others , and carbon atoms from glucose acetylcarnitine The standard acylcarnitine analysis using tandem MS cannot discriminate between stereoisomers and other isobaric compounds, which have the same nominal mass but a different molecular structure.

These compounds can be separated using liquid chromatography-tandem MS This is illustrated by C4-OH-carnitine, which can be derived from the CoA ester of the ketone body Dhydroxybutyrate, D-C4-OH-carnitine , the FAO intermediate Lhydroxybutyryl-CoA L-C4-OH-carnitine , and Lhydroxyisobutyryl-CoA, an intermediate in the degradation of valine L-isoC4-OH-carnitine The fact that acylcarnitines can be measured in plasma illustrates that they are transported across cell membranes.

Two transporters have been implicated in the export of acylcarnitines. In addition to import, OCTN2 can export acyl carnitines Also, the monocarboxylate transporter 9 SLC16A9 may play a role in carnitine efflux Although these putative transporters have been identified, the exact nature of this transport is unknown, but seems largely dependent on the intracellular acylcarnitine concentration Early studies in rodent heart, liver, and brain mitochondria proved mitochondrial efflux of acylcarnitines and suggested this to be dependent on the substrate and tissue as well as the availability of alternative acyl-CoA—utilizing reactions In humans, acylcarnitine efflux is exceptionally well-evidenced by the acylcarnitine profiles of patients with an FAO defect From a more physiological view, diets and fasting modulate the plasma acylcarnitine profile, which reflects changes in flux through the FAO pathway 13 , 16 , 38 , However, exact rates of acylcarnitine production in relation to the FAO flux under different conditions remain to be determined.

It is expected that muscle or liver contribute largely to acylcarnitine turnover. Early studies showed that liver acylcarnitines correlated with plasma acylcarnitines in fasted macaques, but the individual chain lengths were not studied A liver—plasma relation is plausible, considering that the liver accounts for most of the FAO activity during fasting.

Human data are lacking, but muscle acylcarnitines did not correlate with plasma acylcarnitines during short-term fasting The physiological role of acylcarnitine efflux to the plasma compartment is unknown, but several scenarios are likely. Acylcarnitine formation prevents CoA trapping, allowing continuation of CoA-dependent metabolic processes 21 , In addition to plasma, acylcarnitines are found also in bile and urine 42 , 43 , suggesting that acylcarnitine efflux may serve as a detoxification process.

Moreover, intestinal reuptake of bile acylcarnitines is possible. Questions that remain are the contribution of specific tissues and organs to plasma acylcarnitine levels and the turnover rates of the individual acylcarnitine species in plasma.

FAO may be quantitatively and qualitatively different in insulin-resistant subjects compared with healthy subjects, but a more pertinent conundrum is if increased FAO is either capable to limit insulin resistance via decreasing lipid accumulation or increasing insulin resistance via accumulation of incomplete FAO products such as acylcarnitines 1 — 3 , 13 , Several theories describe mechanisms within the cytosol that can cause insulin resistance Fig.

It has generally been accepted that chronic overnutrition leads to increased cytosolic lipid content of insulin-responsive tissues such as liver and skeletal muscle. This negatively affects the insulin sensitivity of these tissues by inhibiting insulin signaling via intermediates as ceramide, diacylglycerol, gangliosides, and possible other long-chain FA-derived metabolites 1 , 3 , 5 — 8 , Although contested now, cytosolic lipid accumulation was also suggested to arise from mitochondrial dysfunction and, as a consequence, decreased FAO rate 2 , 9 , 14 , 45 , Likewise, increased levels of malonyl-CoA were suggested to limit the mitochondrial entrance of long-chain FAs by blocking CPT1, thus resulting in accumulating cytosolic long-chain FAs and decreasing FAO rate Mechanisms of lipid-induced insulin resistance.

After transportation into the cell, FA can be stored, oxidized, or used as building blocks and signaling molecules not all shown. Excess lipid supply and subsequent accumulation in insulin-sensitive tissues such as skeletal muscle is proposed to interfere with different insulin-responsive metabolic pathways via various mechanisms.

Firstly 1 , increased intracellular lipid content inhibits insulin signaling via lipid intermediates such as ceramides, diacylglycerol DAG , or gangliosides GM3 via effects on protein phosphatase A 2 PPA2 and protein kinase B Akt , protein kinase C PKC , or effects on the insulin receptor in the cell membrane 1 , 3 , 5 — 8 , Effects of lipid intermediates on inhibitors of nuclear factor-κβ NFκB kinase subunit β and c-Jun N-terminal kinase 1 are not depicted.

The second mechanism 2 is a decreased number of functional mitochondria resulting in lower FAO rates and increased accumulation of cytosolic lipid, again interfering with insulin sensitivity 2 , 9. Finally 3 , metabolic overload of mitochondria leads to incomplete β-oxidation.

In this figure, oxidation of FA outpaces the TCA and respiratory chain RC , resulting in intramitochondrial accumulation of FAO intermediates like acylcarnitines. These subsequently impinge on insulin signaling 1 , 48 , 50 — In this figure, only the direct effects of acylcarnitines on nuclear factor-κβ have been proposed Alternatively, more recent mechanistic 13 , 47 , 48 and metabolomic 49 — 54 studies associated obesity-induced insulin resistance with intramitochondrial disturbances.

In this model, lipid overload leads to increased rather than decreased FAO in skeletal muscle. This coincides with accumulating acylcarnitines, an inability to switch to carbohydrate substrate, and a depletion of TCA intermediates, suggesting that FAO flux does not match TCA flux, leading to incomplete FAO 13 , 47 , In vitro interfering with FA uptake in L6 myocytes or a coordinate induction of FAO and TCA enzymes by exercise or PPARγ coactivator 1α overexpression prevented insulin resistance 13 , Moreover, using carnitine to stimulate FAO without affecting the TCA in these myocytes was dose-dependently associated with insulin resistance Zucker Diabetic Fatty rats, a model for more severe insulin resistance, had higher acylcarnitines but lower TCA intermediates such as citrate, malate, and succinate in skeletal muscle, again suggesting that increased FAO induces insulin resistance when not followed by proportionally increased TCA activity The available studies on acylcarnitine metabolism and the relationship with insulin resistance will be discussed in the next sections with a focus on human studies.

Interestingly, carnitine infusions increased FAO in lean healthy subjects, but only when high-dose insulin was coadministered 57 , 58 , which may be explained by an increased muscle OCTN2 expression under these conditions The importance of insulin for cellular carnitine uptake is underscored by the finding that insulin and carnitine administration lowered muscle malonyl-CoA and lactate concentrations, whereas muscle glycogen increased These findings are supported by animal studies, which demonstrated that carnitine levels were diminished in skeletal muscle of multiple insulin-resistant rat models.

A high-fat diet HFD exacerbated the age-related decrease of tissue carnitine content in these rats primarily skeletal muscle, liver, and kidney Moreover, carnitine supplementation of HFD animals decreased plasma glucose levels and homeostasis model assessment indices 60 , Likewise, carnitine supplementation improved insulin-stimulated glucose disposal in mouse models of diet-induced obesity and genetic diabetes Recently, it was shown that 6 months of carnitine supplementation improved glucose homeostasis in insulin-resistant humans Although supplementation of carnitine possibly augments FAO and insulin sensitivity, the lower carnitine levels in diabetes patients are unexplained.

On the one hand, carnitine uptake is insulin-dependent and therefore the absence of or resistance to insulin may be the cause of lower carnitine levels. On the other hand, higher lipid load may lead to higher acylcarnitine concentrations and thus lower free carnitine. In addition, several studies reported on the carnitine shuttle and its effects on the rate of FAO in the development of insulin resistance.

Obese subjects had lower CPT1 and citrate synthase content in muscle and lower FAO, suggesting that lesions at CPT1 and post-CPT1 events i. Although short-term inhibition of CPT1 with etomoxir in humans did not impede insulin sensitivity despite increased intramyocellular lipid accumulation 64 , prolonged inhibition in rats resulted in the accumulation of intramyocellular lipid and increased insulin resistance while doubling adiposity despite feeding a low-fat diet These results all led to the assumption that low FAO rates due to decreased function of CPT1 were associated with insulin resistance, possibly caused by an accumulation of intramyocellular lipid intermediates and their interference with insulin signaling.

Indeed, CPT1 activity increased after an endurance training program in obese subjects, coinciding with increased FAO, improved glucose tolerance, and insulin sensitivity However, this may also be explained by the stimulatory effect of endurance training on mitochondrial function i.

In contrast to the model in which excess FAO induces insulin resistance, these data suggest that decreasing mitochondrial FA uptake results in elevated intramuscular lipid levels and subsequent insulin resistance. However, increasing FAO by carnitine treatment in animals and humans permits mitochondrial FA uptake and oxidation that benefits insulin sensitivity.

These observations will have to be reconciled with other studies that implicated incomplete FAO and acylcarnitine accumulation in the pathogenesis of insulin resistance. Older work reported elevated acylcarnitine levels in obese insulin-resistant subjects 15 , but acylcarnitines were not suggested to be implicated in insulin resistance at that time.

The shortest acylcarnitine, acetylcarnitine, is of particular interest because it may illustrate the controlling role of acetyl-CoA on substrate switching and thus metabolic flexibility. The mitochondrial enzyme carnitine acetyl-CoA transferase CrAT converts acetyl-CoA to the membrane-permeable acetylcarnitine and permits mitochondrial efflux of excess acetyl-CoA that otherwise could inhibit pyruvate dehydrogenase Infusing intralipid decreased insulin sensitivity while increasing muscle acetylcarnitine The same was true for plasma and muscle acetylcarnitine levels under high FAO conditions starving , suggesting upregulation of CrAT to traffic acetyl-moieties In contrast to lower CrAT expression in diabetic subjects 68 , plasma acetylcarnitine levels showed significant positive correlation with HbA 1c levels over a wide range of insulin sensitivity, suggesting upregulation of CrAT in insulin-resistant states There is some complexity, as both lipid and glucose oxidation funnel into acetylcarnitine as supported by different findings 68 , First, the insulin-mediated suppression of muscle acetylcarnitine occurred under high FAO conditions, but not postabsorptively i.

Also, muscle acetylcarnitine correlated negatively with FAO in the postabsorptive state 71 , whereas plasma acetylcarnitine correlated with plasma glucose levels in the postprandial state In light of these data, the question is interesting if CrAT really favors FA-derived acetyl-CoA over glucose-derived acetyl-CoA because this might imply intracellular compartmentalization of acetyl-CoA Moreover, glucose-derived acetyl-CoA can be carboxylated by ACC, producing the CPT1 inhibitor malonyl-CoA.

Direct effects of FAO-derived acetyl-CoA on insulin action are unknown. C4-OH-carnitine i. In fasted humans, plasma and muscle C4-OH-carnitine increased The increase in C4-OH-carnitine in these animal and human studies is quantitatively much more pronounced then the increase in acetylcarnitine; thus, C4-OH-carnitine production may exert greater demands on cellular carnitine stores.

Moreover, ketone bodies yield acetyl-CoA, which stimulates PDK4 and thus inhibits glucose oxidation In summary, under conditions characterized by higher FAO, elevated short-chain acylcarnitines may reflect higher lipid fluxes, but a direct relation to insulin resistance remains to be established.

Metabolomics showed that branched-chain and aromatic amino acids isoleucine, leucine, valine, tyrosine, and phenylalanine 74 significantly correlated with present or future diabetes 54 , 74 , In line with this, the branched-chain amino acid—derived C3- and C5-carnitine, together with FA-derived C6- and C8-carnitine, were higher in obese and DM2 subjects compared with lean controls 17 , In the same study, C4-dicarboxylcarnitine C4DC-carnitine , also derived from branched-chain amino acid metabolism, showed a positive correlation with basal glucose levels and HbA 1c In comparison with obese non—insulin-resistant subjects, DM2 subjects also had higher C3- and C5-carnitine levels compared with controls during insulin administration.

In this study, C3- but not C5-carnitine correlated negatively with glucose disposal At first glance, correlations of acylcarnitines to surrogate markers of insulin resistance fit with mitochondrial overload and incomplete FAO. Acylcarnitines, however, also directly reflect the oxidation rate of FA and amino acids, which is supported by human nutritional intervention studies 16 , 33 , 38 , The uncertainty regarding the direct interference of short-chain acylcarnitines and their metabolism with insulin-signaling processes and insulin sensitivity warrants care when attributing a primary role for amino acid—derived acylcarnitines in the induction of insulin resistance.

Long-chain FA such as palmitic acid were associated with insulin resistance, making a role for long-chain acylcarnitines such as C16 in insulin resistance conceivable 3 , In , Hoppel et al. The hypothesis that obesity-induced alteration in the acylcarnitine profile are caused by incomplete FAO was based largely on two animal studies by the same group showing that long-chain acylcarnitine species C16, C, C, and C18 were persistently increased in diet-induced obese rats, in both the fed and fasted state 13 , As reported for humans, most acylcarnitine species decreased upon refeeding in the chow-fed control group, but not in the obese animals, suggesting they were incapable of adjusting their metabolism in response to refeeding.

Although excessive and incomplete FAO can be responsible for insulin resistance, it can be argued that FAO probably must be in relative excess to oxidation in TCA and respiratory chain in order to guarantee continuous energy supply.

Obese and insulin-resistant humans had higher plasma long-chain acylcarnitine levels compared with lean controls Upon insulin infusion, long-chain acylcarnitines decreased overall, but to a lesser degree in the diabetic subjects.

This was in agreement with lower resting energy expenditure, indicating ongoing FAO or lipid flux metabolic inflexibility Moderate correlations between acylcarnitine profiles and various clinical characteristics i. The DM2 subjects were unable to suppress acylcarnitines during insulin infusion in contrast to matched obese controls; therefore, elevated long-chain acylcarnitines in the diabetic group likely reflect increased lipid flux and illustrate the tight connection of acylcarnitines with FAO flux Postprandially, plasma long-chain acylcarnitines did decrease in obese insulin-resistant subjects, but the magnitude of this decrease correlated with both premeal insulin-mediated glucose disposal rates and FAO and has been largely explained by nadir levels of C, C14, and Ccarnitine This showed that the more insulin-sensitive subjects are, the more capable they are at metabolizing FAs.

Metabolomics in healthy, overweight, calorie-restricted subjects yielded comparable results; in this study, acylcarnitines correlated significantly with plasma insulin and free FA levels, albeit with low correlation coefficient All in all, acylcarnitines with longer chain lengths are associated with insulin resistance, which seems logic in the light of known effects of long-chain FAs on insulin signaling.

Indeed, acylcarnitines can reside in cell membranes because they are amphipathic molecules. Increasing chain length favors partitioning into the membrane phase e. It is interesting to speculate that long-chain acylcarnitines can interfere with insulin signaling directly within the cell membrane 3.

In contrast, acylcarnitines seem to track with higher lipid flux and as such may only indicate higher FAO. The concept of lipotoxicity is generally accepted in the field of obesity-induced impairment of insulin sensitivity, and more and more attention has attributed to intramitochondrial alterations and impairments in FAO, thereby focusing on acylcarnitines 1.

Collected evidence shows that acylcarnitines have distinct functions in mitochondrial lipid metabolism. The transmembrane export of acylcarnitines suggests that they not only prevent the accumulation of noxious acyl-CoAs, but also reduce CoA trapping, which is crucial for many metabolic pathways 21 , Additionally, the metabolism of short-chain acylcarnitines and the interaction of acetyl-CoA and acetylcarnitine via CrAT may regulate the pyruvate dehydrogenase complex, thereby affecting glucose oxidation Besides mitochondrial need to liberate CoA and export acetyl-CoA, acylcarnitines may simply reflect the FAO flux.

The concept of increased, though incomplete, FAO by disproportional regulation of FAO, TCA, and respiratory chain is attractive to explain insulin resistance. However, there remains doubt about this mechanism, and there is no proof that acylcarnitines play a role in the induction of insulin resistance itself.

Acylcarnitines are present under physiological conditions, and their levels vary according to dietary circumstances 13 , 16 , 38 , The acylcarnitine fluxes are unknown but probably much lower than FAO flux. Moreover, it can be argued that flux of FAO probably will be in relative excess to downstream oxidation in TCA and respiratory chain to guarantee continuous substrate supply and allow fine tuning and anticipation for metabolic changes e.

L-carnitine and insulin sensitivity González-OrtizSandra O. InxulinL-carnitine and insulin sensitivity Hernández-SalazarEsperanza Martínez-Abundis; Effect of Sensitkvity L -Carnitine Administration on Insulin Sensitivity Vegan-friendly skincare Lipid Profile ssensitivity Type 2 Insuli Mellitus Patients. Ann Nutr Metab 1 September ; 52 4 : — Aim: It was the aim of this study to evaluate the effect of oral L -carnitine administration on insulin sensitivity and lipid profile in subjects with type 2 diabetes mellitus. Subjects and Methods: A randomized, double-blind, placebo-controlled clinical trial was carried out in 12 subjects with type 2 diabetes. Six subjects received L -carnitine 1 g orally 3 times a day before meals for a period of 4 weeks.

L-carnitine and insulin sensitivity -

Effect of Oral L -Carnitine Administration on Insulin Sensitivity and Lipid Profile in Type 2 Diabetes Mellitus Patients Subject Area: Endocrinology , Further Areas , Nutrition and Dietetics , Public Health.

Manuel González-Ortiz ; Manuel González-Ortiz. Medical Research Unit in Clinical Epidemiology, Specialties Hospital, Medical Unit of High Specialty, West National Medical Center, Mexican Institute of Social Security, and Cardiovascular Research Unit, Physiology Department, Health Science University Center, University of Guadalajara, Guadalajara, Mexico.

This Site. Google Scholar. Sandra O. Hernández-González ; Sandra O. Eduardo Hernández-Salazar ; Eduardo Hernández-Salazar. Esperanza Martínez-Abundis Esperanza Martínez-Abundis. Ann Nutr Metab 52 4 : — Article history Received:.

Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Abstract Aim: It was the aim of this study to evaluate the effect of oral L -carnitine administration on insulin sensitivity and lipid profile in subjects with type 2 diabetes mellitus. You do not currently have access to this content.

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Digital Version Pay-Per-View Access. BUY THIS Article. All subjects gave written informed consent after the protocol was fully explained. Participants who intended to donate blood during the study period or participants who have donated blood less than three months before the start of the study were not included to minimize the risk of anaemia due to repetitive blood sampling in this study.

Participants were not included in case they did not wanted their treating physician to be informed about participation in the study. Furthermore, if participants did not want to be informed about unexpected medical findings participation in the study was not possible.

Finally, vegetarians were not included because of the altered whole body carnitine status. The study was set up as a single blind, placebo-controlled randomized cross-over design.

The study was conducted at Maastricht University Medical Center, The Netherlands, between December and June Participants were instructed to maintain their usual physical activity patterns and to not change dietary behavior while participating in the study.

During visit 1, participants came in the morning after an overnight fast. Body composition fat percentage and fat free mass was determined. Subsequently, maximal oxygen uptake VO 2max and maximal power output were determined during an incremental cycling test on a stationary bike to determine training status.

On each of the following visits visit 2, 3 and 4 , participants came in at h after an overnight fast. On each of these visits visit 2, 3 and 4 , a hyperinsulinemic euglycemic clamp was performed to assess peripheral insulin sensitivity. Two hyperinsulinemic euglycemic clamps were performed with simultaneous infusion of lipids.

The sequence of these different hyperinsulinemic-euglycemic clamp conditions was randomly assigned. Participants were blinded for treatment. The half-life of release of carnitine from skeletal muscle is hours, therefore a wash-out period of at least two weeks was used to prevent carry over effects of the L-carnitine and lipid infusion.

Primary outcome was the effect of additional L-carnitine in combination with lipid infusion on insulin sensitivity and metabolic flexibility compared to only lipid infusion.

Secondary outcome measures were plasma and skeletal muscle acylcarnitine profiles. During the first visit, participants came in after an overnight fast. Thoracic gas volume was predicted based on equations included in the software.

From these data, body composition fat mass, fat free mass and fat percentage was calculated as described by Siri [ 25 ]. Directly after the body composition determination during the first visit, all participants performed a routine incremental exhaustive cycling test on a stationary bike to determine maximal oxygen uptake VO 2 max and maximal power output W max as reported previously [ 26 ] for characterization of the participants and to confirm that the participants were not exercise-trained.

Briefly, after a five-minute warming-up period, the workload was increased every 2. Oxygen uptake was measured continuously throughout the test using indirect calorimetry Omnical, Maastricht, The Netherlands. At visit 2, 3 and 4, insulin sensitivity was assessed during a 6-hour hyperinsulinemic-euglycemic clamp.

Participants refrained from strenuous exercise three days preceding the clamp and monitored their food intake in a food diary. A standardized carbohydrate rich meal was consumed by all participants the evening prior to the clamp.

At the day of the clamp, participants reported to university at h after an overnight fast from h onwards. Next to the infusion of insulin and glucose, infusion of Intralipid or saline and L-carnitine or saline were started. Intralipid consisted of pure soya-oil including linoleic acid, linolenic acid, oleic acid, palmitic acid and stearic acid.

All included lipids are long chain triglycerides LCT. On the day of the hyperinsulinemic-euglycemic clamp visit 2, 3 and 4 , skeletal muscle biopsies were taken upon 6 hours of insulin stimulation.

In the control arm, an additional muscle biopsy was taken in the morning after an overnight fast. Muscle biopsies were taken from the m.

Muscle tissue was immediately frozen in melting isopentane and stored at —80°C until further processing. Skeletal muscle acylcarnitine species were determined using mass spectrometry as described previously [ 29 ]. Total short-chain acylcarnitine species included the sum of C3 until C5 carnitine species.

C6 until C12 acylcarnitine species were defined as medium-chain acylcarnitine species. Long-chain acylcarnitine species represented C14 until Cacylcarnitine species. During the hyperinsulinemic-euglycemic clamp, the hand was heated in a hot box 55°C to allow arterialized venous blood sampling from the hand vein.

The arterialized venous blood samples were immediately centrifuged and plasma was frozen in liquid nitrogen and stored at °C until analyzed. The sample size was calculated based on the results from previous carnitine infusion studies reporting clinically significant improvements in insulin sensitivity after carnitine infusion of 0.

The intraindividual variation SD of the difference in insulin sensitivity in repeated measurements is reported to be 0. An interim-analysis was performed after eight participants completed the entire study with all three intervention arms 17 participants were recruited for screening by then , revealing no effect of the carnitine treatment.

Therefore, the study was terminated prematurely after eight participants. The statistical analysis was performed using SPSS All results are presented as mean ± SEM.

A one-way ANOVA was carried out to investigate differences in insulin sensitivity M-value , metabolic flexibility ΔRER and skeletal muscle acylcarnitine species between study arms.

A two-way ANOVA for repeated measures was performed to test differences in GIR, oxidation rates and plasma acylcarnitines. In case of a significant F-value, Bonferroni post-hoc analysis were performed.

No drop-outs were reported. All participants had a sedentary life style not engaged in regular physical activity. Their maximal oxygen uptake VO 2 max Participant enrollment and allocation are presented in Fig 1 whereas characteristics are presented in Table 1.

Diagram of the progress through the phases of this randomized, controlled crossover study with young lean male participants. At baseline, plasma FFA levels were comparable between study arms ±47 vs. As a result, peripheral insulin sensitivity, expressed as the M-value, was blunted during the lipid infusion compared to the control condition Basal glucose oxidation were comparable between study arms but glucose oxidation upon 6 hours of insulin infusion was increased in the control condition from 5.

However, glucose oxidation remained low during the infusion of lipid from 6. In line with these findings, lipid oxidation was comparable between study arms at baseline but was elevated after 6-hours of lipid infusion and suppressed in the control arm 1. Metabolic flexibility, expressed as ΔRER clamp-basal , was decreased upon lipid infusion compared to control 0.

L-carnitine did not change the lipid-induced decrease in metabolic flexibility 0. Plasma free carnitine levels were similar at baseline Data are expressed as means ± SEM. Note: in A the lines of the control and lipid conditions are overlapping. C2 concentrations decreased in the CON trial over time from 5.

With lipid infusion, C2 concentrations decreased during the first hour 5. Infusion of L-carnitine in addition to lipids prevented the decrease in C2 concentrations after one hour resulting in significantly higher C2 levels compared to CON and LIPID. Plasma medium and long-chain acylcarnitines were not different between groups in the basal state after an overnight fast.

Because of Bonferroni correction for multiple testing, p-values of 0. Dark grey bars represent the pre-clamp muscle biopsy. In the present study, we aimed to investigate whether free carnitine availability could alleviate lipid-induced insulin resistance.

We hypothesized that intravenous infusion of L-carnitine would increase the availability of free carnitine in skeletal muscle, which could prevent the development of lipid-induced insulin resistance and metabolic inflexibility during acute lipid infusion.

These values exceed normal reference values This level of plasma hypercarnitinemia is comparable to earlier studies that also used L-carnitine infusions of similar dosage to reach hypercarnitinemia in the plasma [ 21 , 35 ].

Although plasma hypercarnitinemia occurred, no differences in skeletal muscle free carnitine concentration were found upon L-carnitine infusion.

This is surprising, as the infusion of insulin has been shown to stimulate uptake of carnitine and combinations of carnitine and insulin have been shown to increase carnitine content in muscle [ 36 ].

It is yet unclear why carnitine concentrations did not increase in muscle tissue. However, this remains speculation and future studies will have to investigate potential mechanisms. Unfortunately, we did not perform a clamp with intravenous infusion of L-carnitine, without additional lipid infusion.

The latter could have revealed whether lipid infusion indeed hampered carnitine uptake versus insulin infusion alone. Furthermore, the participants of the current study were young and healthy and it is expected that their carnitine availability in muscle was already high to start with.

It is conceivable that therefore an increase in muscle carnitine concentration upon infusion is less likely, although this requires further study. The increase in lipid availability as a result of lipid infusion lead to strongly elevated plasma free fatty acid levels, as reported before [ 3 , 34 ].

It was previously reported that due to this rise in FFA levels, glucose infusion rates GIR , insulin sensitivity and metabolic flexibility decreases after 2—4 hours of lipid infusion [ 3 , 4 , 34 , 46 — 48 ]. Furthermore, carbohydrate oxidation was reduced and lipid oxidation increased in the insulin-stimulated state, reflecting a blunted metabolic flexibility upon insulin stimulation.

However, these changes were similar in the conditions with or without infusion of L-carnitine. As carnitine needs to be taken up in the muscle to exert an effect on insulin sensitivity according to our hypothesis, it is not be surprising that insulin sensitivity was not affected in the present study.

In contrast to our findings, beneficial effects of L-carnitine infusion has been reported previously in overweight patients with type 2 diabetes.

Furthermore, Mingrone et al. However, in these studies, skeletal muscle free carnitine availability is not reported. It should be noted that in these studies, no lipid infusion was used and therefore, no lipid-induced insulin resistance occurred and the uptake of carnitine may have been more efficiently stimulated by insulin.

Whether improved skeletal muscle free carnitine availability indeed underlies the beneficial metabolic effects that were reported previously, remains to be shown.

In the current study, plasma acetylcarnitine concentrations were reduced upon insulin stimulation in the control trial. Next to acetylcarnitine levels, reduced short-, medium- and long-chain acylcarnitine levels have been reported in situations of hyperinsulinemia.

We here confirmed this reduction in short-, medium- and long-chain acylcarnitines levels upon insulin infusion. These decreases in acylcarnitine species are likely to reflect a decreased lipid oxidation caused by hyperinsulinemia, as previously reported [ 49 , 50 ].

Indeed, decreased lipid oxidation and increased glucose oxidation were observed upon hyperinsulinemia in the control trial. Lipid infusion increased plasma acetylcarnitine, medium- and long-chain acylcarnitines, probably reflecting increased efflux of β-oxidation intermediates by tissues such as liver and muscle [ 51 , 52 ].

The main contributor to the plasma acetylcarnitine elevations might be increased production by β-oxidation and subsequently release of acetylcarnitine by the liver, as indicated by earlier studies using a porcine animal model or human volunteers to assess trans-organ acylcarnitine fluxes [ 52 , 53 ].

Plasma C3 acylcarnitines and the sum of plasma short-chain acylcarnitines C3 to C5 did not change upon lipid infusion, contrary to the other acylcarnitine species.

Since C3 is mainly derived from branched-chain amino acids, this might explain the different kinetics. As plasma acylcarnitine concentrations are significantly higher upon carnitine infusion, these data indicate the necessity of free carnitine availability in the formation of acylcarnitine species suggests that carnitine infusion can further stimulate the efflux of β-oxidation intermediates from the liver.

Surprisingly, skeletal muscle acetylcarnitine concentrations remained unaffected by lipid infusion as well as lipid combined with L-carnitine infusion.

Contrary, Tsintzas et al. Although we cannot provide a direct explanation for this discrepancy, the more than two-fold higher plasma FFA concentration in the study of Tsintzas might be of relevance.

Future research is necessary to unravel what is underlying this difference. Furthermore, skeletal muscle short-chain acylcarnitine C3-C5 levels decreased upon insulin infusion in the control trial.

Medium- and long-chain acylcarnitine seemed to decrease as well, although not reaching significance. Insulin reduces lipolysis resulting in decreased plasma FFA availability, and as a consequence, glucose oxidation increases. The decrease in skeletal muscle acylcarnitine species upon insulin therefore probably reflects this decreased FFA availability resulting in a transition of lipid towards glucose oxidation induced by hyperinsulinemia [ 49 , 50 ].

Lipid infusion increased plasma FFA concentrations despite high insulin concentration. Therefore, the decrease in short- and medium-chain acylcarnitines in skeletal muscle tissue as found in the control trial upon insulin was blunted upon the combination of lipid and insulin infusion, which may indicate higher skeletal muscle lipid oxidation rates upon the elevation of plasma lipids by lipid infusion.

Remarkably, this effect was only seen on the short and medium chain acylcarnitine species and not on the long chain species: lipid infusion did not blunt the insulin-induced reduction in long-chain acylcarnitine species. Although we cannot provide a direct explanation for this effect, it could be speculated that during acute lipid overload, accumulation of β-oxidation intermediates does mainly happen at later passages through the β-oxidation.

A study limitation is the low number of participants in the current study. According to our sample size calculation, 13 participants needed to perform the entire study. Upon eight finalized participants, an interim analysis was performed.

No treatment effect was observed in the study group as a whole, as well as in the two strata on short- and long-term statin therapy considered separately. The pathogenesis of arterial hypertension in T2D is multifactorial and involves the renin—angiotensin—aldosterone and endothelin-1 systems, increased oxidative stress, and inflammatory processes.

Among these pathogenetic mechanisms, impaired insulin sensitivity appeared to play a pivotal role [ 30 ]. Owing to this complexity, reduction of SBP to the normal range is seldom achievable in diabetic patients despite multidrug therapy. Previous studies in patients with diabetes demonstrated that intravenous l -carnitine administration could improve insulin sensitivity [ 12 , 13 ].

Our pilot study also found that 2 g per day of oral ALC improved insulin sensitivity in patients with higher insulin resistance and effectively decreased SBP in all nondiabetic hypertensive participants with a high cardiovascular risk profile [ 14 ].

However, the results from the current trial challenge the findings of these studies. The dose of ALC was identical to that of the pilot study and other trials reporting benefits of oral l -carnitine in different clinical settings [ 17—21 , 23 ].

First, our study population consisted of patients with T2D on hypoglycemic treatment compared with patients without diabetes in the pilot study. Despite that, GDR in the present trial was slightly higher than in the pilot study and was within the range 3.

Thus, the severity of insulin resistance is an unlikely explanation for treatment failure in our present study. Second, patients with diabetes were older mean age, Finally, recruited patients had lower SBP values as compared with those initially assumed for sample size estimation, which might have reduced the statistical power of the analyses.

Another crucial difference concerned statin use: all patients in the current study received simvastatin whereas only one subject was on statin in the pilot study. Statin therapy is known to potentiate the effect of antihypertensive drugs [ 32 , 33 ] through vasodilation, which is due to increased nitric oxide synthase activity [ 34 ], downregulation of angiotensin II-type 1 receptors [ 35 ], and endothelin-1 production [ 36 ].

Thus, pretreatment with simvastatin might have prevented any possible additional beneficial antihypertensive effect of ALC. Additionally, simvastatin has been shown to increase HbA 1c levels and to worsen insulin sensitivity [ 37 , 38 ]. Actually, we observed a significant increase in HbA 1c after 6 months in both ALC and placebo groups, which was particularly evident in the short-term simvastatin stratum.

This confirms that initial treatment with simvastatin may worsen HbA 1c , and that ALC cannot counteract this detrimental effect. We could not detect the same effect in patients on long-term statins, because HbA 1c values in both ALC and placebo groups were virtually identical throughout the study.

However, even in these patients, ALC failed to improve the glycemic profile. Despite finding no change in the GDR, we could observe some signs of improvement in insulin sensitivity with a significant decrease of HOMA-IR in both ALC and placebo groups at 6 months.

In the short-term simvastatin stratum, ALC reduced HOMA-IR along with a significant decrease in insulin concentration, suggesting a possible initial metabolic effect of the study drug.

However, the difference between groups was not significant, and this effect was not observed in the group of patients on ALC in the long-term statin stratum, implying that long-term statin therapy might have negated any beneficial effect of ALC on insulin sensitivity.

To avoid any potential confounding effect of the duration of statin therapy on study findings, we a priori stratified patients according to previous statin therapy YES or NO. Moreover, we found no relationship between duration of statin therapy and treatment effect data not shown.

Thus, whether previous treatment with rosuvastatin might have contributed to mask the metabolic effects of ALC cannot be definitely excluded. The tentative lipid-lowering action of l -carnitine and ALC has been linked to increased fatty acid β -oxidation and reduced oxidative stress due to mitochondrial dysfunction improvement [ 7 , 9 ].

Although the results from some small trials exploring the effect of the combined therapy with l -carnitine and simvastatin on lipid profile in T2D were encouraging [ 21—23 ], our results suggest that the effects of ALC on lipid profile parameters are limited when the drug is used as an add-on statin therapy.

Of note, no adverse event could be directly attributed to the study drug. The prospective, randomized, placebo-controlled design of the trial together with the gold standard methods used for insulin sensitivity and GFR measurements in a subgroup of patients are the major strength of our study.

We also formally tested the effect of ALC on top of standardized simvastatin therapy to prevent the confounding effect on metabolic profile of the eventual previous YES or NO statin therapy.

Finding that body weight and body mass index BMI were comparable at baseline and remained unchanged in different groups and strata during the study reasonably excludes the possibility that study results were confounded by systematic changes in diet and physical activity introduced during the trial.

We intentionally did not standardize BP-lowering therapy during the run-in, because we wanted to test the BP lowering effect of ALC in a context that reflects real life. Thus, the distribution of different BP-lowering medications and of their different combinations in our study population reflected the distribution in the average population of patients referred to a diabetology unit.

This enhanced the generalizability of the study findings. Alternatively, finding that the proportion of patients using antihypertensive medications and the distribution of different antihypertensive agents and of their different combinations were comparable between groups can be taken to suggest that data were very unlikely confounded by concomitant BP-lowering therapy, even if it was not standardized.

Although concomitant medication changes were not recommended throughout the study period, adjustments in antihypertensive and antidiabetic treatments were conceded in selected cases to avoid acute clinical complications during the trial. However, the adherence pattern to chronic treatments was stable and the differences in antihypertensive and antidiabetic medication changes during the study period between treatment groups and strata were not statistically significant.

A potential limitation of this study was the unavailability of baseline and follow-up measurements of plasma carnitine levels.

However, it is well known that plasma carnitine is low in patients with T2D, especially in the presence of dyslipidemia or microvascular complications [ 39 ].

This evidence strengthens the rationale of ALC use in this cohort. Alternatively, we wanted to test the possible BP-lowering effect of ALC above and beyond that of available medications in everyday clinical practice, a context in which serum carnitine level is a parameter that cannot be considered routinely for selection of potential candidates for treatment.

In the case of encouraging findings, the role of serum carnitine as a tool to identify patients who may benefit the most from ALC therapy could have been evaluated in further studies. Oral ALC does not improve either SBP control or the lipid and glycemic profile in diabetic hypertensive patients on stable statin therapy.

We hypothesized that the possible hypotensive and hypolipidemic effect of ALC is blunted by statin use. It is worth exploring this objective in patients with and without diabetes and with hypertension who do not require treatment with statins.

DIABASI Study Organization: Members of the DIABASI Study Organization were as follows: Principal Investigator—N. Ruggenenti, G. Perico, S. Rota, B. Ruggiero, A. Panozo, M. Abbate, B. Pahari, K. Courville, S.

Prandini, V. Lecchi, G. Trevisan, A. Corsi, A. Dodesini, R. Rota, C. Aparicio UO Malattie Endrocrine e Diabetologia—ASST Papa Giovanni XXIII, Bergamo, Italy ; A. Bossi, A. Parvanova, I. Iliev, S. Yakymchuk [UOC Malattie Endocrine e Centro Regionale per il Diabete Mellito—ASST Bergamo Ovest—Ospedale Treviglio-Caravaggio, Treviglio Bergamo , Italy]; A.

Bossi, I. Petrov Iliev, A. Parvanova, V. Lecchi [UOC Malattie Endocrine e Centro Regionale per il Diabete Mellito—ASST Bergamo Ovest—Ospedale SS. Trinità, Romano di Lombardia, Bergamo , Italy]; A. Belviso, M. Trillini, S. Yakymchuk [ASST Bergamo Ovest—Poliambulatorio Extra Ospedaliero Brembate Sopra, Bergamo , Italy]; Monitoring and Drug Distribution—N.

Rubis, W. Calini, O. Carminati, D. Perna, G. Giuliano, I. Foiadelli, G. Gaspari, F. Carrara, S. Ferrari, N. Stucchi, A. Boccardo, S. Scientific Writing Academy —Tutor: David G. Warnock, MD, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Participants: Matias Trillini, MD, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy; Aneliya Parvanova, MD, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy; Sreejith Parameswaran, MD, Jawaharlal Institute of Postgraduate Medical Education and Research, India; Jonathan S.

Note: The Scientific Writing Academy is a project sponsored by IRCCS - Istituto di Ricerche Farmacologiche Mario Negri Bergamo, Italy and endorsed by the International Society of Nephrology that aims to teach the tools necessary to succeed in publishing scientific papers in international journals to researchers and physicians from around the world.

Stefano Rota and Barbara Ruggiero helped in patient screening, inclusion, and monitoring. We thank Olimpia Diadei and Wally Calini for valuable work in monitoring the study, and the staff of the Clinical Research Center and Diabetology Units for contribution to patient care and conducting the study.

We are also indebted to Andrea Panozo, Bishnu Pahari, Karen Courville, Patricia Espindola, Silvia Prandini, Veruscka Lecchi, and Svitlana Yakymchuk for care of the study participants.

A Pomezia, Rome, Italy , including the costs of the study and freely supplying the study medication ALC or placebo capsules.

The funding source had no role in study design, data collection, analysis and interpretation, writing of the report, and decision to submit the article for publication.

gov NCT registered 31 January and ClinicalTrialsRegister. eu EUDRACT registered 23 September and G. had the original idea, wrote the main protocol, coordinated the study centers, and critically revised the manuscript.

Parvanova, M. contributed to patient selection, monitoring, and care. Perna and F. conducted the statistical analysis. monitored the study. were responsible for the execution and interpretation of centralized laboratory measurements. with the Scientific Writing Academy attendants interpreted the data and wrote the first draft of the manuscript Appendix 2.

Perna, A. contributed to data analyses and interpretation. revised the first draft of the manuscript, and P. Parvanova, and M. wrote the final version.

All authors critically revised the manuscript and approved the final draft. No medical writer or editor was involved in the writing of the manuscript. Colosia AD , Palencia R , Khan S.

Prevalence of hypertension and obesity in patients with type 2 diabetes mellitus in observational studies: a systematic literature review. Diabetes Metab Syndr Obes. Google Scholar. American Diabetes Association. Standards of medical care in diabetes— Diabetes Care.

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Ruggenenti P , Perna A , Ganeva M , Ene-Iordache B , Remuzzi G ; BENEDICT Study Group. Impact of blood pressure control and angiotensin-converting enzyme inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: a post hoc analysis of the BENEDICT trial. J Am Soc Nephrol. Boutitie F , Gueyffier F , Pocock S , Fagard R , Boissel JP ; INDANA Project Steering Committee.

INdividual Data ANalysis of Antihypertensive intervention. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med.

Nordestgaard BG , Chapman MJ , Ray K , Borén J , Andreotti F , Watts GF , Ginsberg H , Amarenco P , Catapano A , Descamps OS , Fisher E , Kovanen PT , Kuivenhoven JA , Lesnik P , Masana L , Reiner Z , Taskinen MR , Tokgözoglu L , Tybjærg-Hansen A ; European Atherosclerosis Society Consensus Panel.

Lipoprotein a as a cardiovascular risk factor: current status. Eur Heart J. Stephens FB , Constantin-Teodosiu D , Greenhaff PL. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle.

J Physiol. Eckel RH , Grundy SM , Zimmet PZ. The metabolic syndrome. Foster DW. The role of the carnitine system in human metabolism. Ann N Y Acad Sci. Zhou YP , Berggren PO , Grill V. Mingrone G. Carnitine in type 2 diabetes.

Capaldo B , Napoli R , Di Bonito P , Albano G , Saccà L. Carnitine improves peripheral glucose disposal in non-insulin-dependent diabetic patients. Diabetes Res Clin Pract. Mingrone G , Greco AV , Capristo E , Benedetti G , Giancaterini A , De Gaetano A , Gasbarrini G.

l -Carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr. Ruggenenti P , Cattaneo D , Loriga G , Ledda F , Motterlini N , Gherardi G , Orisio S , Remuzzi G.

For more information about PLOS Subject L-carnitine and insulin sensitivity, click here. Low carnitine L-carnitine and insulin sensitivity may underlie the development of insulin resistance and metabolic L-carnihine. Intravenous lipid infusion Prenatal vitamins plasma L-cafnitine fatty acid FFA concentration and is Sensitibity model Sports nutrition fuel simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility. Therefore, eight volunteers participated in all three intervention arms and were included for analysis. L-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short- medium- and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Marieke G. Schooneman insuulin, Frédéric M. VazSander M. HoutenMaarten R. Soeters; Acylcarnitines : Reflecting or Inflicting Insulin Resistance? L-carnitine and insulin sensitivity

Author: Voodoora

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