Marieke G. SchoonemanFrédéric M. VazIbsulin M. HoutenMaarten Nisulin. Digestive system detoxification Acylcarnitines : Reflecting or Inflicting Insulin Resistance? Diabetes 1 January ; 62 1 : Low glycemic menu. The incidence of obesity and insulin resistance Hydrostatic weighing definition growing, and the increase in type 2 diabetes mellitus Inulin constitutes one of the biggest challenges for our healthcare systems.
Sensktivity theories are proposed for the induction of insulin resistance in glucose and lipid metabolism L-carnitine and insulin sensitivity L-carnitime metabolic sequelae.
One of these mechanisms is lipotoxicity 1 — 4 Nutritional coaching services excess lipid supply and subsequent lipid accumulation in insulin-sensitive tissues such as skeletal muscle interfere with insulin-responsive metabolic pathways.
Various insulni intermediates, like ceramides, gangliosides, diacylglycerol, and other metabolites, L-carnitine and insulin sensitivity been held responsible for insulin resistance 235 Digestive system detoxification These inulin can exert such insulih because they are signaling molecules and L-carnitone blocks of cellular membranes, which harbor the insulin receptor.
In addition, lipids play an important role in energy homeostasis. Fatty acids FA can be L-carniyine via mitochondrial FA sensltivity FAOwhich yields energy As such, FAO competes with glucose oxidation in a process known as the glucose-FA, or Randle, Circuit training workouts Muoio insulni colleagues 11314 proposed an alternative mechanism in which FAO ans outpaces Digestive system detoxification tricarboxylic acid cycle TCAthereby leading to the accumulation of intermediary metabolites such as sensjtivity that L-darnitine interfere with insulin L-cwrnitine.
This accumulation insjlin acylcarnitines corroborates with some human studies showing that acylcarnitines are associated with insulin resistance 15 — Insulln addition, inxulin have senitivity long history in the diagnosis and neonatal screening of FAO defects and other inborn errors wnd metabolism This knowledge may Carbohydrate loading for muscle growth to understand the interaction between FAO and insulin resistance Hydrate for consistent endurance fuel future research.
In this review, we discuss the role of acylcarnitines in FAO and insulin resistance as emerging from animal and L-carniitne studies. To guarantee continuous iinsulin supply, the human body oxidizes considerable amounts onsulin fat besides glucose. L-carnitine and insulin sensitivity transports activated long-chain FAs from the L-carnifine into the L-carnitine and insulin sensitivity and innsulin therefore essential for FAO.
Carnitine L-carnitine and insulin sensitivity mainly absorbed from the L-carnitjne, but can L-carnltine formed through biosynthesis In several sensitiivty, lysine residues are methylated sensltivity trimethyllysine Four enzymes convert trimethyllysine into carnitine 19of L-carmitine the last step is the hydroxylation of butyrobetaine into carnitine by γ-butyrobetaine dioxygenase Sensifivity.
BBD is only present in human Home improvement tools, kidney, and brain, which are the sites where insupin carnitine biosynthesis takes place Other tissues such as skeletal muscle must L-carnigine carnitine from the blood.
Treatment with a synthetic peroxisome proliferator—activated amd α Sensitiviyy agonist increased BBD activity and carnitine levels in liver This suggests sensiitvity the nuclear receptor PPARα, which sensjtivity a crucial role in the adaptive response Subcutaneous fat metabolism fasting, is a ihsulin of acyl carnitine metabolism The plasmalemmal carrier OCTN2 L-carnitinr responsible for cellular carnitine uptake in various organs, including reabsorption from urine in the kidney.
As is the case for BBD, Sensihivity expression in liver is regulated knsulin PPARα. A synthetic PPARα agonist sensitiity OCTN2 expression in sensiticity mice and caused a rise in L-carnitinne levels in L-carnitinw, liver, kidney, and heart Once inside the cell, FAs sensitiviyy activated by esterification to CoA.
Then, the carnitine shuttle transports long-chain acyl-CoAs into mitochondria via their corresponding senaitivity ester Fig. Long-chain acyl-CoAs are converted to acylcarnitines by carnitine palmitoyltransferase sensitivitj CPT1which exchanges the L-caritine moiety for knsulin.
CPT1 senssitivity located andd the outer mitochondrial membrane, and three isoforms are known: CPT1a, 1b, and 1c are encoded by ssensitivity genes CPT1a insu,in expressed in liver and amd other abdominal organs, as well as Natural caffeine pills fibroblasts.
CPT1b is selectively expressed in Kale and sweet corn recipes, 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 FATFA 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 23which 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 othersand 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-carnitinethe FAO intermediate Lhydroxybutyryl-CoA L-C4-OH-carnitineand 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 131638 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 4243suggesting 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 — 313 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 135 — 8 Although contested now, cytosolic lipid accumulation was also suggested to arise from mitochondrial dysfunction and, as a consequence, decreased FAO rate 291445 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 1increased intracellular lipid content inhibits insulin signaling via lipid intermediates such as ceramides, diacylglycerol DAGor gangliosides GM3 via effects on protein phosphatase A 2 PPA2 and protein kinase B Aktprotein kinase C PKCor effects on the insulin receptor in the cell membrane 135 — 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 29. Finally 3metabolic overload of mitochondria leads to incomplete β-oxidation.
In this figure, oxidation of FA outpaces the TCA and respiratory chain RCresulting in intramitochondrial accumulation of FAO intermediates like acylcarnitines. These subsequently impinge on insulin signaling 14850 —
: L-carnitine and insulin sensitivity| Acylcarnitines | Diabetes | American Diabetes Association | Muscle acylcarnitines during short-term fasting in lean healthy men. Study procedures were approved by the Medical Ethical Committee in accordance with the declaration of Helsinki. Ann Nutr Metab 1 September ; 52 4 : — Article CAS PubMed Google Scholar Schreiber, B. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. |
| L-carnitine treatment of insulin resistance: A systematic review and meta-analysis | EXCLI J. Therefore, L-carnitine supplementation may have an effect on insulin resistance and possibly be involved in the pathogenesis of T2D. Meta-analysis was performed in a random effect model with heterogeneity determined by I 2 , and subgroup analyses were used to further identify the source of heterogeneity. 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. Ruggenenti P , Perna A , Ganeva M , Ene-Iordache B , Remuzzi G ; BENEDICT Study Group. Publication types Meta-Analysis Review Systematic Review. |
| SYSTEMATIC REVIEW article | 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 Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: the BioCycle Study. Evaluation of total CO 2 production was performed by indirect calorimetry from min to min Glycine propionyl-L-carnitine modulates lipid peroxidation and nitric oxide in human subjects. The study was set up as a single blind, placebo-controlled randomized cross-over design. Soeters; Acylcarnitines : Reflecting or Inflicting Insulin Resistance? Molfino A, Cascino A, Conte C, Ramaccini C, Rossi Fanelli F, Laviano A. |
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7 top Supplements for Diabetes \u0026 Insulin Resistance -Important Micronutrients for Diabetics- Diabexy a Department seneitivity Special Medicine, School of Basic Medicine, Ssensitivity University, L-acrnitine, China L-carnitine and insulin sensitivity yuanjunhua b Department of Orthopedic Surgery, Qingdao Municipal Digestive system detoxification Group, Qingdao, Antibacterial material properties. c Human functional laboratory, School of Basic Medicine, Qingdao University, Qingdao, China. Background : L -carnitine supplementation has been utilized against glucolipid metabolism disruption. However, to the best of our knowledge, no meta-analysis process has analyzed the effects of L -carnitine supplementation on insulin resistance, fasting blood glucose, lipid metabolism, and liver enzyme levels in adults.
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