Carnitine homeostasis in humans
Carnitine is a vitamin-like water soluble small molecule featuring a number of essential roles in intermediary metabolism. The primary physiological role is associated with the cellular energy producing processes through the transport of long-chain fatty acids from the cytosol into the mitochondria, where their degradation takes place via β-oxidation. This role is fundamental, since neither the free long chain fatty acids, nor their Coenzyme-A esters can cross the inner mitochondrial membrane on their own; the transport is possible exclusively in carnitine ester form5.
Beyond its classical physiological role, carnitine has additional crucial functions in the body. Notably, carnitine modifies the acyl-CoA/CoA ratio, which in turn regulates the activity of several mitochondrial enzymes involved in tricarboxylic acid cycle (TCA), fatty acid oxidation, urea cycle and gluconeogenesis7. It is involved in energy storage in the form of acetyl carnitine, and modulates the toxicity of partially metabolized acyl groups by facilitating their excretion in carnitine ester form8. Furthermore, L-carnitine has been demonstrated to bear anti-inflammatory and antioxidant properties9–11 and improves insulin sensitivity, protein nutrition, dyslipidemia, and membrane stability12
Carnitine is present in the body as free and esterified form (acylcarnitines). Most of the endogenous carnitine pool is distributed between the skeletal and cardiac muscle (approximately 98%) and only less than 1% is located within the plasma.
Plasma transports only the carnitine and acylcarnitines, therefore it is not surprising in which, their plasmalemmal concentrations are relatively low. In healthy adults, free L-carnitine concentration of plasma is 40–50 μmol/l, that of acetylcarnitine (the most abundant ester) is typically 3–6 μmol/l. Total L-carnitine concentration is approx. 50–60 μmol/l15. Since carnitine has no known metabolic function in plasma, changes in plasma carnitine concentrations can be understood only in the relationship with other metabolic or tissue specific information. Majority of the total carnitine content of the body can be found in muscles due to the large mass of the skeletal muscle, and only very small amounts are present in plasma or extracellular compartments. In addition, the concentration of carnitine is much higher in kidney and in liver than in plasma14.
Carnitine and its derivatives and insulin resistance
Several human and animal studies investigated the effect of lipid oversupply on insulin resistance and it has been found in which, via multiple mechanisms, involving the accumulation of intracellular lipids in ectopic tissues (i.e., lipotoxicity), the oversupply of dietary fat leads to insulin resistance19. In particular, it was observed in which, within muscle the accumulation of fatty acyl CoA derivatives/metabolites inhibits both insulin signaling and glucose oxidation4.
Impact of L-carnitine supplementation on glucose metabolism
The effect of L-carnitine supplementation on glucose metabolism in humans were widely investigated using a variety of methods (Table 1). Euglycaemic hyperinsulinaemic clamp studies demonstrated that L-carnitine supplementation has an effect on glucose disposal28–32. Ferrannini et al. examined healthy young volunteers and discovered intravenous L-carnitine infusion was associated with a significant (17%) stimulation of whole body glucose utilization. Carnitine-induced enhancement of non-oxidative glucose disposal was observed, while net oxidation of glucose was apparently unaffected28.
Several mechanisms have been suggested in support of the favorable effect of carnitine on glucose metabolism: the enhancing of the mitochondrial oxidation of long chain acyl CoA, the accumulation, of which, would otherwise lead to insulin resistance in muscle and heart; modulating the intramitochondrial acetyl-CoA/CoA ratio and the activity of the pyruvate dehydrogenase complex (PDHC); altering the expression of glycolytic and gluconeogenic enzymes; modifying the expression of genes of the insulin signaling cascade, stimulation of the insulin-like growth factor-1 (IGF-1) axis and IGF-1 signaling cascade38.
Carnitine and its derivatives in diabetes complications
Inexplicably, there are a very limited number of studies which effectively investigate the role of L-carnitine levels in the clinical course of diabetes and the development of its late complications. Consequently, the results are reportedly controversial.
The detected lower levels of carnitine in diabetic patients with diabetic complications encouraged researchers, suggesting that L-carnitine supplementation may likely have therapeutic consequences18,29. Although some animal studies42,43 demonstrated the beneficial effects of L-carnitine in the management of diabetic complications, in consideration of human studies the effects of L-carnitine in healthy subjects or in T2D patients are yet, controversial37.
In addition to L-carnitine its derivatives, acetylcarnitine (ALC) and propionyl-carnitine (PLC), are promising therapeutic agents in the treatment of diabetic complications. ALC has been observed to cross the blood-brain barrier through a sodium-dependent saturable process and improves neuronal energetic and repair mechanisms, while modifying acetylcholine production in the central nervous system45. A number of clinical trials were conducted to evaluate the efficacy of ALC in diabetes. De Grandis et al. investigated the efficacy and tolerability of ALC in the treatment of diabetic neuropathy over a 1-year period, focusing on the effects of the treatment on electrophysiological parameters and pain symptoms. They observed in which ALC was well tolerated and improved the neurophysiological parameters and reduced pain46. The analysis of two randomized placebo-controlled trials revealed ALC treatment is efficacious in alleviating symptoms, particularly pain, and improves nerve fiber regeneration and vibration perception in patients with established diabetic neuropathy47. Clinical trials of ALC administration in type 2 diabetic polyneuropathy have shown beneficial effects on nerve conduction slowing, neuropathic pain, axonal degenerative changes and nerve fiber regeneration48. In another study, Giancaterini et al. evaluated the effect of ALC administration on glucose uptake and oxidation rates and they reported the beneficial effects of ALC in patients with T2D mellitus49.
PLC has been demonstrated to exert a protective effect in cardiac and endothelial dysfunction, to hinder the progression of atherosclerosis, and to promote some of the cardiometabolic alterations which frequently accompany insulin resistance50. Furthermore, PLC protects plasma membranes and reduces vascular-related symptoms in diabetic patients51.
The question whether acylcarnitines reflect or inflict insulin resistance was the focus of a recent review59. Lipotoxicity is believed to play a crucial role in the induction of insulin resistance and increased attention is turning toward the acylcarnitines via the theory of the role of impairments of fatty acid oxidation in insulin resistance. Acylcarnitines possess distinct functions in the mitochondrial lipid metabolism. It is suggested in which acylcarnitines not only prevent the accumulation of noxious acylCoAs, but also reduce CoA trapping. Additionally, the metabolism of short-chain acylcarnitines and the interaction of acetyl-CoA and acetylcarnitine through carnitine acetyl transferase may regulate the pyruvate dehydrogenase complex, thus have an effect upon glucose oxidation.
Today, acylcarnitine profile analysis is extensively used in the investigation of metabolic derangements observable in T2D and several studies demonstrated in which altered AC content is associated with insulin resistance, therefore, pharmacological interventions targeting acylcarnitine accumulation may likely prove to be a promising treatment strategies in the management of T2D.
Safety concerns of L-carnitine supplementation
In recent years, gut microbiota metabolism of L-carnitine has become a topic of focus in several studies62–65. It is reported in which dietary L-carnitine consumption results in TMA (trimethylamine) release via the gut microbiota, which is then converted into TMAO (trimethylamine-N-oxide) by hepatic FMO (flavin monooxygenase). Animal studies suggested that TMAO promote atherosclerosis and increased cardiovascular risk62,64, moreover, a significant positive correlation has been found between fasting plasma levels of TMAO and incident major cardiovascular events in a human study65.
Referência :
(1) Nutr Diabetes. 2018 Mar 7;8(1):8.
