The Role of Carnitine in Diabetes Mellitus

The rapidly increasing prevalence of Diabetes Mellitus and its distinctive contribution to burden of disease, globally and within Australia has lead to the chronic illness being of focus in the streams of public health policy and being identified as an are where there is promising potential for health improvements. The National Health Priority Areas (NHPA), identify diabetes mellitus as a central contributor to the burden of disease within Australia. Recognising the efforts necessary to reduce the incidence and prevalence of the disease need a holistic approach focusing not only treatment, but including prevention and management on a continuum (Aihw.gov.au, 2017).

Overview

A nutrient of focus is carnitine. Carnitine is known for its performance in transporting long-chain fatty acids into mitochondrial matrix of beta-oxidation. 
The essential nutrient is also necessary for the outward flow of acyl groups out of the mitochondria (Ringseis, Keller & Eder, 2011 p. 23). In an article outlining the role of carnitine regarding the assurance of glucose levels being at equilibrium and insulin sensitivity, it is explained that the accumulation of acyl-CoA directly correlates with the development and increase of insulin resistance. Regarding treatment and prevention, carnitine supplementation has been identified as a viable option for the prevention and to combat insulin resistance present in Type 2 Diabetes, as well as supporting glucose homeostasis within cells. According to the aforementioned research article; more recent studies point toward carnitine as a causative factor for insulin resistance, when present in insufficient amounts, specifically linked to when an individual is obese and therefore in chronic metabolic stress. Which is known to reduce as well as be reversed, by carnitine supplements  (Ringseis, Keller and Eder, 2011 p. 37).

Carnitine is a water-soluble quaternary amine and is essential for normal tissue function. Carnitine synthesis is dependent on the availability of several co-factors including the micronutrients, Vitamin C, Vitamin B6 and iron; a deficiency in these nutrients can lead to carnitine deficiency, which is a result of the deficiency comorbidities. L-Carnitine in various tissues is managed and kept within the normal range because as a result of renal processes of absorption through cat-ion transporters, all dependent on carnitine’s availability in the diet (Bae et al., 2015 p. 11). The main sources of carnitine are found in animal products, such as; meat (red meat) and dairy products. However, surprisingly vegetarians, who consume less carnitine from diet, due to reduced consumption of meat products, still maintain an adequate level of carnitine, which indicates that the human body can adequately synthesise carnitine. This is estimated to be at 0.19mg per kg body weight (Ringseis, Keller & Eder, 2011 p. 45). Generally carnitine is absorbed from foods, and can also be biosynthesized from lysine and methionine. However, the level of carnitine in the body is chiefly dependent on its prevalence in diet (Bae et al., 2015 p. 34). A 2012 Nutrition Research article expands on the possibility of L-carnitine having an effect in preventing complications relating to type 1 and type II diabetes. The article stated that through observations of lower L-carnitine levels, an increase of studies have risen focusing on patients with diabetes and carnitine as a supplement and the ‘therapeutic implications’ of that (Liepinsh et al., 2012 p. 12). Findings have shown that the effects of L-carnitine in healthy subjects aren’t straight forward and the narrow ratio of human adult studies, specifically with diabetic patients at various stages of being affected by the burden of disease (Liepinsh et al., 2012 p. 13).

In a controlled study undertaken by Ringseis, Keller and Eder. Where 16 studies were of individuals with metabolic disorders, 6 studies included healthy individuals and an animal study on 19 rats were subjects for testing of glucose tolerance and insulin sensitivity and how the presence of carnitine links to their association. Out of these studies a total of ten studies were considered suitable for evaluation and for results to be drawn from and discussed. The study characteristics are as follows; randomized control trial with a set timeframe that fluctuated depending on the subject of focus (Ringseis, Keller & Eder, 2011 p. 10). In this article Ringseis et al., states that carnitine and it’s by products (ALC and PLC) strengthen the utlisation of glucose by acting as a catalyst in for Pyruvate dehydrogenase complex (PDHC), which is crucial in the oxidation process of glucose. Therefore, carnitine strongly reduces intramitochondrial acetyl-CoA levels resulting in a 10- to 20-fold decrease in the acetyl-CoA/ CoA ratio. This mechanism of action of carnitine and ALC is supposed to be responsible for the enhancement of glucose utilization in both healthy and type 2 diabetic subjects (Liepinsh et al., 2012 p. 20).

In a hospital based study, Bashi and Al-Farha (2010) sought to find out the effectiveness of L-carnitine as a supplement in combination with other medications for patients with diabetes mellitus. Hospital volunteers (54) in this study all took the supplement of L-carnitine and had several tests throughout. These tests measured fasting plasma glucose (FPG), Hba1c, serum creatinine and urea and all of these showed a lowering effect by the end of the study due to the L-carnitine supplement (Bashi and Al-Farha, 2010 p.16). It is stated in the study that these findings could be due to the L-carnitine activating the receptors in the kidney for carnitine and increase β-oxidation and action of the kidney. This study has limitations in that it’s framework is weak and validity is affected because of it. Were these findings to be more solid, another study would need to be conducted, with the use of a double blind RCT so major differences can be perceived between a control and intervention group. However, these findings can still have a strong practical application as shown by all p-values being at (p<0.001) and this implies that the supplementation lowers fasting plasma glucose and blood Hba1c, while also improving renal function by decreasing serum creatinine and urea (Bashi and Al-Farha, 2010 p. 5).

Looking at a study with stronger protocol, Rahbar et al. (2005) also looked at the effect on supplement L-carnitine and its effect on fasting plasma glucose and Hba1c but also serum triglycerides. The participants (35) were patients from a diabetic center and were put into a double-blind placebo-controlled clinical trial spanning 12 weeks with measurements taken at baseline, midway and end points. It was found that when added to pre-existing antidiabetic medication (glyburide and metformin), L-carnitine significantly lowered fasting plasma glucose levels, but increased fasting triglyceride, in long-term patients with type II diabetes mellitus (Rahbar et al., 2005 p. 15). Unlike Bashi and Al-Farha (2010), Hba1c lowering was not a significant result, showing contradictions in results. It is more likely for the results of Rahbar et al. (2005) to be more applicable to a hospital setting as the scientific rigour in the study is more concrete. Implications of this research indicate a stronger evidence base for the use of L-carnitine supplements in patients with diabetes mellitus.

People living with diabetes mellitus are automatically at a higher risk of heart disease events and patients should strive to reduce CVD risks when they have diabetes mellitus (Expert Panel, 2001). Derosa et al. (2003) wanted to see the effect of L-carnitine of plasma lipoprotein levels in hypercholesterolemic patients that had diabetes mellitus as serum lipoprotein levels can be used to predict atherosclerosis or can be used as an index of prognosis and severity of CVD. A sample size of 94 patients participated (with no attrition) in a randomized double-masked, placebo-controlled clinical trial with data gathered from BMI and blood tests at 3 stages and also incorporating the use of food diaries. The study found that “L-carnitine significantly lowered the plasma Lp(a) level compared with placebo in selected hypercholesterolemic patients with newly diagnosed type 2 DM” (Derosa et al., 2003). The limitations of this study is how narrow it’s exclusion criteria is. The implications of this study would be further study to a broader group that also include hyper-Lp(a) diabetic patients but the current data shows a definitive improvement due to the addition of L-carnitine.

While L-carnitine intake as a nutraceutical is proven to be effective by the aforementioned literature, the dietary inclusion of nuts is also quite effective. In a Tehran Lipid and Glucose Study, Asghari and Ghorbani (2017), looked at the dietary inclusion of nuts and its association with diabetes incidences.  It is known that nuts are low in carbohydrates and therefore consumption in various forms can lead to greater glycemic control. Participants of a Middle Eastern population (1984) were taken through phases between 2005 to 2014 in order to obtain dietary data via a food frequency questionnaire.  A trained nutritionist carried out these tests that involved face-to-face interviews where participants were required to provide details about their nut consumption in the previous year. Participants in this study all completed blood samples and numerous tests throughout. These tests measured fasting plasma glucose (FPG), glucose tolerance test (OGTT) and triglyceride assays (TG). Nut consumption was then measured into 4 categories of <1, 1-1.99, 2-3.99 and 4> servings/per week.  Findings concluded that servings of 4 and above resulted in reduced incidences compared to participants who had less than 1 serving a week (Asghari and Ghorbani, 2017).  To further back-up this study, the Nurses Health Study (NHS) also conducted tests, which involved consumption per week to strongly suggest nut consumption has a positive effect being a protective factor Strozyk and Pachocka (2017).  Variables included age, overweight or obesity status, physical activity, family history, diet type and smoking. Portion sizes were based on 28g with results showing 7 and above portions being resulted in fewer occurrences in type 2 diabetes. Of the nuts being tested: Macadamia, Pecan, Pine, Brazil, Walnut, Hazelnut, Almond, Pistachio, Cashew and Groundnuts, walnuts were shown to be of most important in primary prevention of type 2 diabetes. This is due to the fact that walnuts contain a high amount of alpha-linolenic acid, which has been proven to improve insulin sensitivity. It is also declared that 2 portions a week will decrease the likelihood of type 2 diabetes occurring (Strozyk and Pachocka, 2017) similarly to the previous study (TLGS), which had concluded that between 2-4 servings a week had the most effective outcome in incidences of type 2 diabetes.

Method

To find relevant literature, the question used was ‘effect of L-carnitine/nuts on the treatment and prevention of diabetes mellitus.’ Some inclusion criteria included; Diabetes, L-carnitine, Biochemistry, Diabetes Mellitus, Carnitine, Protein, Lipoprotein, Glucose, Hba1c, Nuts and DM Prevention. There was not much exclusion criteria for the studies researched. The only two categories excluded were child only, adolescent only and elderly only studies. All articles were appraised using  the Academy of Nutrition and Dietetics Evidence Analysis Library Worksheet Template and Quality Criteria Checklist.

Results

In Rahbar’s  et al (2015) study, there was a significant decline in fasting blood glucose in patients from the L-Carnitine Group. On the other hand, patients in the placebo group had a non significant rise in FPG. Consequently, there was a significant difference between the placebo and the L-Carnitine group. In Patients administered with L-Carnitine , there  was an increase in blood TG concentration within the first 12 weeks. However, there were no changes in blood TG in patients in the placebo group. Changes in TG were vividly different between the participants in the placebo group and the L-carnitine group. Additionally, after 12 weeks of L-carnitine administration, there was an increase in fasting serum. Nonetheless, there were no changes in the placebo group. Additionally, fasting serum (Apo A-1) also rose in patients from the L carnitine group (Bae et al., 2015 p. 15). However, there were no significant changes in the fasting serum in patients from the placebo group. Notably, there lacked any statistitically important changes in LDL-C, LP(a), WHR, BMI in the placebo or –Carnitie Group after 6th and 12th week. Additionally, there were no any clinically observed events related to the intake of L-Carnitine.

In accordance to Bae et al (2015) study results, after the 12th treatment week, 89.7% of patients admoinistered with carnitine-orotate exhibited normalization of levels of serum ATL whereas 17.9 patients exhibited normalization in placebo groups. At the 6th and 12th weeks, patients in the Complex carnitine group showed a significant decline in levels of ATL with respect to the hepatic CT analysis, patients administered with complex carnitine-oriotate exhibited a rise in values of mean liver attenuation as well as LAI after the 12th treatment week. Moreover, in the 12th treatment week, a decline in HBA1c was noted in patient from the complex carnitine-orotate. Nonetheless, there were no significant changes in the participants HBA1c in the placebo group.

In accordance to results from a study, participants who had a high rate of nut intake showed higher levels of protein, carbohydrates, fat, PUFA and fiber. Research on the relation between nut consumption varieties and MetS risks, made it vivid that consumption of walnuts had an inverse relation with MetS risks. After adjustments in diabetes family, gender, age, smoking, fast glucose serum, physical activity, a significant decline in MetS risks was observed (Bae et al., 2015 p. 16). Additionally, peanuts, almonds, hazelnuts as well as pistachios had no relation to the MetS risks. Moreover, in a fully adjusted model, there was a 3% reduction of MetS incidences with an increased in consumption of walnuts. Additionally, a stratified analysis exhibited that total consumption minimized the MetS risk in participants irrespective of their age. However, consumptions of walnut only minimized the MetS risks to elderly participants.  
Discussion
With respect to the studies, it is evident that administration of L-carnitine in addition with hypoglymic drugs over duration of weeks, significantly minimizes the FPG in patients with type II diabetes by approximately 13%. However, the effects magnitude did differ among various subjects with some of the participants showing a 17% decline as well as others only showing slight FPG marginal changes. Nonetheless, Rahbar’s  et al (2001) did not observe the significant impacts of L-carnitine on fasting body glucose in patients who are newly diagnosed without showing various diabetic complications. The L-Carnitine concentration is highly minimized in retinopathic, neuropathic as well as nephropathic patients compared to diabetic patients without showing complications. Rahbar’s  et al (2001) study examined the effect of L-carnitine on lipidemic and glycemic parameters in patients having long term diabetes type 2 as well as evidence of any diabetic complications as signs of retinopathy, mephropathy and neuropathy. The study revealed that L carnitine raised concentration of TG in diabetic patients. The results of this study wee in alliance with a study with a study by Rodrigues et al (1990) and also contradicted with results from a study by Derosa et al (2003). According to Abdel-aleem et al (1997) L-carnitine had a different effect in diabetic cells compared to non diabetic cells (Rahbar et al., 2005 p. 23). Additionally, it did not increase oxidation of fatty acids. This mechanism does provide an explanation of TG increase in diabetic patients caused by L carnitine. Carnitine increases he amount of cytopalmsic acetylCoA due to private dehydrogenize. Likewise, acetyl-COA is a malonyl COA substrate which is a fatty acid substrate and CPT 1potent inhibitor. Therefore, it inhibits L-carnitine effect during intramitochondrial fatty acids transportation in patients diagnosed with diabetes. in the ‘AUTHOR’s study, Apo B100 increased significantly in patients administered with L-carnitine. The fatty acids and Apo B100 increase makes the liver produce more VLDl and eventually increases TG levels. In addition, Gaetano et al (1995) made reports that L carntine does inhibit insulin’s hypolipidemic effect in patients having type II diabetes. Moreover, insulin in relation with L carnitine does increase fatty acids concentration. In the AUTHORS study, Lp(a) concentration minimized though not as expected. In comparison to Sitori (2000) and Derosas (2003) study, L-carnitine significantly managed to reduce the LP(a) concentration in plasma of non diabetic and diabetic patients.  A major reason that led to different results, is that the Rahbar’s  et al (2001) study used patients with low concentration levels compared to Sitori ‘s and Derosa’s  study which used patients with high concentration of LP(a).

In Bae et al (2015) study, there was no change in weight within 12 weeks of treatment. Nonetheless, patients serum ALT levels did normalize in about 89.7b% of the patient treated using complex carnitine orotate. Moreover, analysis of hepatic CT exhibited minimization in the content of hepatic fat in participants treated with COC.     Carnitine carries fatty acids across mitochondrial membrane for oxidation which is vital in the conversion of fats into energy. By minimizing fatty acids oxidation during hepatocytes, there is an increase in hepatic fatty acids which causes an increase in triglyceride within hepatocytes cytoplasm. The mitochondrion is the main site for oxidation of fatty acids (Rahbar et al., 2005 p. 20). Hepatocytes occupy 18% of the liver and are mitochondrial rich. However, new studies have revealed that hepatic mitochondrial dysfunction is vital to NAFLD pathogenesis. Oxidation of fatty acids increases in mitochondria like a metabolic adaptation towards fat accumulation. However, the adaptation does induce oxidative stress leading to mitochondria dysfunction. Therefore, carnitine roles during mitochondria oxidation does explain improvement observed in hepatic steatosis as well as liver function in the participants treated using complex carnitine orotate.

Apart from the hepatic steatosis improvement, participants treated using complex carnitine=orotate showed an improvement in glycemic control. Carnitibe’s beneficial effect on insulin sensitivity as well as glucose tolerance has been shown in numerous studies. It is vivid that carnitine enables oxidation of mitochondria in long chained fatty acids. The accumulation of long chained fatty acids as well as other metabolites does impair insulin signaling contributing to the creation of resistance of insulin in the heart as well as in skeletal muscles.  According to existing studies, diabetic patients have minimized concentrations of plasma free carnitine in comparison to healthy people. This does show the relation between glucose intolerance and impaired carnitine status. Participants in Bae’s study were all diabetic and exhibited a drop in HbA1c after the 12th treatment week. In a recent research, it was reported that using carnitime orotate complex for treatment did minimize systemic oxidative stress and raised mitochondrial number copies in patient having an imparted glucose metabolism.

Moreover, after 12 weeks of treatment using complex carnitime-orotate there was a significant drop in fasting glucose, HOMA-IR and HbA1c. The findings show that hepatic steatosis improvement is related with glycemic control improvement in association to insulin resistance.  There exists rich evidence that links hepatic steatosis to insulin resistance which does play a vital role in type II diabetes pathogenesis. In spite of the close relation between hepatic steatosis and insulin resistance, it is still hard for researchers to vividly establish the causal association between glucose metabolism and NAFLD.

Findings from Rahbar et al., (2005) also align to other studies that have studied the association between nut consumption and MetS. Consumption of nuts is recommended by the AHA.   the advantageous effect of consuming nuts with respect to insulin resistance, modulating inflammation, glycaemic control and serum lipids have also been affirmed by the recent meta analysis and systematic reviews.  By considering that consistent insulin resistance and hyperglycaemia does play a vital role in the DM development as well as its complications, any agent with an ability to ameliorate such negative conditions should also minimize the DM risk. With respect to ADA, glycaemic control does have z vita role in management and prevention of DM. Previous findings suggest that nuts could be beneficial through modulation of the insulin responses and the lowering of postprandial glucose. The health benefits related to nuts could also be associated to their unique fatty acids content which includes: antioxidant vitamins, photochemical, omega three fatty acids, minerals. The high PUFA and MUFA contents in nuts could reduce accumulation of fats in an individual’s body through facilitating oxidation and improving thermo genesis. Likewise, nuts are rich in dietary fiber and plant based protein which delays gastric emptying as well as reduces gastrointestinal transit absorption, hence consequently leading to increase in satiety. Therefore, the findings of this study do suggest that nut consumption that by healthy and diabetic patients could minimize the potential risk of the condition through different mechanism like weight control, modification of insulin resistance, modulation of glycaemic control, lowing of lipids, antihyperglycaemic and ant oxidative effects.   However, it is evident that the main role association between nuts and type II diabetes is that nuts protect hone from developing diabetes.  This is also affirmed by other studies that reported that nut consumption is a protective factor that hinders development of diabetes.  In particular, these studies have also shown that walnuts are of great significance in preventing type two diabetes due to the factor that they have alpha-linolenic acid. This acid does increase sensitivity level of insulin. Additionally, frequent nut consumption is also related to a decreased probability of developing non insulin based diabetes mellitus.

Conclusion

As shown from the data above, the use of nuts in diet and the addition of L-carnitine has a positive correlation with improved outcomes for people with diabetes mellitus as well as reduced incidence of diabetes mellitus in the population, the use of further study should be done to solidify current research evidence.

References

Asghari, G., Ghorbani, Z., Mirmiran, P., & Azizi, F. (2017). Nut consumption is associated with lower incidence of type 2 diabetes: The Tehran Lipid and Glucose Study. Diabetes & metabolism, 43(1), 18-24.

Bae, J., Lee, W., Yoon, K., Park, J., Son, H., & Han, K. et al. (2015). Improvement of Nonalcoholic Fatty Liver Disease With Carnitine-Orotate Complex in Type 2 Diabetes (CORONA): A Randomized Controlled Trial. Diabetes Care, 38(7), pp.1245-1252. http://dx.doi.org/10.2337/dc14-2852

DallalBashi, A.Y., Al-Farha, A.M. and Abd, M., 2010. EFFECT OF L-CARNITINE ON CERTAIN BIOCHEMICAL PARAMETERS IN DIABETIC PATIENTS. Tikrit Medical Journal, 16(1).

Derosa, G., Cicero, A., Gaddi, A., Mugellini, A., Ciccarelli, L. and Fogari, R. (2003). The effect of l-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. Clinical Therapeutics, 25(5), pp.1429-1439.

Expert Panel on Detection, E., 2001. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Jama, 285(19), p.2486.

Liepinsh, E., Skapare, E., Vavers, E., Konrade, I., Strele, I., & Grinberga, S. et al. (2012). High l-carnitine concentrations do not prevent late diabetic complications in type 1 and 2 diabetic patients. Nutrition Research, 32(5), 320-327. http://dx.doi.org/10.1016/j.nutres.2012.03.010

Rahbar, A., Shakerhosseini, R., Saadat, N., Taleban, F., Pordal, A. and Gollestan, B. (2005). Effect of L-carnitine on plasma glycemic and lipidemic profile in patients with type II diabetes mellitus. European Journal of Clinical Nutrition, 59(4), pp.592-596.

Ringseis, R., Keller, J., & Eder, K. (2011). Role of carnitine in the regulation of glucose homeostasis and insulin sensitivity: evidence from in vivo and in vitro studies with carnitine supplementation and carnitine deficiency. European Journal Of Nutrition, 51(1), 1-18. http://dx.doi.org/10.1007/s00394-011-0284

Stróżyk, A. K., & Pachocka, L. (2017). The role of nuts consumption in the primary and secondary prevention of type 2 diabetes. Clinical Diabetology, 6(1), 26-33.