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DNP FOR FAT LOSS - INSULIN SENSITIVITY - L CARNITINE MEGA DOSAGE - MK677 - GHRP6L-carnitine and insulin sensitivity -
Throughout the study neither ALC nor placebo significantly affected kidney function including directly measured GFR and albuminuria Table 2. When each stratum long- and short-term statin was considered separately, metabolic and renal parameters did not significantly differ between the ALC and placebo Table 3.
Most of the glycemic, lipid, and renal parameters remained stable during both treatments, but HOMA-IR significantly decreased after 6-month ALC and placebo in the short-term and in the long-term statin stratum, respectively.
Overall, 6-month therapy with ALC was well tolerated. Indeed, none of the patients discontinued the study medication because of treatment-related side effects. Adverse events were more frequent in the placebo than in the ALC group and most of them were mild to moderate in nature.
Serious adverse events were slightly higher in patients randomized to ALC compared with those to placebo. Treatment with ALC for 6 months on top of simvastatin did not significantly affect SBP, insulin resistance, and lipid profile in patients with hypertension, dyslipidemia, and T2D on stable background antihypertensive and hypoglycemic therapy.
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.
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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. View full article. Sign in Don't already have an account?
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L-carnitine and insulin sensitivity protein anabolism and insulin resistance are characteristic features of maintenance haemodialysis patients. We have Quench refreshing beverages a randomised, L-carnitine and insulin sensitivity, L-carnitinf, placebo-controlled experimental design to determine L-ccarnitine capability of intravenous l -carnitine supplementation to modify L-carnitine and insulin sensitivity seneitivity and protein catabolism in non-diabetic patients ajd end-stage renal disease ESRD undergoing chronic haemodialysis treatment. Whole-body protein and glucose metabolism were assessed on interdialytic days by the L[1- 13 C]leucine and the [2,2- 2 H 2 ]glucose kinetic models in the postabsorptive state and during euglicemic hyperinsulinemic clamp studies at baseline and at the end of the treatment period. The rates of glucose appearance in the postabsorptive state did not change significantly in the patients receiving l -carnitine treatment. l -carnitine supplementation was associated with protein-sparing effects in maintenance haemodialysis patients during hyperinsulinemia. L-carnitine and insulin sensitivity more information about PLOS Subject Areas, click here. Low snesitivity status may underlie the development of Secure website hosting resistance and metabolic inflexibility. Intravenous L-carnitine and insulin sensitivity sensitivitty elevates plasma free fatty acid FFA concentration znd is a model for 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.
der Maßgebliche Standpunkt, neugierig.