C. Ramaccini

Caloric restriction and L-carnitine administration improves insulin sensitivity in patients with impaired glucose metabolism.

BACKGROUND Reduced circulating and tissue carnitine levels, possibly leading to impaired mitochondrial function, have been postulated to be involved in the pathogenesis of insulin resistance. However, whether L-carnitine administration may improve insulin sensitivity in patients with impaired fasting glucose (IFG) or type 2 diabetes mellitus (DM-2) is still controversial. The aim of the study was to explore the role of L-carnitine supplementation in influencing insulin sensitivity. METHODS A randomized controlled study involving adult outpatients was designed. Adult patients referred to the outpatient clinic and within 10 days of the diagnosis of IFG or DM-2 were consecutively enrolled. Exclusion criteria were concomitant antidiabetic therapy and modifications of lifestyle during the previous 4 weeks. Patients were randomly assigned to receive a hypocaloric diet for 10 days (group C; n = 8) or the same dietetic regimen in addition to oral L-carnitine (2 g twice daily) supplementation (group LC; n = 8). Oral glucose tolerance test (OGTT), fasting plasma insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed at the beginning and end of the study. Data were statistically analyzed using the Student t test for paired and unpaired data. RESULTS OGTT at 2 hours improved in both groups. Only in the L-carnitine-supplemented group did plasma insulin levels and HOMA-IR significantly decrease when compared to baseline values. CONCLUSIONS Considering the role of caloric restriction in increasing the intestinal uptake of carnitine, the results suggest that oral L-carnitine administration, when associated with a hypocaloric feeding regimen, improves insulin resistance and may represent an adjunctive treatment for IFG and DM-2.

Autophagy is induced in the skeletal muscle of cachectic cancer patients

Basal rates of autophagy can be markedly accelerated by environmental stresses. Recently, autophagy has been involved in cancer-induced muscle wasting. Aim of this study has been to evaluate if autophagy is induced in the skeletal muscle of cancer patients. The expression (mRNA and protein) of autophagic markers has been evaluated in intraoperative muscle biopsies. Beclin-1 protein levels were increased in cachectic cancer patients, suggesting autophagy induction. LC3B-I protein levels were not significantly modified. LC3B-II protein levels were significantly increased in cachectic cancer patients suggesting either increased autophagosome formation or reduced autophagosome turnover. Conversely, p62 protein levels were increased in cachectic and non-cachectic cancer patients, suggesting impaired autophagosome clearance. As for mitophagy, both Bnip3 and Nix/Bnip3L show a trend to increase in cachectic patients. In the same patients, Parkin levels significantly increased, while PINK1 was unchanged. At gene level, Beclin-1, p-62, BNIP3, NIX/BNIP3L and TFEB mRNAs were not significantly modulated, while LC3B and PINK1 mRNA levels were increased and decreased, respectively, in cachectic cancer patients. Autophagy is induced in the skeletal muscle of cachectic cancer patients, although autophagosome clearance appears to be impaired. Further studies should evaluate whether modulation of autophagy could represent a relevant therapeutic strategy in cancer cachexia.

Carnitine Administration Reduces Cytokine Levels, Improves Food Intake, and Ameliorates Body Composition in Tumor-Bearing Rats

Increased cytokine expression contributes to the pathogenesis of cancer anorexia–cachexia syndrome. Carnitine may reduce inflammation in chronic diseases. We tested the effects of L-propionylcarnitine (PC group) or saline (C group) on food intake (FI), body composition, and inflammatory status of MCA-sarcoma-bearing rats. On tumor appearance, rats were randomly assigned to daily i.p. injection of L-propionylcarnitine (250 mg/kgBW/d; n = 8) or saline (equal volume; n = 8). FI and fat-free mass wasting improved in PC rats only (p < .01 vs. controls). Cytokines’ levels decreased in PC rats vs. controls (p < .02). Results suggest that carnitine may ameliorate cancer anorexia–cachexia, via reduction of the inflammatory status.

Stimulation of the Nicotine Antiinflammatory Pathway Improves Food Intake and Body Composition in Tumor-Bearing Rats

Inflammation contributes to the pathogenesis of cancer anorexia-cachexia syndrome. Nicotine administration reduces cytokine levels and mortality during sepsis. Therefore, nicotine administration may result in improved anorexia-cachexia. Sixteen male Fischer rats inoculated with MCA sarcoma were assigned to random injections of nicotine (NIC; 200 mg/kg BW/d) or saline (C). Food intake (FI), body weight, body composition, interleukin (IL)-1, IL-6 levels were evaluated. Data were analyzed via Students t-test for paired and unpaired data and ANOVA. FI started declining 12 days after tumor inoculation both in C and NIC rats, but the decline was significantly attenuated by nicotine administration. At the end of the study, lean body mass wasting was more severe in C rats than in NIC rats (P < 0.05), whereas a trend toward attenuation of fat mass depletion was observed. IL-1 circulating levels were significantly lower in NIC rats than in C rats (114 ± 21 pg/mL vs. 190 ± 35 pg/mL, respectively; P < 0.01), whereas the reduction of IL-6 levels in NIC rats was only marginally not significant when compared to C rats (555 ± 174 pg/mL vs. 721 ± 160 pg/mL, respectively; P = 0.06). Our data suggest that the nicotinic antiinflammatory pathway may represent an interesting and possibly effective therapy for anorexia-cachexia syndrome.

Timing of antioxidant supplementation is critical in improving anorexia in an experimental model of cancer

Increased oxidative stress may contribute to cancer anorexia, which could be ameliorated by antioxidant supplementation. methylcholanthrene (MCA) sarcoma-bearing Fisher rats were studied. After tumour inoculation, rats were randomly assigned to standard diet (CTR group, n = 6), or to an antioxidant-enriched diet (AOX group, n = 8). Eight more rats (STD-AOX group) switched from standard to antioxidant diet when anorexia developed. At the end of the study, food intake (FI, g/d), body weight and tumour weight (g) were recorded, and plasma samples were obtained. On day 16, anorexia has appeared only in CTR and STD-AOX animals. At the end of the study, FI in AOX animals was still higher than in the other groups (p = 0.08). No differences in body and tumour weights were observed among groups. However, hydrogen peroxide and interleukin-1β levels were significantly reduced only in AOX rats. Data obtained suggest that early antioxidant supplementation improves cancer anorexia, ameliorates oxidative stress and reduces inflammation.

L-CARNITINE ADMINISTRATION IMPROVES INSULIN SENSITIVITY IN PATIENTS WITH IMPAIRED GLUCOSE METABOLISM

Rationale: Insulin resistance and type II diabetes are characterized by hyperglycemia and hyperinsulinemia. Insulin resistance may be associated with mitochondrial dysfunction. L-carnitine, an intramitochondrial carrier of acylic groups, is a molecule involved in lipids and carbohydrates metabolism. Lcarnitine therefore may modulate cell energy metabolism. We designed a study to investigate the effects of oral L-carnitine administration on plasma glycemic and insulinemic profile in patients with impaired fasting glucose or diabetes mellitus type II. Methods: The effect of L-carnitine was investigated in 16 patients (12 males and 4 females); the mean age ± SD was 66.69±13.37 y. Patients were randomly assigned to two groups. The first group (LC, n=8; 5 M and 3 F) received L-carnitine (4 grams/day) and 1200 or 1400 Kcal/day standard diet for women or men respectively, for 10 consecutive days. The second group (C, n=8; 7 M and 1 F) received only 1200 or 1400 Kcal/day standard diet for women or men respectively, for 10 consecutive days. Oral glucose tolerance test (OGTT, basal and 2 hours), fasting plasma insulin levels and Homeostasis Model Assessment (HOMA-IR) were assessed in each group before and after treatment. Results: Fasting plasma glucose levels were not statistically different in the two groups after treatment. OGTT-2 hours significantly improved after treatment both in LC (232.62±64.75 mg/dl vs 146.25±59.04 mg/dl, p=0.015) and C group (193.25±64.11 mg/dl vs 128±53.29 mg/dl, p=0.04). Interestingly, we observed a significant improvement in plasma insulin levels and HOMA-IR after treatment in LC group (7.04±2.6 μU/ml vs 4.51±1.79 μU/ml, p=0.04; 1.95±0.79 vs 1.17±0.51, p=0.03). No significant differences in plasma insulin levels and HOMA-IR were observed in C group. Conlcusions: L-carnitine in association with low calorie diet significantly ameliorates OGTT-2 hours, reduces plasma insulin levels and diminishes insulin resistance, as indicated by HOMA-IR improvement.