Thierry Charles Coste

Beneficial effects of gamma linolenic acid supplementation on nerve conduction velocity, Na+, K+ ATPase activity, and membrane fatty acid composition in sciatic nerve of diabetic rats.

Metabolic and vascular abnormalities are implicated in the pathogenesis of diabetic neuropathy. Two principal metabolic defects are altered lipid metabolism resulting from the impairment of delta-6-desaturase, which converts linoleic acid (LA) into gamma linolenic acid (GLA), and reduced nerve Na+, K+ ATPase activity. This reduction may be caused by a lack of incorporation of (n-6) fatty acids in membrane phospholipids. Because this ubiquitous enzyme maintains the membrane electrical potential and allows repolarization, disturbances in its activity can alter the process of nerve conduction velocity (NCV). We studied the effects of supplementation with GLA (260 mg per day) on NCV, fatty acid phospholipid composition, and Na+, K+ ATPase activity in streptozotocin-diabetic rats. Six groups of 10 rats were studied. Two groups served as controls supplemented with GLA or sunflower oil (GLA free). Two groups with different durations of diabetes were studied: 6 weeks with no supplementation and 12 weeks supplemented with sunflower oil. To test the ability of GLA to prevent or reverse the effects of diabetes, two groups of diabetic rats were supplemented with GLA, one group for 12 weeks and one group for 6 weeks, starting 6 weeks after diabetes induction. Diabetes resulted in a 25% decrease in NCV (P < 0.0001), a 45% decrease in Na+, K+ ATPase activity (P < 0.0001), and an abnormal phospholipid fatty acid composition. GLA restored NCV both in the prevention and reversal studies and partially restored Na+, K+ ATPase activity in the preventive treatment group (P < 0.0001). These effects were accompanied by a modification of phospholipid fatty acid composition in nerve membranes. Overall, the results suggest that membrane fatty acid composition plays a direct role in NCV and confirm the beneficial effect of GLA supplementation in diabetic neuropathy.

Increased Tissue Arachidonic Acid and Reduced Linoleic Acid in a Mouse Model of Cystic Fibrosis Are Reversed by Supplemental Glycerophospholipids Enriched in Docosahexaenoic Acid

An imbalance in (n-6)/(n-3) PUFA has been reported in cystic fibrosis (CF) patients. Glycerophospholipids enriched in docosahexaenoic acid (GPL-DHA) have been shown to regulate the (n-6)/(n-3) fatty acid ratio in the elderly. Here, we tested the effect of GPL-DHA supplementation on PUFA status in F508del homozygous CF mice. GPL-DHA liposomes were administrated by gavage (60 mg DHA/kg daily, i.e. at maximum 1.4 mg DHA/d) to 1.5-mo-old CF mice (CF+DHA) and their corresponding wild-type (WT) homozygous littermates (WT+DHA) for 6 wk. The PUFA status of different tissues was determined by GC and compared with control groups (CF and WT). There was an alteration in the (n-6) PUFA pathway in several CF-target organs in CF compared with WT mice, as evidenced by a higher level of arachidonic acid (AA) in membrane phospholipids or whole tissue (21 and 39% in duodenum-jejunum, 32 and 38% in ileum, and 19 and 43% in pancreas). Elevated AA levels were associated with lower linoleic acid (LA) and higher dihomo-gamma-linolenic acid levels. No DHA deficiency was observed. GPL-DHA treatment resulted in different PUFA composition changes depending on the tissue (increase in LA, decrease in elevated AA, DHA increase, increase in (n-6)/(n-3) fatty acid ratio). However, the DHA/AA ratio consistently increased in all tissues in CF+DHA and WT+DHA mice. Our study demonstrates the effectiveness of an original oral DHA formulation in counter-balancing the abnormal (n-6) fatty acid metabolism in organs of CF mice when administrated at a low dose and highlights the potential of the use of GPL-DHA as nutritherapy for CF patients.

French mothers' milk deficient in DHA contains phospholipid species of potential interest for infant development.

Objectives: An insufficient human milk docosahexaenoic acid (DHA) level was reported worldwide, which leads to the question of the sufficiency of the DHA supply for infant development in the French Mediterranean area. Also, among milk lipids, phospholipids may be of high potential interest for infant brain development, being a specific vector of DHA and providing plasmalogens. We aimed to estimate the consumption of such milk compounds by preterm and term infants. Materials and Methods: Milk samples from 22 lactating French women living in a port city, Marseille, were collected in a neonatology department from a single full-breast expression using an electric pump. Amounts of triglycerides, total phospholipids and plasmalogens, and fatty acid profile were determined by gas chromatography, and cholesterol by enzymatic assay. Results: Depending on the infant dietary guidelines we referred to, 46% or 82% of milk samples were below the recommended DHA level (0.4% or 0.7%), and a majority exhibited high linoleic acid/&agr;-linolenic acid and n-6/n-3 ratios, probably resulting from high linoleic acid together with low fish and seafood products consumption. DHA carried by phospholipids in a majority of specimens met the requirements for brain development for term but not for premature infants. Milk plasmalogen levels ranged from 3.4 to 39.2 mg/L. Conclusions: Our results support the recommendation of DHA supplementation to French mothers living in a Mediterranean port city, and of decreased linoleic acid intake, to reach optimal milk composition for infant health. DHA-containing phospholipids including plasmalogen species may represent important bioactive human milk compounds.

Les supplémentations nutritionnelles en acides gras polyinsaturés dans le traitement de la neuropathie diabétique périphérique

Resume L’acide linoleique et l’acide alpha linolenique sont les deux acides gras essentiels et les precurseurs des familles d’acides gras polyinsatures n-6 et n-3 respectivement. Ces acides gras polyinsatures exercent un puissant role regulateur a la fois sur les cellules par leur incorporation dans les phospholipides membranaires, mais aussi sur la microcirculation par la production d’eicosanoides. Le diabete induit une diminution de la synthese de ces acides gras polyinsatures par une inhibition des desaturases, enzymes intervenant dans leurs voies de synthese. La baisse de la biodisponibilite de ces acides gras polyinsatures va produire de profonds bouleversements dans les membranes et dans la microcirculation. Ces perturbations metaboliques sont impliquees en partie dans la survenue des complications degeneratives du diabete comme la neuropathie. Les interventions nutritionnelles a base d’acides gras polyinsatures ont donne des resultats encourageants sur la neuropathie experimentale mais aussi en clinique. Dans la famille des n-6, l’acide gamma linolenique et l’acide arachidonique permettent de prevenir les anomalies physiologiques associees a la neuropathie. Les resultats avec les acides gras de la famille des n-3 sont un peu plus mitiges, sans doute a cause de l’utilisation conjointe d’acide eicosapentaenoique et d’acide docosahexaenoique. En effet, l’acide eicosapentaenoique peut avoir un effet deletere par competition avec l’acide arachidonique dont la concentration est deja diminuee en cas de diabete. Toutefois, l’utilisation de phospholipides enrichis en acide docosahexaenoique a permis d’obtenir des resultats prometteurs dans la neuropathie experimentale. L’utilisation d’acides gras purifies, presentes sous differentes formes, peut ouvrir la voie a de nouvelles perspectives therapeutiques pour le patient diabetique.

Génétique des complications du diabète : neuropathie périphérique

La neuropathie diabetique est une complication frequente du diabete de type 1 et 2. L’hyperglycemie chronique et/ou la carence en insuline dans le nerf peripherique entrainent des troubles metaboliques et vasculaires, responsables des alterations fonctionnelles et des anomalies histologiques caracteristiques observees au niveau de la fibre nerveuse. Des facteurs genetiques ont ete recemment mis en evidence, suggerant l’existence d’une predisposition et/ou d’une protection a la neuropathie diabetique pour certains patients. La recherche de facteurs genetiques par l’etude des polymorphismes de genes impliques dans les differentes voies metaboliques et vasculaires se developpe actuellement avec des resultats encore contradictoires. Les donnees des principales etudes sont rappelees dans cet article. L’identification de genes candidats permettra dans le futur de mieux identifier et prendre en charge les patients a risque de neuropathie diabetique.