Posts Tagged ‘diabetes and omega3’

Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPAR α/γ activity in microvascular endothelial cells.

Saturday, September 10th, 2011

Raffaele De Caterina, MD, PhD, Institute of Cardiology, “G. d’Annunzio” University – Chieti, C/o Ospedale SS. Annunziata, Via dei Vestini, 66013 Chieti, Italy, Tel: +39 0871 41512, Fax: +39 0871 553 461, E-mail: rdecater@unich.it.

Abstract

Microvascular dysfunction occurs in insulin resistance and/or hyperinsulinaemia. Enhanced uptake of free fatty acids (FFA) and oxidised low-density lipoproteins (oxLDL) may lead to oxidative stress and microvascular dysfunction interacting with CD36, a PPARα/γ-regulated scavenger receptor and long-chain FFA transporter. We investigated CD36 expression and CD36-mediated oxLDL uptake before and after insulin treatment in human dermal microvascular endothelial cells (HMVECs), ± different types of fatty acids (FA), including palmitic, oleic, linoleic, arachidonic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids. Insulin (10⁻⁸ and 10⁻⁷ M) time-dependently increased DiI-oxLDL uptake and CD36 surface expression (by 30 ± 13%, p<0.05 vs. untreated control after 24 hours incubation), as assessed by ELISA and flow cytometry, an effect that was potentiated by the PI3-kinase inhibitor wortmannin and reverted by the ERK1/2 inhibitor PD98059 and the PPARα/γ antagonist GW9662. A ≥24 hour exposure to 50 μM DHA or EPA, but not other FA, blunted both the constitutive (by 23 ℜ∓ 3% and 29 ± 2%, respectively, p<0.05 for both) and insulin-induced CD36 expressions (by 45 ± 27 % and 12 ± 3 %, respectively, p<0.05 for both), along with insulin-induced uptake of DiI-oxLDL and the downregulation of phosphorylated endothelial nitric oxide synthase (P-eNOS). At gel shift assays, DHA reverted insulin-induced basal and oxLDL-stimulated transactivation of PPRE and DNA binding of PPARα/γ and NF-κB. In conclusion, omega-3 fatty acids blunt the increased CD36 expression and activity promoted by high concentrations of insulin. Such mechanisms may be the basis for the use of omega-3 fatty acids in diabetic microvasculopathy.

boosting omega-3 intake through diet or supplements might be a safer way to improve insulin sensitivity in patients with diabetes or pre-diabetes as well as helping to prevent retinopathy a major form of blindness

Wednesday, July 13th, 2011

Omega-3 fatty acids -fats commonly found in fish oil specifically EPA and DHA — were shown several years ago to prevent retinopathy, a major form of blindness, in a mouse model of the disease. A follow-up study, from the same research team at Children’s Hospital Boston, now reveals exactly how omega-3’s provide protection, and provides reassurance that widely used COX-inhibiting drugs like aspirin and NSAIDs don’t negate their benefit.
The findings, published in the February 9th issue of Science Translational Medicine, also suggest that omega-3’s may be beneficial in diabetes.
Retinopathy — an eye disease caused by the proliferation of tortuous, leaky blood vessels in the retina — is a leading cause of blindness, affecting 4.1 million Americans with diabetes (a number expected to double over the next 15 years) and many premature infants. Another 7 million-plus Americans have age-related macular degeneration (AMD); this too will increase as the population ages. The most common “wet” form of AMD is also caused by abnormal blood vessel growth.
The ability to prevent these “neovascular” eye diseases with omega-3 fatty acids could provide tremendous cost savings, says Children’s ophthalmologist Lois Smith, MD, PhD, senior investigator on the study. “The cost of omega-3 supplementation is about $10 a month, versus up to $4,000 a month for anti-VEGF therapy,” she says, referring to drugs such as Macugen and Lucentis used in AMD and diabetic retinopathy. “Our new findings give us new information on how omega-3s work that makes them an even more promising option.”
Omega-3 fatty acids, highly concentrated in the retina, are often lacking in Western diets, which tend to be higher in omega-6 fatty acids. In Smith’s previous study, mice fed diets rich in omega-3 fatty acids by Smith’s team had nearly 50 percent less pathologic vessel growth in the retina than mice fed omega-6-rich diets. Smith and colleagues further showed that the omega-3 diet decreased inflammatory messaging in the eye.
In the new study, they document another protective mechanism: a direct effect on blood vessel growth (angiogenesis) that selectively promotes the growth of healthy blood vessels and inhibits the growth of abnormal vessels.
In addition, Smith and colleagues isolated the specific compound from omega-3 fatty acids that has these beneficial effects in mice (a metabolite of the omega-3 fatty acid DHA, known as 4-HDHA), and the enzyme that produces it (5-lipoxygenase, or 5-LOX). They showed that COX enzymes are not involved in omega-3 breakdown, suggesting that aspirin and NSAIDs — taken by millions of Americans — will not interfere with omega-3 benefits.
“This is important for people with diabetes, who often take aspirin to prevent heart disease, and also for elderly people with AMD who have a propensity for heart disease,” says Smith. (One drug used for asthma, zileuton, does interfere with 5-LOX, however.)
Finally, the study demonstrated that 5-LOX acts by activating the PPAR-gamma receptor, the same receptor targeted by “glitazone” drugs such as Avandia, taken by patients with type 2 diabetes to increase their sensitivity to insulin. Since these drugs also increase the risk for heart disease, boosting omega-3 intake through diet or supplements might be a safer way to improve insulin sensitivity in patients with diabetes or pre-diabetes. “There needs to be a good clinical study in diabetes,” Smith says.
Smith works closely with principal investigators at the National Eye Institute who are conducting an ongoing multicenter trial of omega-3 supplements in patients with AMD, known as AREDS2. The trial will continue until 2013. An earlier retrospective study, AREDS1, found higher self-reported intake of fish to be associated with a lower likelihood of AMD.
In addition, Smith is collaborating with a group in Sweden that is conducting a clinical trial of omega-3 fatty acids in premature infants, who are often deficient in omega-3. That study will measure infants’ blood levels of omega-3 products and follow the infants to see if they develop retinopathy. If results are promising Smith will seek FDA approval to conduct a clinical trial in premature infants at Children’s.
Meanwhile, in her lab work, Smith plans to continue seeking beneficial lipid pathways, while looking for the most harmful omega 6 metabolites. “We found the good guys, now we’ll look for the bad ones,” says Smith. “If we find the pathways, maybe we can selectively block the bad metabolites. We would hope to start with drugs that are already available.”
Przemyslaw Sapieha and Andreas Stahl in Smith’s lab were co-first authors on the study. Funders include the National Eye Institute, the Children’s Hospital Boston Mental Retardation and Developmental Disabilities Research Center, Research to Prevent Blindness, the Alcon Research Institute, MacTel Foundation, the Roche Foundation for Anemia Research and the V. Kann Rasmussen Foundation.

Omega 3 fish oil may help activate anti-diabetic genes

Tuesday, March 8th, 2011

Fish oils may help to activate anti-diabetic genes

Polyunsaturated fatty acid fish oils may activate genes that regulate fat cell differentiation and glucose homeostasis, according to new research on mice.

The new study published in Journal of Nutritional Biochemistry suggests supplementation with omega3 fish oil activates the transcription factor PPARγ, increasing regulation of adipocytes and helps to maintain glucose homeostasis.

“We demonstrated that adipogenic genes and glucose metabolism genes were elevated in PPARγ transgenic mice when fed fish oil. This transgenic mouse model provided direct evidence to demonstrate omega 3 , especially EPA  regulate glucose homeostasis through interaction with PPARγ,” wrote the researchers, led by Dr Yu-Hsiang Yu from the National Taiwan University

Vital roles

Peroxisome-proliferator-activated receptor γ (PPARγ) is considered an important transcription factor in regulating fat cell (adipocyte) differentiation, and is also known to play a vital role in maintaining glucose homeostasis. The transcription factor is a target for many anti-diabetic drugs as activation promotes glucose dispersal.

Activation of PPARγ occurs through the binding of specific ligand molecules; however, polyunsaturated fatty acids such as arachidonic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are also known to have a high binding affinity for PPARγ.

Previous studies suggest that polyunsaturated fatty acids (PUFA) and their metabolites are able to regulate PPARγ activity, demonstrating that DHA treatment increases PPARγ-responsive gene expression in a cell model.

However, most research demonstrating PPARγ activity uses in vitro cell models and there is currently no direct evidence available to demonstrate that polyunsaturated fatty acids are able to activate PPARγ in vivo.

The authors said the current experiment was designed to determine the potential for PUFA, particularly EPA and DHA, to activate the function of PPARγ in vivo.

Wild-type and transgenic mice – with over expressed PPARγ –were supplemented with either fish oil or PPARγ ligands (rosiglitazone) for four months to investigate whether fish oils have similar effects to true PPARγ ligands in vivo.

Results

Dietary rosiglitazone fed mice had a significantly lower feed intake, but had no significant effect on body weight or fat pad weigh, whereas fish oil supplementation did not significantly decrease feed intake, but significantly decreased body and fat pad weight, found the researchers.

Dr. Yu and colleagues reported that adipogenic genes (LPL, FAT, SREBP-1c and FAS) were markedly up-regulated by rosiglitazone supplementation. Fish oil supplementation increased LPL and FAT, but not SREBP-1c or FAS; however, stained muscle sections indicated no lipid accumulation in skeletal muscle.

Researchers noted that transgenic mice fed a fish oil supplementation had increased expression of adipogenic and glucose uptake genes, leading to reduced plasma glucose concentration.

Natural regulator

The authors suggested that polyunsaturated fatty acids, particularly EPA and DHA, may serve as a natural regulator of glucose uptake in vivo, stating that such effects are mainly mediated through PPARγ activation.

“Our data demonstrated that the PPARγ-regulated glucose metabolism genes, GLUT-4 and ADN were dramatically increased in skeletal muscle of PPARγ transgenic mice when fed rosiglitazone or fish oil, suggesting activation … by either ligand,” concluded the authors.

Source: Journal of Nutritional Biochemistry

“The function of porcine PPARγ and dietary fish oil effect on the expression of lipid and glucose metabolism related genes”

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