DM, NAFLD, and conjugated linoleic acid (omega 6); what is the link

DM, NAFLD, and conjugated linoleic acid (omega 6); what is the link Mona Hegazy Professor of Internal Medicine Hepatology Department Cairo University Egypt

Agenda Congugated lionleic fatty acid NAFLD and insuline resistance CLA and NAFLD In EGYPT What to take to be safe

Essential fatty acids; are necessary for human health, but the body can not make them, so you have to get them through food Two main fatty acids essential in diet are linoleic (omega-6), and alpha-linolenic (omega-3) fatty acids. Both of them are polyunsaturated fatty acids. They are bioactive lipids/fa serve as functional food that are important in modulating metabolism and body weight

linoleic acid (omega 6) Linoleic acid (in large amount in vegetable oil) Gamma-linoleic acid GLA ( linoleic acid converted into GLA in the body, also it present in some plants borage& black currant seeds oil )

linoleic acid (omega 6) Arachidonic acid AA ( it is the break down of GLA) Conjugated linoleic acid CLA Salas-Salvado J, et al. 2006 Critical reviews in food science and nutrition,46;6:479-488 Hung h L, et al 2007. obesity surgery,17;11. 1457-1463

The biological activity of CLA was first discovered in the year 1987 by a team of researchers who showed that; it could help fight cancer in mice. Later, other researchers discovered that, it could also reduce body fat levels. Eulittz K, et al 1999. Lipid,34;4:873-877 Sehat N, et al 1999. Lipids,34;8: 407-413

There are 28 different forms of CLA, but two of the most important ones are c9, t11 and t10, c12 The difference between the CLA forms is that the double bounds are arranged differently. Fabbrini E, et al (2010). Hepatology, 51:2:679-689

This miniscule in different double bounds arrangement can make a world of difference to our cells.

CLA is a natural trans-fat that is found in many healthy foods. Industrial trans-fats are harmful, while natural one in animal foods are not. The main dietary sources of CLA are animal foods from ruminants, such as cows, goats and sheep. The total amount of CLA in these foods varies greatly depending on what the animals ate ( CLA content is 300-500% higher in beef and dairy from grass-fed cows, compared to grain-fed cows) Hung H L, eta l, (2007), Obesity Surgery,17: 11: 1457-1463.

It is important to keep in mind that: the CLA you find in supplements is NOT derived from natural foods. It is made by chemically altering safflower and sunflower oils. The lionleic acid in the oils turned into CLA via chemical process. Foods are mostly c9,t11, while the supplements are very high in t10, c12, which is never found in large amounts in nature. So, CLA taken in supplement does not have the same healt effects as CLA gotten from foods Park Y & Pariza (200&). Food Research International, 40;3: 311-323.

Health benefits of conjugated linoleic acid Combating DM & obesity: CLA converted to gamma GLA in the body, defeciency of GLA predispose people to develop IR, also GLA can prevent diabetic neuropathy. GLA decrease fat deposition in the body Cardivascular effect ( LDL, TGs, while HDL) Anti-inflammatory effects (activating the powerful peroxisome proliferator activated receptor PPARs system. Potent anti-cancer, Rheumatoid artheritits, atopic dermatitis, multiple sclerosis and osteoporosis. Das UN (2008). Lipid Health Dis. 15; 7:37 & Kelley DS, et al. (2009). British J. of Nutrition,101:5:701-708

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NAFLD and insulin resistance

NASH may be present in up to 66% of individual with morbid obesity and/ or type 2 DM. Chalasani N, et al. Gastroenterology 2012,45; 112-18 Up to 85% of subjects with NAFLD compared to 30% in controls are insulin resistant and have abnormal glucose metabolism (pre-diabetes or T2DM) of which they were unaware. Ortiz-Lopez C, et al. Diabetes care.2012,74; 243-39

NAFLD as a component of the metabolic syndrome has often been identified with insulin resistance, but only limited studies have carried out actual measurements of insulin sensitivity among this group of individuals For inter-population comparisons, it is necessary to know normal values of HOMA-IR for each population. Although HOMA-IR has been widely used, there is hardly any consensus on the cut-off points for classification of insulin resistance.

HOMA-IR index cut-off values Tehran University. Iran HOMA-IR Sensitivity Specificity Non-diabetic 1.77% 57.3% 65.3% Non-diabetics 3.88% 49.7% 69.6% (metabolic syndrome) Diabetics 4.33% 45.4% 69% Esteghamati A, et al. Nutrition& Metabolism 2010 Spain Non-diabetics 1.84% 63% 73.5% Non-diabetics, 2.05% 48.8% 72.3% (metabolic syndrome) Diabetics 3.46% 51.6% 81.3% Gayoso-Diz P, et al. Gut 2011

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Conjugated Linoleic acid, insulin resistance and NAFLD

Liver plays an important role in energy homeostasis. As it converts excessive dietary glucose into FA which exported as TG. Liver is an important target for CLA effects irrespective of the physiological condition. Halad GV, et al.2009. European J. of Nutrition,48;7:409-418

Cis-9, trans-11 CLA promotes insulin sensitivity by reducing adipose inflammation. It enhances hepatic mitochondrial function and protects against oxidative stress by increasing activities of mitochondrial antioxidant enzymes. Of the different CLA isomers, trans-10,cis-12 CLA causes increased lipid accumulation leading to hepatic steatosis. Degrace P, et al (2003). Dig Dis Sci;25(10):2622-2628 Rosso N, et al. 2014. World Journal Gastroenterol, 20; 9 :38-49.

Trans-10, cis 12 CLA causes severe lipodystrophy reducing the levels of leptin and adiponectin, which leads to hepatic steatosis. Re-establishing the levels of leptin or adiponectin either through external supplementation (in case of leptin), or induction using rosiglitazone (in case of adiponectin), attenuated hepatic steatosis condition and normalized the insulin levels in trans-10, cis-12 CLA-fed mice. Nagao K, et al. 2008. lipids in health and disease.7;8:214-121

In Egypt

In faculty of Medicine, Cairo University (2015-2016). We had conducted a study on lean and obese diabetic patients, they also had different grade of NAFLD severity, Non of our patients or the healthy controls had history of taking any forms of linoleic FA supplementation.

All our patients were controlled on oral hypoglycemic medications. All clinically and anthropometrically assessed. HOMA-IR was calculated, and CLA serum level had been assessed.

BMI of different groups 35 14 30 12 25 10 208 156 104 52 0 CLA level in normal and diabetics Healthy healthy contol participants DM Diabetic with with normal normal BMI BMI Obese Obese DMdiabeics CLA (ng/ml) BMI

CLA in diabetic patients with NAFLD 15 10 5 CLA (ng/ml) Column1 0 Mild steatosis moderate steatosis severe steatosis

Axis Title Relation between CLA & HOMA-IR in diabetic patients with NAFLD Chart Title 18 16 14 12 10 8 6 4 2 0 mild steatosis moderate severe steatosis steatosis Axis Title CLA(ng/ml) HOMA-IR

Axis Title NAFLD & BMI in diabetic patients 35 30 25 20 15 10 5 0 Mild steatosis Chart Title Moderate severe steatosis steatosis Axis Title BMI

CLA was significantly lower in diabetic patients compared to healthy participants. There is definitive association between CLA and obesity. In NAFLD patients subgroups, CLA was lower in in diabetic with mild steatosis ( almost Non-NASH), and lowest level recorded in patient with severe steatosis (NASH) What we had assess was mainly c9,t11 because non of our patients was taken CLA supplementations through their lifes.

What to take to be safe and beneficial

Foods are mostly c9,t11, while the supplements are very high in t10, c12, which is never found in large amounts in nature. So, CLA taken in supplement form does not have the same healt effects as CLA gotten from foods Park Y & Pariza (2013). Food Research International, 40;3: 311-323.

In Obese, non-diabetics with high insulin resistance, Diabetics,and NAFLD patients, reduce the total calories intake, recommend weight loss, but keep 1 serving fat/day(saturated)

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