alkyl resorcinol, appetite control, type 2 diabetes, Uncategorized

Wheat and rye alkylresorcinols

Background, biomarker or bioactive?

The value of a diet rich in whole grain wheat and rye, excellent sources of alkyl resorcinols, is well recognized. Biskup and coworkers (2016) reviewed bioactive compounds in common wheat and spelt wheat in relation to glycemic control. These bioactive ingredients included not only alkyl resorcinols, but also policosanol, betaine, phytosterols, tocochromanols, myoinositol, lignans, benzoxazinoids, and phytic acid. Direct in vivo and in vitro studies with isolated rye and wheat alkylresorcinols as well as alkyl resorcinols from other sources are fewer in number.

Perhaps these alkyl resorcinols in wheat and rye are what make whole grains a natural treatment for type 2 diabetes.

beneficial compounds in whole grain wheat cardol, betaine, lignan, phytic acid,
Some of the beneficial compounds in whole grain wheat.

Alkyl resorcinols tend to be saturated, i.e. no double bonds in the 15-21 carbon alkyl chains.     The ratios of C17 to C21 chains seem to be popular biomakers for rye versus wheat consumption.  Rye has a higher proportion of C:17 to C:21 alkyl resorcinols than does wheat. Some studies have examined alkyl resorcinols as inhibitors of cyclooxygenase and lipoxygenase, enzymes that utilize the 20 carbon, highly saturated arachindonic acid.  Two endogenous endocannabionids, 2-arachidonyldiacylglycerol and anandamide, are derivatives of endocannabinoids.  Rare, unsaturated, alkyl resorcinols have proven to be interesting.

Saturated long chain alkyl resorcinols next to endocannabinoids 2-AG and annandamide
Saturated long chain alkyl resorcinols next to endocannabinoids 2-AG and annandamide

Whether the metabolites or the grain AR themselves elicit health benefits is unknown.

Those at lower risk of type 2 diabetes tended to have a higher C:17 to C:21 ratio suggesting that a rye diet may be better suited for T2D prevention (Biskup 2016). In a follow up review, Biskup and coworkers (2017) examined potential bioactive compounds in whole grain cereals and their possible roles in prevention of T2D. Alkylresorcinols binding to carbohydrate digesting enzymes α-amylase and  α–glucosidase was speculated to be a factor.

Post menopausal Danish women on a calorie restricted diet lost a greater percentage of body fat when their diets were supplemented with whole wheat versus refined wheat (Kristensen 2012).

In a Danish population of 8-11 year old children, the plasma ratio of C:17 to C:21 alkyl resorcinols was inversely correlated with plasma insulin concentration (Damsgaard 2017).
A Swedish study of adults (Biskup 2016) found that total plasma alkyl resorcinols was not a good predictor of type 2 diabetes. There was however an inverse correlation between the T2D risk and the C:17 to C:21 alkyl resorcinols.  Some other substance in rye might be confounding the results.

The Ontario Ministry of Agriculture, Food, and Rural Affairs sponsored a study of alkyl resorcinols from Triticale grain in mice fed a high fat diet (Agil 2016). This study tested the hypothesis that (1) alkyl resocrinols from a local product would mitigate negative biomarkers associated with a high fat diet. (2) Vitamin E (α-tocopherol) was used for comparison of potential antioxidant activity due to chemical resemblances to alkyl resorcinols. (3) Bran was a third intervention in the high fat diet. None of the three interventions affected weight gain and other body composition parameters. Promising alkyl resorcinol results were observed for fasting blood glucose and glucose tolerance.

A study of Oishi (2015) and coworkers concluded that wheat AR increased glucose tolerance and and insulin sensitivity by suppressing hepatic lipid accumulation and intestinal cholesterol absorption in a mouse model.

Oishi and coworkers compared three groups of mice

  1.  One group was fed a normal refined diet. This group was simply a reference and not used for statistical analysis.
  2. The second group was fed a diet high in fat and sucrose (FS).
  3. The third group was fed an FS diet containing 0.4% (w/w) wheat bran alkylresorcinols (FS-AR).

Parameter.

Whole wheat AR, mouse

Food intake

AR↓

Diet weight gain

AR↓

Epidymal fat

AR↓

Liver triglyceride

AR↓ compared to F/S, same as control diet

Serum triglyceride

No difference in groups

glucose

AR ↓fasting, ↑ insulin induced uptake

insulin

Partial return to baseline response

Akt phosphorylation

AR more responsive to insulin

intestinal bacteria Lactobacillus ↑, Prevotella ↑, Enterococcus ↓

 

Food intake Many have attributed the ability of whole grain foods to decrease the appetite to the bulk they provide and other components such as starches. It is important to note that these other components are removed from consideration by feeding the mice purified AR. It is also interesting to note that the high fat diet with AR, calorie intake was similar to the control diet.

Weight gain Weight gain of the control and F/S-AR groups were indistinguishable. Mice fed the F/S diet reached about 34 g at the end of the study. Addition of AR decreased this weight gain to about 28 g.

Epidymal fat. The epidymus is a structure that connects the testicle to the vas deferens. This structure is associated with a fat pad that is widely used as an index of visceral adiposity in rats (Flamment. AR reduced the epidymal fat pad from just under 6% to just under 4% in mice fed a diet high in fat and sucrose (p<0.01). In this study, mice fed a normal diet had an epidymal fat pad weight of only 2% of the total body weight (Oishi 2015).

Triglycerides   AR did not influence the serum triglyceride content. AR reduced liver triglyceride content from about 30 to about 20 mg per gram tissue. Instead of being released into the blood, feces seem to account for this mass discrepancy of triglycerides.

Serum glucose and insulin. Mice fed the high F/S had 5 hour fasting glucose over 200 mg/dL. Supplementation of the high FS diet with AR decreased the fasting glucose, but not to the baseline of 100 mg/dL of the control diet group (Oishi 2015). Uptake of intraperitoneally injected glucose, was improved but not returned to the baseline of the control diet group.

Akt, is a serine/threonine-specific protein kinase that plays a key role in glucose metabolism in response to insulin. Oishi and coworkers hypothesized that AR would return signaling through this kinase in mice fed a high F/S diet to normal levels. Insulin induced significantly more Ser473 and Thr308 phosphorylation in the FS-AR group than the FS group.  Baseline phosphorylation did not differ between the 2 groups.

Intestinal bacteria  The gut microbiota are beginning to be linked to obesity.   Prevotealla is a genus associated with a high carbohydrate and fiber diet as compared to Bacteroides being associated with a high protein and fat European diet.  No change was observed for the Bacteroides genus.  An increase was seen in the Lactobacillus genus.

Metabolites of long chain alkyl resorcinols from wheat and rye.
Metabolites of long chain alkyl resorcinols from wheat and rye.

Sun and coworkers (2017) found that the whole grain metabolite DHPPA was a good predictor of type 2 diabetes as well as impaired glucose regulation in a Chinese population. Use of DHPPA as a biomarker is agnostic to the C:17 vs C:21 alkyl resorcinol that characterize many Nordic studies.  Note the structure of DHPPA.

What could be the mechanism of action?

Biskup (2017) suggested inhibition of α-amylase, an enzyme found in the saliva and secreted by the pancreas into the small intestine.  www.RCSB.org was searched for structures of human α-amylase bound to something that resembled an alkyl resorcinol.

ethyl caffeate inhibition of alpha-amylase, implications for long shain acryl resorcinols.
ethyl caffeate inhibition of alpha-amylase, implications for long shain acryl resorcinols.

Ethyl caffeate inhibits α-amylase  by disordering precisely those polypeptide chain segments that make up the active site binding cleft.   Note that the positions of hydroxyl groups on the benzene ring of caffeic acid are slightly different than that of resorcinol.

resorcinol stabilizes the insulin hexamer
The insulin peptide exists as a hexamer, stabilized by resorcinol. Would the 5′ alkyl group influence the stability of the hexamer?

Phenol and derivatives like resorcinol along with zinc have been used to stabilize the insulin hexamer such that it slowly breaks up into the active monomeric form.  This image was obtained from Openi.  Insulin, injected in the hexamer form, slowly breaks up into the active monomeric form in the blood.  In the interaction map from 1EVR (rcsb.org) rescorcinol is hydrogen bonding to Cys11 and Cys6 of the alpha subunit and His5 of the F subunit.  A Leu12 of the B subunit interacts with the 5′ region of the resorcinol ring.  It is unknown if an alkyl chain in tis position would prevent an interaction.

 

References

Agil R, Patterson ZR, Mackay H, Abizaid A, Hosseinian F.z92016) Triticale Bran Alkylresorcinols Enhance Resistance to Oxidative Stress in Mice Fed a High-Fat Diet. Foods. 2016 Jan 5;5(1). pii: E5

Andersson U, Dey ES, Holm C, Degerman E. Rye bran alkylresorcinols suppress adipocyte lipolysis and hormone-sensitive lipase activity. Mol Nutr Food Res 2011;55(Suppl 2):S290–3.

Biskup I, Kyrø C, Marklund M, Olsen A, van Dam RM, Tjønneland A, Overvad K, Lindahl B, Johansson I, Landberg R. (2016) Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and risk of type 2 diabetes in Scandinavian men and women. Am J Clin Nutr. 104(1):88-96.

Biskup I, Gajcy M, Fecka I.(2017)The potential role of selected bioactive compounds from spelt and common wheat in glycemic control. Adv Clin Exp Med. 26(6):1013-1019. Review.

Damsgaard CT, Biltoft-Jensen A, Tetens I, Michaelsen KF, Lind MV, Astrup A, Landberg R. (2017) Whole-Grain Intake, Reflected by Dietary Records and Biomarkers, Is Inversely Associated with Circulating Insulin and Other Cardiometabolic Markers in 8- to 11-Year-Old Children. J Nutr. 147(5):816-824.

Gunenc A, Kong L, Elias RJ, Ziegler GR.(2018) Inclusion complex formation between high amylose corn starch and alkylresorcinols from rye bran. Food Chem. 259:1-6

Kristensen M, Toubro S, Jensen MG, Ross AB, Riboldi G, Petronio M, Bügel S, Tetens I, Astrup A.(2012)Whole grain compared with refined wheat decreases the percentage of body fat following a 12-week, energy-restricted dietary intervention in postmenopausal women. J Nutr.142(4):710-6.

Oishi K, Yamamoto S, Itoh N, Nakao R, Yasumoto Y, Tanaka K, Kikuchi Y, Fukudome S, Okita K, Takano-Ishikawa Y. (2015)Wheat alkylresorcinols suppress high-fat, high-sucrose diet-induced obesity and glucose intolerance by increasing insulin sensitivity and cholesterol excretion in male mice. J Nutr. 145(2):199-206.

Sun T, Rong Y, Hu X, Zhu Y, Huang H, Chen L, Li P, Li S, Yang W, Cheng J, Yang X, Yao P, Hu FB, Liu L. (2017) Plasma Alkylresorcinol Metabolite, a Biomarker of Whole-Grain Wheat and Rye Intake, and Risk of Type 2 Diabetes and Impaired Glucose Regulation in a Chinese Population. Diabetes Care. 2017 Dec 20. pii: dc171570. doi: 10.2337/dc17-1570.

 

Does any of this sound commercially viable?

Does any of this sound commercially viable?  Would anyone buy a gluten free extract from wheat bran that contained alkyl resorcinols?  If you have any thoughts on this matter, don’t hesitate to contact me.   I’ve some ideas for large scale extraction of these compounds.

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