Saturday, June 7, 2008

Wheat: Raises Insulin and Upregulates 'Bad' Genes

Ancient Wheat: 'Gladiator '
'Now We Are Free' Hans Zimmer, Lisa Gerrard

Can our food alter gene expression?

Absolutely so!

As Hippocrates once said, 'Let food by thy Medicine... and Medicine thy Food.' I'm sure he didn't mean medications as they exist now as chemicals or benzene rings (derived from petroleum) mass synthesized in factories for global consumption. The below FUNGENUT study recently showed the importance of how different sources of carbohydrate containing foods immediately changes gene expression in our favorite organ -- the omentum -- the stubborn fat lying on our bellies -- yes, the one covering up your those fabulous 6-pack abs. (Diagram: Ludwig, D. (2002) JAMA )

In a small group of subjects, 2 diets (Rye-Pasta -- mildly lower in GI; Oat-Wheat-Potato -- high GI carbs) were compared for 3 months. At the end no change in weight or insulin resistance, insulin levels, or glucose concentrations occurred. The profile for insulin (1st phase) secretion mildly improved in the Rye-Pasta group.
Interestingly, other than showing that wheat sucks (and perhaps oat and potato) gene expression was entirely affected by simple changes in carbohydrate content and the Glycemic Index (GI measures how long and how fast glucose enters the blood stream after consumption). Rye (endosperm) bread has a GI (glycemic index) of approximately 60-70. Pasta's GI is about 60-70 as well (depending on the type and how al dente/not-overcooked).

Wheat bread on the other hand is about 90-100 (close to pure glucose). Oats about 70 and potatoes 80-100 (without cream or butter which slows the uptake of starches into the stomach blood circulation which would effectively lower the GI). American Russet potato even exceeds glucose, 110 (!wow).

"Prior microarray studies found differences in gene expression between overweight and lean individuals (2) and after energy restriction (3); however, changes in the ratio of fat to carbohydrate did not alter gene expression (3). The study by Kallio et al makes a significant contribution to the literature by demonstrating the potentially major effects of dietary composition on gene regulation, independent of energy intake and body weight. Two specific findings concerning the low-insulin-response diet merit particular attention: the down-regulation of both hormone-sensitive lipase (HSL) and TCF7L2. "

"HSL, a key enzyme in the release of fatty acids from adipose tissue, has been proposed to affect body weight and metabolic variables. Mice made deficient in HSL by genetic manipulation are resistant to genetic- or diet-induced obesity (4, 5). Women carrying an allele associated with decreased HSL activity have lower fasting and simulated insulin concentrations, and men with this allele have lower nonesterified fatty acid concentrations (6)..."

"The transcription factor TCF7L2 is the strongest known genetic predictor of type 2 diabetes. A microsatellite within intron 3 of this transcription factor occurs with increased frequency in individuals with type 2 diabetes, which corresponds to an estimated population attributable risk of 21% (7)..."

"The present study (BELOW) has direct implications concerning our understanding of the dietary glycemic index (GI). The GI is a system for classifying carbohydrate-containing foods according to how blood glucose concentrations change in the postprandial period (reviewed in reference 8). High-GI meals produce greater postprandial insulin concentrations and C-peptide excretion than do nutrient-controlled low-GI meals. Observational and interventional studies have linked GI to the risk of obesity, diabetes, heart disease, and cancer, although the topic remains much debated. One factor contributing to this ongoing controversy is the relative paucity of data regarding the relevant molecular mechanisms. If differences in insulin secretion mediate the genetic effects observed by Kallio et al, similar effects would be expected to occur with both low-GI and high-GI diets. This possibility is supported by a human study and several rodent studies, which showed potentially beneficial changes in the expression of HSL and other relevant genes with a low-GI diet (8, 9)."

Contrastingly, the high-GI wheat (+oat+potato) diet upregulated 62 genes including those associated with activation of DEATH GENES:
-- Stress
-- Oxidative damage
-- Impaired immunity

So... high carb diet translates to... the equivalence of a STRESS RESPONSE. The authors discuss in more depth the results from the FUNGENUT Study..."Interestingly, the 12-wk oat-wheat-potato diet seemed to especially activate genes responding to stress. The oxidative stress pathway, interleukin pathway, and inflammation mediated by the chemokine and cytokine signaling pathway were also activated. Moreover, the present data suggest that the oat-wheat-potato diet, which induced repeated high insulin responses, can provoke alterations in immune status and inflammation. It is well established that adipose tissue has a role in inflammation (39). Cross-sectional epidemiologic data suggest that whole grains and a low-glycemic-index diet may reduce systemic inflammation in women with T2DM (40). Up-regulation of gene expression for serum and glucocorticoid-regulated kinase suggests activation of the glucocorticoid axis, which can occur in response to various stress stimuli (cytokines, aldosterone, growth factors, oxidative stress, heat shock protein activation, and glucocorticoids) (41). Activation of the pituitary-adrenal glucocorticoid axis may be involved in the pathogenesis of the metabolic syndrome (42)."

Dietary carbohydrate modification induces alterations in gene expression in abdominal subcutaneous adipose tissue in persons with the metabolic syndrome: the FUNGENUT Study.
Kallio P, et al.
Am J Clin Nutr. 2007 May;85(5):1169-70.
Department of Clinical Nutrition, Food and Health Research Centre, University of Kuopio, Kuopio, Finland.
BACKGROUND: Diets rich in whole-grain cereals and foods with a low glycemic index may protect against type 2 diabetes, but the underlying molecular mechanisms are unknown.
OBJECTIVE: The main objective was to test whether 2 different carbohydrate modifications--a rye-pasta diet characterized by a low postprandial insulin response and an oat-wheat-potato diet characterized by a high postprandial insulin response--affect gene expression in subcutaneous adipose tissue (SAT) in persons with the metabolic syndrome.
DESIGN: We assessed the effect of carbohydrate modification on SAT gene expression in 47 subjects [24 men and 23 women with a mean (+/-SD) age of 55 +/- 6 y] with the features of the metabolic syndrome in a parallel study design. The subjects had a mean (+/-SD) body mass index (kg/m(2)) of 32.1 +/- 3.8 and a 2-h plasma glucose concentration of 8.0 +/- 2.3 mmol/L. Adipose tissue biopsies were performed, and oral-glucose-tolerance tests and other biochemical measurements were conducted before and after the intervention.
RESULTS: We detected 71 down-regulated genes in the rye-pasta group, including genes linked to insulin signaling and apoptosis. In contrast, the 12-wk oat-wheat-potato diet up-regulated 62 genes related to stress, cytokine-chemokine-mediated immunity, and the interleukin pathway. The insulinogenic index improved after the rye-pasta diet (P=0.004) but not after the oat-wheat-potato diet. Body weight was unchanged in both groups.
CONCLUSIONS: Dietary carbohydrate modification with rye and pasta or oat, wheat, and potato differentially modulates the gene expression profile in abdominal subcutaneous adipose tissue, even in the absence of weight loss.
PMID: 17490981

These wonderful graphs from Finland researchers illustrate how the toxic effects of grain sources of carbohydrates occur when wheat and rye are fed to healthy volunteers. Above a glucose blood concentration of 150 mg/dl (=8.3 mmol/L), glucose starts to cause changes in protein folding and glycosylating proteins and tissues. Diabetes micro-vascular complications like eye/kidney/nerve ending damage are related to toxic concentrations of glucose. Imagine sugar coating the organs over time. The higher the concentration, the longer the duration, the more thicker and more damaging the sugar coating. Insulin is controlled by several factors. Food is one of the most potent controllers, with carbohydrates and their respective GIs raising insulin levels the most. Excessive insulin induces inflammation, which can progress and cause arterial stiffness, high blood pressure, Metabolic Syndrome, obesity, and also heart disease. Longevity has been associated with lower insulin levels. The below trial demonstrates the direct relationship in 18-year old men between fasting insulin and the existence of cardiovascular markers. The curves for low or no GI foods have no peaks and in comparison are relatively flat. Without a surge in insulin, inflammation is kept at bay.

Foods with no or little GI:
-- Non-starchy vegetables
-- Protein (tofu, meat, fish, etc)
-- Monounsaturated fat
-- Omega-3 PUFA
-- Saturated fat

The goal for an optimzed health status for nearly all metabolic and cardiovascular goals is NORMAL. Therefore the optimal range for insulin is as low as possible less than 5 - 10 mIU/L. The goal for glucoses pre-meal is less than 83 (=4.6mmol/L) and after meals less than 110 to 120 (=6.1 to 6.67mmol/L).

Relationship between fasting insulin and cardiovascular risk factors is already present in young men: the Verona Young Men Atherosclerosis Risk Factors Study.
Bonora E, et al. Eur J Clin Invest. 1997 Mar;27(3):248-54.
The associations between fasting plasma insulin concentration and risk factors for cardiovascular disease were examined in 979 18-year-old men participating in the Verona Young Men Atherosclerosis Risk Factors Study, a cross-sectional population-based study. Body mass index (BMI), waist-to-hip ratio (WHR), plasma triglycerides and uric acid concentrations, and blood pressure values significantly increased, and the high-density lipoprotein (HDL)-total cholesterol ratio decreased, across quartiles of fasting insulin. Total and low-density lipoprotein cholesterol, concentrations did not change significantly with the increase in fasting insulin levels. After adjustment for BMI, WHR, smoking, alcohol intake and physical activity, only plasma triglycerides significantly increased across insulin quartiles (F = 7.1; P less than 0.001). However, systolic blood pressure and uric acid were close to statistical significance (P = 0.06-0.07). Multiple linear regression analysis confirmed that plasma insulin was independently correlated with plasma triglycerides and, to a lesser extent, with blood pressure and uric acid concentration. This analysis pointed out that BMI was a stronger independent predictor of all cardiovascular disease risk factors than fasting insulin. When subjects were categorized according to the number of metabolic and haemodynamic disorders occurring within the same individual, subjects with multiple disorders (i.e, three or four) had higher plasma insulin levels than those with none or few disorders, even after adjusting for BMI, WHR and behavioural variables (F = 4.0; P less than 0.01). These results indicate that hyperinsulinaemia is already associated with a cluster of cardiovascular disease risk factors in young adulthood, the strongest independent association being with plasma triglycerides. PMID: 9088862


Dr. B G said...

Thank you -- Cute video! (need to delete the 2 hypens) Are you Ms. Allport?

Gyan said...

Is the metabolic response to high-GI diet better for physically active subjects?

I also wonder how the wheat was fed to the subjects-as a breakfast cereal or as a bread or as a porridge or some ethnic preparation.

Does the added fat not matter?. is it not material if the fat be butter or margerine?

Dr. B G said...

Hi Gyan,

I don't believe high GI is ever good for athletes... or non-athletes. And the whole carb loading thing is an urban myth as well :)
Remember several famous marathoners develop MIs -- they probably had some metabolic derangement secondary to their high GI diets (and high inflammatory responses to chronic endurance training/events) AND probably some toxic heart risk factor like elevated Lp(a).
--Jim Fixx
--Alberto Salazar
--et cetera

In the study, I believe they used wheat bread, potatos (including an instant mashed version), and oatmeal. The researchers did not address glycemic index per se but these foods all have high GIs 90-100.

As you are aware margarine is hydrogenated and makes it very 'unnatural'. I feel real (pasture fed if possible) butter is the best.


Dr. B G said...

Dr. Davis wrote about marathon runners here (sorry haven't learned how to hyperlink

Dr. William Davis said...

Dr. BG--

Great thoughts!

I shudder to think that I spent the first 35 years of my life indulging in what amount to a high-GI diet, but telling myself it was good for me.

I only hope years of low-GI can unwind the damage!

Dr. B G said...

Hi Dr. Davis!

I feel the exact way! My pancreas has been quite 'pounded' over several decades of my life...sadly...

However I am so grateful that I discovered Track Your Plaque and your amazing BLOG. Not only does my pancreas have a chance of rejuvenation, but vitality and longevity can be longterm realities too :)

I hope many others will be as fortunate!

Thank you!

Stephan Guyenet said...


Just wanted to let you know, your blog is #3 when you Google FUNGENUT. Keep up the good work and soon your post will be higher than the NCBI link, haha!

I'm really interested to know whether the effect was due to the wheat or the glycemic index. I think you know which way I lean but it would be nice to get some hard data.

Dr. B G said...

Hey Stephan!

THANKS! I didn't know that :)

I need to see if there exist follow up studies to the FUNGENUT b/c gene expression is HAWT right now. I'd love to hear your deep thoughts on this topic. Surprisingly neither rye bread nor wheat pasta which both contain gluten did not trigger the stress response genes... White potato of course (naturally gluten-free) did. So...hard to conclude but as you mentioned it's probably the high GI that is more of a factor in this case v. gluten/WAG/etc.


Dr. B G said...

Of course with that said... it's probably the WHEAT.

Pasta-- maybe by boiling the heck out of it, the gluten toxicity is somewhat diluted out? Like legumes/lectins and the process of soaking overnight?

Anonymous said...

In Heat, which is a memoir about a wanna-be chef, the author talks about how the earliest pasta dishes in Italy where made from soaked/fermented flours.

Heat: An Amateur's Adventures as Kitchen Slave, Line Cook, Pasta-Maker, and Apprentice to a Dante-Quoting Butcher in Tuscany

Bill Buford

Dr. B G said...


Sounds like an excellent read! I love cooking books (Heartburn by Nora Ephron and the autobio by Tender at the Bone and Saphires by Ruth Reichl)!!

Our family has been gluten-free for over one year now. Honestly, knowing the damage that gluten/gliadin/ phytic acid cause for my family, I cannot not with good conscience soak or ferment toxic food poisons for them. I wish that were not the case, but for some reason it is.

Paleo, grain free (and mostly dairy and legume-free) is the only way for us right now... We don't even consume much rice b/c I'm too lazy to soak/ ferment it (besides rice raises my blood sugars for like... 5 awful-minutes where I feel like cr*p).

It's funny to look at this one year later... I appreciate your thoughts and will look forward to hearing more of your ideas (and transformations)!


Neonomide said...

Hi G!

I think this goes closely with FUNGENUT so there...

Today I was in a lecture on Nordic diet, which was about metabolomics and in depth markers about metabolic diseases. Here are some studies by the lecturer you might be interested:

Lankinen M, Schwab U, Erkkilä A, et al. Fatty fish intake decreases lipids related to inflammation and insulin signaling – a lipidomics approach. PLoS One 2009; 4:e5258.

Lankinen M, Schwab U, Gopalacharyulu P.V, et al. Dietary carbohydrate modification alters serum metabolic profiles in individuals with the metabolic syndrome. NMCD 2010;20:249-257.

Lankinen M, Schwab U, Seppänen-Laakso T, et al. Metabolomic analysis of plasma metabolites that may mediate effects of rye bread on satiety and weight maintenance in postmenopausal women. J Nutr 2011;141:31-36

Same university and same unit as FUNGENUT. Some nice nutrigenomics stuff was there too.

According to Lankinen, post-meal BG spikes with rye bread are not the bad guy, but lesser insulin response compared to white breads. Lankinen also claimed that rye seems to be quite different (in a better sense) with many metabolic markers compared to other grains ie wheat.

She considered this unknown effect to be the "rye factor".

I of course brought up paleo studies by Lindeberg & Jönsson and asked if there would be any additional effects by total grain elimination. :-)

Who knows, Nordic diet is really pushed nowadays in Scandinavia as an alternative for Mediterranean diet. Many BIG studies going on at the moment and coming. (including a giant randomized trial on Vitamin D !!!)

Here is the pic of Nordic diet pyramid at the moment:

I think it's a remarkable improvement on the old model left, what do you think?

Oh and "no wheat" seems to be a real trend here now, even though reasons are not too obvious.

- Neo

Dr. B G said...

Neo --
I am sorry for the delay -- Love Lankinen -- the work is solid. High GI oats, wheat, white potatoes are sin. I've heard of good anecdotes with barley though it is a gluten grain... Perhaps rye has some similar property as you mentioned? Thank so much for the links -- I saw the metabolomic results but the others are fantastic! Would love to hear more about the presentation! Can you email me? What was the response when you asked about grain elimination??? *haa* I bet Dr.Enfelt the Swedish low carb guy is making a dent... ( He's very cool, met him at MovNat after the AHS.

FUNGENUT is an awesome study -- in vivo human is the best way to go.