Animal Pharm

Absolutely so!




CARBOHYDRATE COMPOSITION OF FOOD PROVIDE MOLECULAR EFFECTS AND LOW-GI CARBS DOWNREGULATE 'BAD' GENES:

"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

Boyd LD, Lampi KJ. Importance of nutrition for optimum health of the periodontium. J Contemp Dent Pract. 2001 May 15;2(2):36-45. Review. PMID: 12167932 Link HERE *good review*




Figure. Activation mechanisms of MMP-2. The full-length MMP-2 can be activated in two ways. Proteolytic activation of MMP-2 by MT1-MMP/TIMP or by other proteases occurs by removal of the autoinhibitory propeptide domain (left arrow) resulting in an active truncated MMP-2. The presence of oxidative stress (ONOO-) and cellular glutathione (GSH) causes the S-gluathiolation of the critical cysteine residue in the propeptide domain, disrupting its binding to the catalytic Zn2+ ion, resulting in an active full-length enzyme. MMP, matrix metalloproteinase; ONOO-, peroxynitrite; TIMP, tissue inhibitor of metalloproteinase. Chow AK, et al. Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol. 2007 Sep;152(2):189-205.


Recently we moved and lost our housekeepers. I've been in the double-dog dumps ever since... So to say the cleaning of the house has been neglected is a very grave understatement. Last week I devoted an inordinate amount of time scouring the calcium deposits off all the toilets in the house... it took so long so I had a long time to think. Why (??!) did I wait so long? Why did I let this thing go?? The work was so much harder and and tougher than had I just kept up with routine maintenance weekly. Right? (Also have spent time weighing the benefits of hiring professionals again) My girlfriends love using CLR (above ad) but I hesitate using such a strong cleaning solvent on the toilets not just for the environmental impact but also the corrosive effects on the pipes (not withstanding other effects such as melting my corneas and the first 2 layers of my skin -- rubber gloves are mandatory).

As I was really getting into the scrubbing and facing the challenge of getting back an immaculate white and tidy bowl, I thought is this what my nazi-Dental Hygienist thinks every time she sees me as she sharpens her metal instruments for scraping tartar and plaque off the teeth? A few years ago I was diagnosed with gum disease with pockets of '4' and '5' and told that implants and antibiotic treatment et cetera might be required some day. When you have periodontal disease, extra cleanings (btw are NOT covered by insurance) and deep scaling/root planing (yes it's as nasty as it sounds) are required to control plaque with the hopes of reducing inflammation and further damage. Gum disease actually involves similar processes that atherosclerosis/heart disease involves, including destruction by excessive MMPs. On the surface of atherosclerotic plaques in our blood vessels, MMPs are found. Destabilization of plaque has been related to overactivity of MMPs. The above article demonstrates the value of vitamin D3 and vitamin A (retinoic acid) and PTH in ameliorating gum disease and correcting the balance between building (osteoblastic activity) and cutting (osteoclastic activity) of our mature gum soft tissues. Interestingly these agents, Vitamins D3 and A, also have incredible plaque-busting benefits in the Track Your Plaque program for CAD regression and eradication. Dr. Davis demonstrated the value of Vitamin D3 in shrinking plaque in coronary arterties and heart disease reversal.


My gum disease now has reversed. I've attributed all the benefits to a low-inflammatory diet (ie rich in good oils, protein, veggies and low low carb), exercise, A-N-D vitamins D3, A and high dose EPA + DHA fish oil. At the end of sumer last year, surprisingly, my lab 25(OH)D3 was extremely low (after being in the sun daily for hours with the kids at the pool). Correction of vitamin D deficiency was one component of improving periodontal disease (obtaining blood levels of 50-60 ng/ml). Happily, at my last visit to the dentist, my gums were given a clean bill of health. Nearly all the pockets were '3's and a few '4's now. The '5's had disappeared and I was told I could return to a normal bi-annual cleaning schedule again (and no more out-of-pocket cleanings). The throbbing that I once felt in the gums are gone too.

Other MMP inhibitors include Doxycline (part of the tetracycline family of drugs). It is a prescription drug which is used in the treatment of periodontal disease and gingival inflammation but has also demonstrated some value in atherosclerosis and preventing heart failure remodeling. PERIOSTAT is a brandname Doxycline indicated by the FDA for treatment of gum disease.

Tessone A, et al. Effect of matrix metalloproteinase inhibition by doxycycline on myocardial healing and remodeling after myocardial infarction. Cardiovasc Drugs Ther. 2005 Dec;19(6):383-90. PMID: 16435072

Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. (see above Figure) Br J Pharmacol. 2007 Sep;152(2):189-205. Epub 2007 Jun 25. Review. PMID: 17592511


I wish I could stick vitamin D in all my toilets everyday... *heh*

Dietrich T, et al. Association between serum concentrations of 25-hydroxyvitamin D and gingival inflammation. Am J Clin Nutr. 2005 Sep;82(3):575-80. PMID: 16155270

Rickets -- a profound vitamin D deficiency condition which frequently involves signficant dental disease (because vitamin D plays a vital role in calcification of teeth and remodeling of soft gum tissues).

Chaussain-Miller C, et al. Dentin structure in familial hypophosphatemic rickets: benefits of vitamin D and phosphate treatment. Oral Dis. 2007 Sep;13(5):482-9. PMID: 17714351

Yamamoto T. Diagnosis of X-linked hypophosphatemic vitamin D resistant rickets.
Acta Paediatr Jpn. 1997 Aug;39(4):499-502. Review. PMID: 9316300

Chaussain-Miller C, et al. Dental abnormalities in patients with familial hypophosphatemic vitamin D-resistant rickets: revention by early treatment with 1-hydroxyvitamin D. J Pediatr. 2003 Mar;142(3):324-31. PMID: 12640383

Dental insurances allow one extra covered dental cleaning during pregnancy. Studies show that the pregnancy-state increases the risk of periodontal disease (likely secondary to cortisol, inflammation, insulin? vitamin D and EPA/DHA deficiency? I would presume). Prevention with an extra cleaning is therefore now advocated. Isn't that interesting? Pregnancy may significantly deplete vitamin D stores (unless replenished) -- in order to construct enough progesterone and estrogen which are also steroidal hormones for supporting the pregnant state. Both pregnancy and lactation also reduce the mother's stores of EPA+DHA in her brain and heart in order to supply the growing fetus/baby's brain and heart. Did you know that a baby's brain is 70% of its birth weight? And did you know that breastmilk is a rich source of 'fish oil' EPA + DHA !

This researcher believes that maternal imprinting can affect CAD risk later in life. By not consuming enough good oils during conception and pregnancy, are we affecting our children later in life? He strongly believes fish oil may protect and even prevent CAD and diabetes in children when maternal EPA and DHA are adequately provided.

Das UN. A perinatal strategy to prevent coronary heart disease. Nutrition. 2003 Nov-Dec;19(11-12):1022-7. Review. PMID: 14624957

Cerná H, et al. Acta Univ Palacki Olomuc Fac Med. 1990;125:173-9. Periodontium and vitamin E and A in pregnancy.
The evaluation of the clinical condition of periodontium by means of the epidemiological indexes and the level of oral hygiene in two weeks intervals in the course of physiological pregnancy in 39 women in good general health revealed the maximum of inflammatory changes of periodontium in the 8th month of pregnancy with the amelioration shortly before delivery. Simultaneous follow-up of the physiological levels of vitamin E and A in four weeks intervals showed the decline of the mean levels of both vitamins in the course of the 8th month and their marked elevation shortly before delivery; therefore remains questionable, if this elevation reaching over their physiological range, contributes to the amelioration of the condition of periodontium observed at the same time. PMID: 2150274

Phenytoin is a drug that increases the liver metabolism of certain drugs and hormones, including Vitamin D and Vitamin A. Seizure and other individuals taking Phenytoin can be at risk not only for osteoporosis but also gum disease (and heart disease and many over conditions) due to subsequently low vitamin D levels. (Isotretinoin is a synthetic vitamin A)

Norris JF, Cunliffe WJ. Phenytoin-induced gum hypertrophy improved by isotretinoin. Int J Dermatol. 1987 Nov;26(9):602-3. No abstract available. PMID: 2965113

Lucchesi JA, et al. Severe phenytoin-induced gingival enlargement associated with periodontitis. Gen Dent. 2008 Mar-Apr;56(2):199-203; quiz 204-5, 224. PMID: 18348382

Hall EE. Prevention and treatment considerations in patients with drug-induced gingival enlargement. Curr Opin Periodontol. 1997;4:59-63. Review. PMID: 9655022

Sobaniec H, et al. Antioxidant activity of blood serum and saliva in patients with periodontal disease treated due to epilepsy. Adv Med Sci. 2007;52 Suppl 1:204-6. PMID: 18229666


Vitamin A is also helpful for reversing gum disease in a condition called Papilon-Lefevre syndrome.

Nazzaro V, et al. Papillon-Lefèvre syndrome. Ultrastructural study and successful treatment with acitretin. Arch Dermatol. 1988 Apr;124(4):533-9. PMID: 2965550

When I think about inflammation and the crucial role fish oil plays in maintaining healthy hearts and minds.... I am not shocked to find out it also regulates healthy gums and oral health. Friends on the TYP forum on the other hand will be shocked that I've reduced my dose of fish oil (slightly) since our family started drinking grass-raised cow milk which is rich in EPA+DHA, CLA, vitamins A D3 E and K2. I love fish oil for all its amazing benefits. Here is more evidence for its healing properties on gingival inflammation (and the hypothesized relationship with vascular inflammation).

Fish oil reduces tooth loss mainly through its anti-inflammatory effects?
Hamazaki K, et al. Med Hypotheses. 2006;67(4):868-70.
Competing at several steps of arachidonic acid metabolism, n-3 fatty acids reduce production of highly active prostaglandins and leukotrienes and exert anti-inflammatory effects. They are also experimentally shown to be anti-osteoporotic. Periodontitis is responsible for most tooth loss in adult populations. If enough n-3 fatty acids are provided, periodontitis with alveolar bone resorption may be controlled, and tooth loss may be prevented. In fact, n-3 fatty acid administration lowered prostaglandin E(2) production, tooth movement and alveolar bone resorption in animal experiments. Aggression, which may be related with tooth loss, was also controlled with fish oil. Our cross-sectional data supported our hypothesis. We recruited 256 men (22-59 y of age) and 95 women (22-66 y), counted the numbers of their remaining teeth, and analyzed the fatty acid composition of the total phospholipid fraction of RBCs. The beta-coefficient of the numbers of remaining teeth and EPA concentrations in the fraction was 0.89 (per 1% EPA, p=0.007) after adjustment for 9 possible confounding factors. Long-term intervention studies with fish oil planned in the future should be able to test our hypothesis by just adding another very simple endpoint in those studies: tooth loss during the intervention period. This hypothesis may explain the linkage between periodontitis/tooth loss and coronary heart disease. PMID: 16759817

Campan P, et al. [Polyunsaturated omega-3 fatty acids in the treatment of experimental human gingivitis] Bull Group Int Rech Sci Stomatol Odontol. 1996 Feb-Mar;39(1-2):25-31. French. PMID: 8720373

Kesavalu L, et al. Omega-3 fatty acid effect on alveolar bone loss in rats. J Dent Res. 2006 Jul;85(7):648-52. PMID: 16798867

Kesavalu L, et al. Omega-3 fatty acid regulates inflammatory cytokine/mediator messenger RNA expression in Porphyromonas gingivalis-induced experimental periodontal disease. Oral Microbiol Immunol. 2007 Aug;22(4):232-9. PMID: 17600534

Requirand P, et al. Serum fatty acid imbalance in bone loss: example with periodontal disease. Clin Nutr. 2000 Aug;19(4):271-6. PMID: 10952799

Iwami-Morimoto Y, Yamaguchi K, Tanne K. Influence of dietary n-3 polyunsaturated fatty acid on experimental tooth movement in rats. Angle Orthod. 1999 Aug;69(4):365-71. PMID: 10456605


Nutritional factors play the same important roles in parallel organs in our body. Perhaps proper vitamins/food and fish oil everyday will not only keep the doctor away...

But also my nazi-hygienist! :)

If only the same were true for all other types of housekeeping.

(Thanks go out to Mr.California for his super-RICH ideas. You deserve an 'S' emblazoned on your chest for sharing your fascinating cardiovascular-related thoughts and insights.)