There’s A Drugless Cure For Diabetes & Obesity: So Why Aren’t Doctors Prescribing It? By Bill Sardi

Main points and summary

• Individuals with metabolic problems (elevated blood sugar, insulin resistance, obesity) are caught in the middle of a major shift in the scientific understanding of what induces these problems. Modern medicine treats diabesity either by a medical model (drugs) or bariatric surgery (gastric band or bypass) when it is now recognized that alterations in the composition of bacteria in the lower intestine (gut) initiate these problems.  Patients may have to venture on their own to put corrective measures into practice.
• Inclusion of more indigestible carbohydrates in the American diet is the most practical remedy but the public is likely to get confused over advice to limit processed carbohydrates (bread, rice, pasta, cereal) vs. increased consumption of bran, pectin and other indigestible carbohydrates. It is unlikely the American public will go back to eating unprocessed foods.  Convenience and prepared foods reign.
• A particular bacterium, Akkermansia muciniphila (AKK), is responsible for the production of butyrate, the major source of cell energy in the gut. The provision of butyrate completely eradicates measures of metabolic illness in laboratory animals but may only produce a transient effect in humans.  The use of other indigestible fibers (bran, pectin, polyphenols) is likely to be the most efficacious.  Indigestible starch is another preferential option.
• Weight reduction can be achieved by these measures via promotion of satiation that results in eating less food and by burning more calories.

How does diabetes get started?

In 2007 researchers in France were the first to report gut bacteria initiates to the onset of adult diabetes and the inability to utilize insulin.[i]  Insulin is a hormone secreted by the pancreas that permits glucose sugar to enter living cells that then produces energy that cells need to function.  Insulin grabs glucose from the blood circulation and puts it into cells.  Glucose, produced in the liver, is the body’s main source of fuel.  When fat, muscle and liver cells begin ignoring insulin, blood sugar levels rise. Prebiotic Fiber with F...Buy New $12.99(as of 12:00 EST - Details)

Gut bacteria produce short-chain fatty acids. (Long-chain fatty acids are found in commonly consumed oils obtained from fish, nuts, avocado, olive, soybean and other plant oils.). Three short-chain fatty acids predominate in the digestive tract (large intestine): butyrate, acetate and propionate and are produced from the fermentation of non-digestible carbohydrates (oligo or polysaccharides, aka fiber).  This knowledge results in recommendation for more fiber in the diet, usually obtained from cereals , fruits and vegetables.  The abundance or shortage of these short-chain fatty acids determine whether humans are healthy or have metabolic problems — insulin resistance, elevated blood sugar levels and obesity.

Diabetics hear they must limit carbohydrate intake (bread, rice, pasta, cereal) which are refined and processed, devoid of bran that can ferment and induce short-chain fatty acids in the lower digestive tract.  So, advice about carbohydrates may be confusing for diabetics.  Carbohydrate reduction accounts for 71% of the reduction in blood glucose levels achieved by short-term fasting.[ii]

AKK BACTERIA

Fast forward to 2018.  Researchers report loss of one specific type of bacteria in the human gut triggers chronic low-grade inflammation that signals cells to ignore insulin.  Akkermansia muciniphila or AKK facilitates the breakdown of fiber into butyrate and acetate, whereas a decline in the volume of AKK triggers living cells to ignore insulin and also results in less butyrate.

When animals were given an antibiotic to increase the proportion of AKK bacteria in their digestive tract, cells began to respond to insulin again.  Provision of butyrate had the same effect.  Without AKK the integrity of the intestines is impaired and leakage of bacterial products (endotoxins) activates white blood cells (monocytes) to arrive in such large numbers as to induce inflammation with resultant insulin resistance.[iii]

Studies involving AKK bacteria have moved from the animal lab to human investigation.  When obese diabetic adults were compared to lean healthy individuals, subjects who exhibited the healthiest metabolism (blood glucose/sugar levels, body fat distribution) had the highest levels of the mucin-controlling AKK bacteria.[iv]

Akkermansia muciniphila is now being heralded as a next-generation beneficial bacterium that promises to quell the diabesity epidemic that has plagued modern populations that consume fiber-poor processed foods.

While there are a broad variety of probiotics being sold, namely offering Acidophilus and Bifidus bacteria, the development of an AKK probiotic dietary supplement looms.  However, probiotics don’t survive and grow like lawn seed.  They only produce a brief response that transiently heightens the immune response.

AKK bacteria does not always produce a beneficial effect, casting doubt on its introduction as a probiotic.  For example, excessive AKK bacteria in lab animals results in elevated blood pressure, a problem that was abolished by the red wine molecule resveratrol.[v]

While AKK is one of the most abundant single species of bacteria in the human gut (0.5 to 5.0% of total bacteria) that is involved in the production and degradation of mucus in the lower digestive tract, various prebiotics can increase the abundance of AKK bacteria by 100-fold (up to 4.5% in a high-fat diet compared to 0.09 to 2.5% for normal chow provided to lab animals).  So maybe a prebiotic that increases the proportion of AKK rather than an AKK probiotic would be the most efficacious.

Given that AKK bacteria levels are low in obese and diabetic individuals and both the antidiabetic drug metformin and bariatric surgery produce a marked increase in AKK bacteria, diabetologists now say a revolution in the treatment of metabolic disorders is at hand.  Agents that increase AKK bacteria within the composition of thousands of species of bacteria in the human gut may also quell gout, fatty liver and inflammatory bowel problems, the latter by increasing the thickness of the mucus barrier in the gut and therefore diminishing toxins that plague many sufferers with irritable bowel.[vi]

While nutritionists are hell-bent on creating fat phobia, butyrate itself is a component of butter (3-4%).  In fact, butter is the richest dietary source of butyrate.[vii]

Not all sources of fiber are equal in their ability to produce butyrate.  Pectin, cellulose and bran are good sources of fiber that generate butyrate.  However, indigestible (resistant) starch produces almost twice as much cell energy (short-chain fatty acids, mainly butyrate) for cells in the lower large intestine than butyrate compared to other sources of fiber (bran, pectin, cellulose).[viii]

Gut bacteria control genes

With the knowledge that butyrate is more than just an agent that governs insulin utilization we begin to understand how butyrate exhibits control over the human library of genes (genome) by its inherent ability to loosen or tighten strands of genes around histone bodies that allow our genes to be in a “read” or “non-read” mode.  The more butyrate the more genes that are activated (make proteins).  This throws the whole topic of gut bacteria and butyrate into the realm of anti-aging pills.  Butyrate has been demonstrated to prevent brain cell death and extend the lifespan of laboratory mice.[ix]  Moreover, butyrate has been demonstrated to have a profound effect on improving learning and memory which has application in maintenance of mental function with advancing age.  Diabetes, insulin resistance and obesity come with advancing age.  Therefore, the link between butyrate and the human genome opens the doorway to healthy aging and prolonged health span and lifespan.Traditionally Fermente...Shannon StongerBest Price: $12.97Buy New $13.09(as of 12:00 EST - Details)

Controls appetite/ burns calories

More intriguing is that butyrate has been demonstrated to reduce appetite in lab animals, not in the gut but in the hypothalamus of the brain where satiation is controlled.  Butyrate acts via a gut-brain connection.  Oral but not intravenous butyrate produced this remarkable effect, which points to the need for butyrate to be present in the digestive tract not just in the blood circulation to exert its biological activity.  Of interest, when researchers severed the vagus nerve that connects the gut with the brain in lab animals given butyrate, this completely negated its appetite reduction effect upon the hypothalamus in the brain.[x]

In animals fed a very high-fat diet, butyrate reduces leptin levels.[xi]   Leptin is the hormone that controls satiation.  Leptin levels continue to rise if there is leptin resistance.

In 2009 researchers first reported that supplemental butyrate prevents insulin resistance in laboratory animals.  Butyrate also prevented obesity among lab animals fed a high-fat diet.  Butyrate accomplished this not by reduced food intake or reduced absorption of dietary fat but by increased burning of calories (thermogenesis).  It was noted that butyrate’s beneficial metabolic activity is similar to those produced by the red wine molecule resveratrol.[xii]

Leading anti-diabetic drug acts as prebiotic

The manipulation of gut bacteria to treat adult diabetes and obesity was realized in 2014 when researchers linked the use of the anti-diabetic drug metformin with an increase in AKK bacteria in the human gut.[xiii]  Metformin, the most widely used anti-diabetic medication, favorably alters the composition of gut bacteria via the increase of AKK bacteria that fosters the production of short-chain fatty acids like butyrate.  This discovery has opened the new door to control obesity and diabetes and aging itself.[xiv]

Fatty liver along with liver fibrosis (scarring), a condition that is estimated to effect one-third of Americans, is alleviated by butyrate.[xv]  There are no proven medicines for fatty liver.

Non-metabolic health benefits

Of acute interest are unrelenting cases of gout.  Gout is known as a malady of meat eaters.   But in modern times gout inexplicably persists in many instances among individuals who don’t consume much meat.  Scientific studies have only recently revealed intestinal bacteria rather than uric acid levels distinguish gout patients from healthy adults.[xvi]  Butyrate is now considered a remedy for gout.[xvii]

There are other non-metabolic health benefits derived from butyrate.  For example, the virulence and growth fate of Lyme disease (Borrelia burgdorferi bacterial infection from contact with ticks) is dramatically reduces.[xviii]

The composition of gut bacteria may make the difference between life and death should a heart attack occur.  When a heart attack was intentionally induced in laboratory animals, the sterilization of bacteria from the gut with antibiotics prior to the heart attack impaired repair mechanisms and survival of the animals which improved after supplementation with butyrate and acetate.[xix]

Butyrate and other short-chain fatty acids (acetate, propionate) play a major role in the regulation of inflammation and in normalizing the immune response.[xx]

AKK bacteria count is low among patients with psoriasis.[xxi]

Fiber intake

There is probably no going back to fiber-rich diets.  Processed convenience foods predominate in developed populations.  So, there is a search for molecules that can be added as fortification of foods, or used as dietary supplements, that boost AKK bacteria and butyrate.

Suggested fiber intake is ~16-35 grams a day.  In Western societies about 20-25 grams of fiber is consumed daily though diets high in fruit and vegetables may provide as much as 60 grams of fiber a day.[xxii]  Efforts to increase plant food consumption have fallen flat.

That leads investigators to the question: can butyrate, normally the by-product of fiber fermentation in the lower large intestine, be provided directly as a dietary supplement to quell insulin resistance?

After years of investigation researchers now say “it is becoming clear that gut bacteria play a preventive role in pathologies such as diabetes, obesity and inflammatory bowel disease.[xxiii]

Oral butyrate supplementation in humans

A trial of oral butyrate supplementation was conducted among healthy and obese adults.  Four grams (2000 milligrams twice a day) of butyrate was employed with limited effects.  Butyrate did, however, encounter white blood cells (monocytes) and inhibit inflammation that typically accompanies their arrival.  The authors of that study say the effect of oral butyrate supplementation “was most likely only transient.”[xxiv]  Researchers says 4000 mg butyrate only produced beneficial effects among younger lean subjects.[xxv]

Enter the polyphenols

The Resistant Starch D...Gregory StevensCheck Amazon for Pricing.So maybe volumes of plant foods don’t need to be consumed to produce a metabolic boost.  While fruits and vegetables have long been recommended for their fiber content, molecules called polyphenols also found in fruits and spices may also promote AKK bacteria.  Commonly known polyphenols are found in grapes (resveratrol), apples and onions (quercetin), catechin (tea), turmeric spice (curcumin), cinnamaldehyde (cinnamon), pomegranate (ellagitannins), olives (oleuropein) and cranberries (proanthocyanidins).

For example, a diet fortified with butyrate-rich butter and grape powder (polyphenols) reduced fat cells and fatty liver along with an increase in AKK bacteria.[xxvi]

Cranberry extract has been found to increase the population of AKK bacteria in lab animals and exert beneficial effects such as reduced insulin resistance and inflammation.[xxvii]

Resveratrol, probably the most studied polyphenol, has been found to produce marked changes in the composition of gut bacteria and improve insulin sensitivity in laboratory mice.[xxviii]

Amino acids

Amino acids promote the production of butyrate, acetate and propionate, but not always in the most desirable way.[xxix]

The amino acid leucine is used by body builders to stimulate muscle growth as it is much more powerful than any other amino acid in this regard.  However, butyrate has been remarkably reported to promote fat burning (ketogenesis) more than leucine.[xxx]  Of note, the combination of leucine + low-dose resveratrol exhibits synergistic action to manage insulin-resistance and obesity in lab animals.[xxxi]

Butyrate dietary supplements are available commercially.  So are an array of polyphenolic nutraceuticals.  However, research studies show indigestible starch produces the most cell energy for cells in the lower digestive tract (see chart below).

Indigestible starch

Resistant (indigestible) corn starch (maltodextrin), commercially available under the trade name Fibersol-2, is a fermentable non-GMO fiber that has GRAS status in the U.S. (Generally Recognized As Safe).  Indigestible maltodextrin (plant sugar) exerts a demonstrable change in gut bacteria in healthy adults.[xxxii] A mixture of fiber (fructooligosaccharide) + indigestible maltodextrin was found to increase short-chain fatty acids by 195.4% in lab animals.[xxxiii]

In a human study among adults with metabolic syndrome (obesity, insulin resistance) Fibersol-2 reduced waist circumference, belly fat, blood sugar and other measures of metabolic health compared to tea consumption for comparison.[xxxiv]  Among diabetic women, 10 grams of indigestible (resistant) starch reduced insulin, insulin resistance, markers of inflammation (TNF) compared to plain starch.[xxxv]

[i] Cani, PD, et al, Metabolic endotoxemia initiates obesity and insulin resistance.  Diabetes 56 (7): 1761-72, 2007.

[ii] Nuttall FQ, et al, Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes. Metabolism 64 (2): 253-62, 2015.

[iii] Bodogai, M, et al, Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells.  Science Translational Medicine 10 (467): eaat4271, 2018.

[iv] Dao MC, et al, Akkermansia muciniphile and improved metabolic health during dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65 (3): 426-36, 2016.

[v] Tain YL, et al, Resveratrol prevents the development of hypertension programmed by maternal plus post-weaning high-fructose consumption through modulation of oxidative stress, nutrient-sensing signals and gut microbiota. Molecular Nutrition Food Research, April e1800066, 2018.

[vi] Cani PD, De Vos WM, Next generation beneficial microbes: the case of akkermansia muciniphila.  Frontiers Microbiology 8: 1765, 2017.

[vii] Newmark HL, Lupton JR, Young CW, Butyrate as a differentiating agent: pharmacokinetics, analogues and current status.  Cancer Letters 78 (1-3), 1994.

[viii] Bourassa MW, et al, Butyrate, neuroepigenetics and the gut microbiome: can a high fiber diet improve brain health?  Neuroscience Letters 625: 56-63, 2016.

[ix] Ferrante RJ, et al, Histone deacetylase inhibition of sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice.  Journal Neuroscience 23: 9418-27, 2003.

[x] Li Z, et al, Butyrate reduces appetite and activates brown adipose tissue via the gut-brain neural circuit.  Gut 67: 1269-79, 2018.

[xi] Pelgrim CE, et al, Butyrate reduces HFD-induced adipocyte hypertrophy and metabolic risk factors in obese LDLr/-.Leiden mice. Nutrients 9 (7): eE714, 2017.

[xii] Gao Z, et al, Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58 (7): 1509-17, 2009.

[xiii] Shin NR, et al, An increase in the Akkermansia spp. Population induced by metformin treatme3nt improves glucose homeostasis in diet-induced obese mice. Gut 63 (5): 727-35, 2014.

[xiv] Vallianou NG, Stratigou T, Tsagarakis S, Metformin and gut microbiota: their interactions and their impact. On diabetes.  Hormones Feb4, 2019.

[xv] Ye J, et al, Butyrate protects mice against methionine-choline-deficient diet-induced non-alcoholic steatohepatitis by improving gut barrier function, attenuating inflammation and reducing endotoxin levels. Frontiers Microbiology 9: Aug. 2018.

[xvi] Guo Z, et al, Intestinal microbiota distinguish gout patients from healthy humans. Scientific Reports 6: 20602, 2016.

[xvii] Goldberg EL, et al, B-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Reports 18 (9): 2077-87, 2017.

[xviii] Lin YH, et al, Short-chain fatty acids alter metabolic and. Virulence attributes of Borrelia burgdorferi. Infection & Immunity 86 (9): e00217-18, 2018.

[xix] Tang TWH, et al, Loss of gut microbiota alters immune system composition and cripples postinfarction cardiac repair.  Circulation 139 (5): 647-59, 2019.

[xx] Morrison DJ, Preston T, Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism.  Gut Microbes 7 (3): 189-200, 2016.

[xxi] Tan L, et al, The Akkermansia muciniphila is a gut microbiota signature in psoriasis. Experimental Dermatology 27 (2): 144-49, 2018.

[xxii] Besten G, et al, The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. Journal Lipid Research 54 (9): 2325-40, 2013.

[xxiii] Montandon SA, Jomayvaz FR, Effects of antidiabetic drugs on gut microbiota composition.  Genes 8 (10): e250, 2017.

[xxiv] Cleophas MCP, et al, Effects of oral butyrate supplementation on inflammatory potential of circulating peripheral blood mononuclear cells in healthy and obese males.  Scientific Reports 9: Issue No. 775, 2019.

[xxv] Bouter KEC, et al, Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects.  Clinical Translational Gastroenterology 9 (5): 155, 2018.

[xxvi] Anhe FF, et al, Triggering Akkermansia with dietary polyphenols: a new weapon to combat the metabolic syndrome. Gut Microbes 7 (2): 146-53, 2016.

[xxvii] Anhe FF, et al, A polyphenol-rich cranberry extrat protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. Population in the gut microbiota of mice.  Gut 64 (6): 872-83, 2015.

[xxviii] Sung MM, et al, improved glucose homeostasis in obese mice treated with resveratrol is associated with alterations in the gut microbiome.  Diabetes 66 (2): 418-25, 2017.

[xxix] Neis EPJG, Dejong CHC, Rensen SS, The role of microbial amino acid metabolism in host metabolism.  Nutrients 8 (4): 2930-46, 2015.The Starch Revolution:...Bethany SilverCheck Amazon for Pricing.

[xxx] St. Pierre V, et al, Butyrate is more ketogenic than leucine or octanoate monoacylglycerol in health adult humans. Journal Functional Foods 32: 170-75, 2017.

[xxxi] Bruckbauer A, et al, Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice. Nutrition Metabolism 9 (1): 77, 2012.

[xxxii] Burns AM, et al, In healthy adults, resistant maltodextrin produces a greater change in fecal bifidofacteria counts and increases stool wet weight: a double-blind, randomized, controlled crossover study. Nutrition Research 60: 33-42, 2018.

[xxxiii] Kao WM, et al, Inclusion of fructooligosaccharide and resistant maltodextrin in high fat diets promotes simultaneous improvements on body fat reduction in fecal parameters.  Molecules 23 (9): E2169, 2018.

[xxxiv] Hashizume C, et al, Improvement effect of resistant maltodextrin in humans with metabolic syndrome by continuous administration.  Journal Nutrition Science Vitaminology 58 (6): 423-30, 2012.

[xxxv] Aliasgharzadeh A, et al, Resistant starch, as a prebiotic, improves insulin resistance and inflammation in women with type 2 diabetes: a randomized controlled clinical trial. British Journal Nutrition 113 (2): 2321-30, 2015.

Indigestible starch promotes satiation.  Most notable is that Fibersol-2 resistant starch has been demonstrated to exert strong anti-cancer properties without any toxicity.[1]

Its drawback is that it is so fermentable it may induce intestinal gas and is reported to produce gastrointestinal discomfort.[2]  However the use of 15 grams of Fibersol-2 resistant starch successfully increases beneficial bacteria counts in adults with only minor gastrointestinal discomfort.[3]  Various doses of Fibersol-2 were employed in another human study and produced no diarrhea and only mild and transient discomfort (gurgling sounds).[4] So it is consumer friendly.

Ferritin (iron storage) and metabolic disease

Another driver of diabesity are high iron storage (ferritin) levels.  Normal healthy ferritin blood levels range from 20-90 nanograms/milliliter and are generally elevated in males who do not experience blood loss as do menstruating females.[5] Higher ferritin (iron storage) levels are associated with insulin resistance and obesity, particularly in males.[6]  Higher iron stores (ferritin) are also found among adults with pre-diabetes.[7]  It is not surprising to learn that metformin, the antidiabetic drug, reduces ferritin (iron storage)[8] as well as increases the AKK bacteria count and butyrate.  Neither is it surprising to learn that metformin is being repurposed as an anti-aging drug.[9]

Given that bran encourages production of butyrate, and within rice bran is a strong iron-controlling molecule (phytic acid or IP6), and IP6 has been demonstrated to exert control over diabetes[10], it may be a desirable component of any regimen employed to prevent diabetes and obesity.  IP6 and its molecular cousin inositol, serve as agents to promote healthy gut bacteria and prevent fatty liver.[11]

Apple pectin, another butyrate booster that has been shown to promote beneficial gut bacteria and reduce inflammation, is on the list of natural remedies for diabesity.[12]

The gut bacteria model of health has been slow to be adopted into the practice of medicine largely due to the initial complexity posed by the vast array of bacterial species involved. The alteration of gut bacteria to prevent diabetes and obesity runs head on into the pharmacologic anti-diabetic drugs that are fraught with side effects (even metformin induces vitamin B12 deficiency[13] which foments nerve problems) and bariatric surgery that is financially rewarding for surgeons but is associated with side effects that include mortality.    It appears individuals with metabolic issues (obesity, diabetes) will have to venture on their own to achieve metabolic wellness.  This report is instructive in that regard. The Starch Solution: E...John McDougall, Mary M...Check Amazon for Pricing.

What to do

• So here is what a health regimen incorporating this information might look like for a person who fits the criteria described in this report battling diabesity, inflammatory syndromes or other related maladies like gout, psoriasis, Lyme disease or inflammatory bowel problems.
• Consume fermented foods like sauerkraut, unsweetened pickles, miso soup.
• Utilize stevia and/or inositol powder as a sweetener.
• Consider pre-biotics over probiotics as they address a wider array of bacteria in the digestive tract.
• Don’t be so phobic over butter, a rich source of butyrate.
• Add more fiber back into your diet that contains bran, polyphenols or pectins, or dietary supplements that provide the same. Be aware, most fiber supplements sold online at Amazon.com are directed at selling relief for constipation.  That isn’t the type of fiber (psyllium husks) this report presents.
• Indigestible (resistant) starch may be of help, particularly for individuals with more acute health challenges and difficulties curbing food intake and maintaining healthy blood sugar levels.
• If struggling with diabetes and insulin resistance, make sure you supplement your diet with vitamin B1 (thiamin) in fat-soluble form (benfotiamine) that averts all of the major consequences of diabetes (neuropathy, nephropathy (kidneys), retinopathy (eyes) and cardiomyopathy (heart)[14] until you find your way out of the problems diabetes presents.

References

[1] So EY, et al, Tumor suppression by resistant maltodextrin, Fibersol-2. Cancer Biology & Therapy 16 (3): 460-65, 2015.

[2] Astina J, Sapwarobol S, Resistant maltodextrin and metabolic syndrome: a review. Journal American College Nutrition Oct 23: 1-6, 2018.

[3] Fastinger ND, et al, A novel resistant maltodextrin alters gastrointestinal tolerance factors, fecal characteristics, and fecal microbiota in healthy adult humans. Journal American College Nutrition 27 (2): 356-66, 2008.

[4] Kishimoto Y, et al, The maximum single dose of resistant maltodextrin that does not cause diarrhea in humans.  Journal Nutrition Science Vitaminology 59 (4): 352-57, 2013.

[5] Shim YS, et al, Association of serum ferritin with insulin resistance, abdominal obesity, and metabolic syndrome in Korean adolescent and adults: the Korean National Health and Nutrition Examination Survey, 2008-2011.  Medicine 96 (8): e6179, 2017.

[6] Kim CH, et al, Association of elevated serum ferritin concentration with insulin resistance and impaired glucose metabolism in Korean men and women. Metabolism 60 (3): 414-20, 2011.

[7] Cheung CL, et al, High ferritin and low transferrin saturation are associated with pre-diabetes among a national representative sample of U.S. adults. Clinical Nutrition 32 (6): 1055-60, 2013.

[8] Behradmanesh S, et al, Effect of metformin on serum ferritin level in women with polycystic ovary syndrome. Iran Red Crescent Medical Journal 13 (7): 487-92, 2011.

[9] Piskovatska V, et al, Metformin as a geroprotector: experimental and clinical evidence.  Biogerontology 20 (1): 33-48, 2019.

[10] Omoruyi FO, et al, The potential benefits and adverse effects of phytic acid supplement in streptozotocin-induce diabetic rats. Advances Pharmacological Science2013: 172494, 2013.

[11] Okazaki Y, Sekita A, Katayama T, Intake of phytic acid and myo-inositol lowers hepatic lipogenic gene expression and modulates gut microbiota in rats fed a high-sucrose diet. Biomedical Reports 8: (5): 466-74, 2018.

[12] Jiang T, et al, Apple-derived pectin modulates gut microbiota, improves gut barrier function, and attenuates metabolic endotoxemia in rats with diet-induced obesity.  Nutrients 8 (3): 126, 2016.

[13] Yang W, Cai XL, Wu H, Ji L, Associations between metformin use and vitamin B12 level, anemia and neuropathy in patients with diabetes: a meta-analysis.  Journal Diabeteshttps://www.ncbi.nlm.nih.gov/pubmed/30615306 Jan 7, 2019.

[14] Balakumar P, et al, The multifaceted therapeutic potential of benfotiamine. Pharmacological Research 61 (6): 482-88, 2010.