Diabetes / Metabolic Syndrome

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

Sections

Information Resources - The Problems with Current Treatment Protocols for Diabetes and Metabolic Syndrome - Links to Scientific Studies

  1. A 2010 New York Times article on Avandia shows the recent concerns over new Diabetic drugs and industry manipulation of research that is being investigated by the government. Avandia, or rosiglitazone, in the thiazolidiedione class along with Actos, was withdrawn from the New Zealand and South Africa market, and the United Kingdom's Commission on Human Medicines also recommended withdrawal from the Euro market due to the cardiovascular risks, which outweighed the benefits: http://www.nytimes.com/2010/02/23/health/23niss.html
  2. A Wikipedia citation explains the pharmacology of Avandia and the other drugs that are a thiazolidinedione class called Rosiglitazone: http://en.wikipedia.org/wiki/Rosiglitazone
  3. A July 13, 2010 article in the New York Times outlines the history of the hiding of serious cardiovascular risks associated with the drug Avandia, a class of glitazones designed to decrease insulin resistance and help with diabetes care. The scandal of hiding important research findings from the public and FDA by SmithKline Beecham (formerly GlaxoKline Smith) may signal a new era in FDA function: http://www.nytimes.com/2010/07/13/health/policy/13avandia.html?_r=1
  4. A July 15, 2010 article in the New York Times reveals that the FDA, once again, allowed a drug to remain on the market despite the history of illegally hiding risks in patient studies and the enormous payouts in product liability from patient harm admitted. GlaxoSmithKline stated that it was assuming a $2.36 billion loss in one quarter for legal liability for the diabetes drug Avandia as well as the antidepressant Paxil: http://www.nytimes.com/2010/07/16/business/global/16avandia.html?src=busln
  5. A December 20, 2012 article in Food Consumer online, outlines the array of health risks and research fraud associated with the newer diabetic drugs, prompting many countries to withdraw drug approval. Both cardiovascular and cancer risks have caused much alarm in the health community, as well as the increased incidence of chronic inflammatory conditions such as sinusitis, and acute upper respiratory infections: http://www.foodconsumer.org/newsite/Non-food/Drug/diabetes_drugs_raises_cancer_risk_1220120136.html
  6. A 2006 study at the Institute of Immunology at Witten/Herdecke University, in Germany, found that the DDP-4 inhibitors, such as Januvia, along with the rise in glucagon-like peptides normally broken down by DDP-4, could increase the risk of promoting colon cancer in early stages, and promote the metastasis, or spreading of colon cancer, by promoting cell migration and growth: http://www.sciencedirect.com/science/article/pii/S0167011506001078
  7. A 2010 study at the David Geffen School of Medicine at the University of California in Los Angeles (UCLA) found that the use of DDP-4 inhibitors, such as Januvia, increased the risk of pancreatic cancer 6-fold as compared to other diabetic therapies, by promoting glucagon-like peptides: http://www.ncbi.nlm.nih.gov/pubmed/21334333
  8. A 2011 study at the David Geffen School of Medicine at the University of California in Los Angeles (UCLA) found that the Glucagonlike Peptide-1 receptor agonists, such as Victoza (liraglutide), present increased risk for pancreatitis and caution concerning long term use increasing pancreatic cancer risk, based on US FDA data from 2004-2009. These newer diabetic drugs, GLP-1 receptor agonists, come with the caveat that the FDA will have to review long-term safety and risk versus benefit in the future with clinical trials and follow-up studies, and that evidence in animal studies showed that they may promote thyroid cancer: http://www.gastrojournal.org/article/S0016-5085%2811%2900172-7/abstract?cc=y=&referrer=https%3A%2F%2Fscholar.google.com
  9. A 2013 article in DrugWatch describes the series of events that led to a renewed review of the top-selling diabetic drugs Avandia, Byetta and Bydureon, with researchers at Johns Hopkins School of Medicine revealing in JAMA that patients taking these drugs experienced double the rate of acute or chronic pancreatitis, which predisposes to an increased risk of pancreatic cancer, especially as these drugs work by increasing levels of glucagon-like peptide-1, a hormone that may act to accelerate precancerous conditions in the pancreas, according to Dr. Peter Butler of UCLA, former editor of the Journal of the American Diabetes Association, and Dr. Edwin A.M. Gale, of the University of Bristol U.K, and professor of diabetic medicine at Southmead Hospital in England: http://www.drugwatch.com/2013/03/20/fda-safety-review-januvia-byetta/
  10. A February 7, 2002 article in the New England Journal of Medicine, outlining the findings of a long-term large randomized controlled trial in diabetic prevention, found that weight loss and increased exercise prevented the onset of true diabetes about twice as well as the standard drug regimen: http://www.nejm.org/doi/full/10.1056/NEJMoa012512
  11. A 2013 study by Dr. Rod Taylor, Professor at the Newcastle University Institute of Cellular Medicine, in Newcastle upon Tyne, United Kingdom, showed that Metabolic Syndrome, or Type 2 Diabetes, can be quickly reversed and cured with a low-caloric diet that sticks to avoidance of starchy and processed foods, and meats, for just a short period of time. The initial first human clinical trial showed a 50 percent complete cure rate using this approach in 2016, and will be followed by larger human clinical trials. Of course, each individual could adopt a workable dietary regimen enhanced by a more holistic program, and not just this specific studied diet to achieve success: http://care.diabetesjournals.org/content/36/4/1047.full
  12. A 2015 study by experts at the U.S. Veterans Affairs Center for Clinical Management Research and the University of Michigan School of Medicine found that reduction in the number of pharmaceuticals prescribed to older diabetic patients when they experienced low Hgb A1C and low blood pressure, termed deintensification, occurred in only 27 percent of cases, despite the alarming adverse health effects. These experts recommended more focus on reducing overtreatment with multiple drugs. This study was published in the Journal of the American Medical Association: http://archinte.jamanetwork.com/article.aspx?articleid=2466632
  13. A 2013 comprehensive report on the use of hemoglobin A1C to diagnose and treat type 2 diabetes, by preventive health care experts at the University of Alberta School of Medicine, in Canada, shows that controversies still exist regarding using A1C alone as a criteria for diabetes, and that there is poor correlation between A1C, fasting glucose levels and glucose tolerance testing (OGTT). The use of a one-size-fits-all A1C level is also controversial, as a number of factors, including concurrent drug use, aging and diet and lifestyle factors can alter the A1C, including statin drug use. A more nuanced and individualized diagnostic criteria and guidelines is needed: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3555653/
  14. A 2012 report from diabetes experts of the World Health Organization (WHO) shows that various pharmaceuticals may alter the A1C level, and that various nutrient protocols can actually lower the A1C beneficially, such as the use of high dose Vitamin C and mixed tocopherols and the replenishment of Vitamin B12 methylcobalamin in anemic patients: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401751/
  15. A 2015 research study at the University of Copenhagen Center for Diabetes Research found in a broad population-based study that the amount of use of antibiotics is clearly related to risk of Diabetes Type 2, sometimes with onset over a decade later than the repeated long courses of antibiotics, showing that the Human Biome is very important to human metabolism, and destruction of the Biome by unnecessary use of antibiotic therapy creates a burden of disease: http://press.endocrine.org/doi/abs/10.1210/jc.2015-2696
  16. A study sponsored by the National Institutes of Health, headed by Dr. Phil Zeitler, a professor of pediatric endocrinology at the University of Colorado, and published in the journal Diabetes Research Today, found that understanding of adolescent diabetes type 2 and Metabolic Syndrome was inadequate at best, in standard medicine, and that a failure to differentiate variations in the patients, and address underlying causes, was creating a crisis in public health: http:/diabetes.researchtoday.net/archive/6/7/8298.htm
  17. An August, 2003, report to the American Diabetes Association by Dr. Phil Zeitler, professor of pediatric endocrinology at the University of Colorado, stated that adolescents and teenagers with Metabolic Syndrome and diabetes type 2 present a dramatic problem for healthcare and health spending in the future, with an increased array of comorbidities (associated diseases and health problems), 60 percent with a finding of insulin resistance, a majority obese or overweight, and a higher incidence of psychiatric disease. In 2012, Dr. Zeitler reported that standard drug treatment for these patients produced a lack of long-term control of their blood sugars and lipids, and suggested implementation of a more thorough and holistic treatment protocol: http://findarticles.com/p/articles/mi_hb4384/is_8_37/ai_n29027282/
  18. An April 29, 2012 article in the New England Journal of Medicine, reported the long-term findings by Dr. Phil Zeitler, a professor of pediatric endocrinology at the University of Colorado, and head researcher on this subject at the National Institutes of Health (NIH), that after four years of standard drug treatment of diabetes type 2 of adolescent onset, that more than half the patients exhibited uncontrolled circulating blood sugars, and 20 percent had serious complications of diabetes that usually landed them in the hospital. The standard treatments with Metformin and Avandia barely outperformed diet and lifestyle regimens alone. The need to explore an expanded treatment protocol was emphasized. Utilization of Complementary Medicine would seen the sensible approach considering the wealth of research findings cited below: http://www.lasvegassun.com/news/2012/apr/29/us-med-diabetes-teens/
  19. A large 2014 study at the Endocrine, Diabetes and Research Centre, in Wellington South, New Zealand found that Metformin use is associated with difficulty in Vitamin B12 absorption and deficiency in about a fifth of patients, with the duration of taking the drug, and the dosage, clearly related to the B12 deficiency: http://www.ncbi.nlm.nih.gov/pubmed/25331307
  20. A 2013 meta-review of scientific study of Complementary Medicine in treating diabetes type 2 and metabolic syndrome, at Peking University, in Beijing, China, found that addition of the Chinese Herbal Formula called Liu Wei di Huang Wan improved treatment outcomes significantly, including levels of fasting blood glucose and postprandial blood glucose. This is a very common tonic formula in TCM herbal medicine: http://www.ncbi.nlm.nih.gov/pubmed/24092243
  21. A 2015 meta-review of all published scientific studies of Berberine in the treatment of diabetes type 2 and metabolic syndrome, at Jiangxi University, Zhejiang University, Wenzhou University, the Center for Primary Care and Integrative Medicine PLLC, in Houston, Texas, and the Cincinnati Children's Hospital Medical Center, in Cincinnati, Ohio, U.S.A. found that evidence strongly supports the efficacy and safety of the Chinese herbal extract Berberine in treatment of diabetes type 2 and metabolic syndrome, and these experts called for larger randomized controlled human clinical trials to determine specific dosages and standardized preparation. Berberine is derived from Coptis chinensis (Huang lian) and Mahonia in the U.S., but is now standardized and included in many nutritional medicine formulas for diabetes and metabolic syndrome: http://www.ncbi.nlm.nih.gov/pubmed/25498346
  22. An April 25, 2012 study from the Harvard Medical School and Joslin Diabetes Center outlined findings that the commonly prescribed drugs to reduce cholesterol, statins, increased the risk of inducing or acquiring diabetes onset by 13 to 25 percent, according to 7 very large studies, and a meta-analysis, the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), and a Harvard meta-analysis of 6 statin trials that included 57,593 patients. The implications are that the protocol of prescribing statin drugs to nearly everyone with minimal evidence of a lipid imbalance or a metabolic syndrome may come with higher risk than benefit. Reducing cardiovascular risk with a healthy treatment regimen, including care from Complementary Medicine, seems like the sensible approach for most of these patients.http://www.nejm.org/doi/full/10.1056/NEJMp1203020
  23. A follow-up study on risk of developing diabetes from statin drug use, by experts in Finland in 2015, showed a dramatic 46 percent risk of advancing from a Metabolic Syndrome to diabetes with statin drug use, clarifying that both induced insulin resistance and the impairment of insulin secretion by the pancreas was noted to explain this phenomenon. The routine prescription of statins in all patients with high LDL-cholesterol apparently contributed greatly to the increases in incidence of diabetes in the last 2 decades: http://www.science20.com/news_articles/statins_increase_risk_of_developing_diabetes_by_46_percent-153748
  24. New research in 2014 revealed that a peptide neurohormone called kisspeptin-1, or K1, may be the missing link between explaining how Metabolic Syndrome advances to Diabetes Type 2, with K1 increasing in expression in the liver over time in response to sustained relative excess of glucagon in cases of insulin resistance. New drugs to simply block K1 will be introduced, but this hormone has been shown to regulate the hypothalamus axis, fertility, puberty, cancer metastasis, and cardiovascular health, and thus the blocking of K1 may have an array of serious adverse effects. This study at the University of Szeged, in Hungary, shows how K1 regulates eicosanoid production that is important in regulating platelet expression and vascular tone: http://www.ncbi.nlm.nih.gov/pubmed/26242914
  25. A 2015 study at the Imperial College of London, in the UK, outlines how kisspeptin regulates fertility and infertility, affecting important hormones such as gonadotropin releasing hormone, FSH and LH, and thus how administering more kisspeptin may be used soon to help with fertility treatment. They also note that kisspeptin is altered by metabolic factors. The implication is that drugs to block kisspeptin may actually contribute to infertility: http://www.ncbi.nlm.nih.gov/pubmed/26194072

Inclusive facts on diabetes are from: Pathophysiology, Clinical Concepts and Disease Processes by Price and Wilson, Cecil's Essentials of Medicine and the Merck Manual - all of which may be explored online

Additional Information and Information Resources - Links to Scientific Studies

Much evidence is accumulating to help guide the modern herbalist and Licensed Acupuncturist in the best course of therapy for the patient with Diabetes and Metabolic Syndromes. Herbal formulas and specifics, as well as novel nutrient medicines, are being heavily researched, and Complementary Medicine is being heavily utilized in many countries in this type of therapy. In addition, despite the difficulties in devising human blinded placebo-controlled clinical trials, these types of proofs of acupuncture have finally been achieved and both provide evidence of acupuncture efficacy in the the treatment of diabetes and Metabolic Syndrome, and help guide Licensed Acupuncturists in improving therapy. Most of the studies of acupuncture in the treatment of diabetes and Metabolic Syndrome utilize physiological studies because of the difficulties in devising blinded placebo, or sham, acupuncture, which is nearly impossible to actually do. Standard allopathic medicine has cynically held the acupuncture science to these types of evidenced proofs, which are only applicable to studies of pills, but today, thousands of well-designed physiological studies have finally been financed and prove that acupuncture does work in this regard, some of which are difficult to design and administer blinded placebo-controlled human trials. This overwhelming scientific evidence is too large to present here, but a few examples with links are provided.

  1. A 2010 report on the broad classification of diabetes, by experts at the American Diabetes Association, presents a conservative, but thorough, explanation of the accepted parameters of this disease. One may note the emphasis on insulin resistance in the vast majority of cases as a dominant concern over insulin deficiency, the need to test for 5 types of autoimmune antibodies, which is still rarely performed, the large contribution of increased use of steroidal drugs and thiazide diuretics to the onset of disease, the contribution of other hormonal imbalances to onset or worsening of diabetes, and the contribution of chronic low-grade viral illness to onset or worsening of diabetes: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797383/
  2. A 2014 multicenter study of diabetes prevention, following a randomized set of patients at risk for diabetes over 7 years, sponsored by the U.S. National Institutes of Health, the Colorado School of Public Health, the Joslin Diabetes Center, and other important medical institutions, found that "effective intervention", or changes in weight and lifestyle alone (e.g. quitting smoking, improving the diet, decreasing antidepressant and statin use), did not explain the lowered diabetes onset and progression rates in either placebo or metformin treated patients, implying that a broader, or more holistic set of factors was involved in study success. These researchers also found that weight gain did play a significant factor in onset and progression of diabetes for those patients in the intensive lifestyle group, or those that were found to have habits that contributed to the disease, such as smoking cigarettes, statin and antidepressant drug use, poor diet, and lack of physical activity. Such studies should point to the need to integrate a more holistic and thorough protocol, integrating Complementary Medicine, to achieve better success: http://www.ncbi.nlm.nih.gov/pubmed/25277389
  3. A 2015 study at Stellenbosch University in South Africa and the University of the Reunion in France outlines the facts concerning the role of Advanced Glycation Endproducts (AGEs) in the creation of oxidative stress on fat cells that leads to insulin resistance, obesity and diabetes. These researchers note that wide array of AGEs, with both endogenous and exogenous sources, and a variety of mechanisms of formation in chronic disease, indicating that there will be no single allopathic drug approach that will solve this cause of chronic diseases, disease symptoms, and obesity. A holistic approach integrated into care is necessary: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386674/
  4. A 2015 multicenter study at the George Institute for Global Health at Oxford University, The Icahn School of Medicine in New York, and the University of Sydney in Australia found that Advanced Glycation Endproducts (AGEs) appear to be the key factor that determines at-risk obesity from healthy obesity, and may be the key modifiable risk factor for insulin resistance, MS, type 2 diabetes and cardiovascular disease progression. Studies have shown that endogenous AGE accumulation is a slowly advancing pathological process that affects proteins with longer lives, such as circulating albumin, and that exogenous AGE intake from fast food and processed foods and snacks may cause acute exacerbation of these disease processes related to AGE accumulation and receptors for AGEs: http://www.ncbi.nlm.nih.gov/pubmed/25695886
  5. A 2013 report by the conservative American Diabetes Association finally noted that many drugs that treat psychiatric disorders, especially the class of anti-psychotics that are increasingly prescribed for a variety of reasons, and often now come with pleasant sounding names, are indeed proven to induce Metabolic Syndrome, or Diabetes Type 2: http://professional.diabetes.org/admin/UserFiles/file/CE/AntiPsych%20Meds/Patient%20Tool%20%231.pdf
  6. A 2014 multicenter study in the United Kingdom found that statin drugs attenuate Insulin-like Growth Factors and fetal development in the first trimester of pregnancy, affecting lectin receptor binding and other metabolic parameters in hormonal insulin metabolism that could contribute to future onset of diabetes or Metabolic Syndrome. Statin drugs have already been associated with increased risk of Metabolic Syndrome, or diabetes type 2, in adults, as well as inhibition of HMG-CoA reductase and mevalonic acid pathway that is important in adequate hormone Vitamin D production and healthy lipoprotein formation and balance, which are linked to cardiovascular disease risk. Biphosphonates, prescribed for osteoporosis and breast cancer also negative affect the mevalonate pathway: http://www.ncbi.nlm.nih.gov/pubmed/25304981
  7. A 2013 list of the many drugs that may affect circulating blood sugar levels is presented on dLife, and while perhaps controversial, reflects the need for a more thorough individualized assessment of the finding of high fasting blood sugar levels before simply starting a complex diabetic drug protocol. There is no harm in reducing medications that could be causing high blood sugars in most cases, improving diets and physical activities, and integrating Complementary Medicine to see if the signs and symptoms can be resolved before jumping to a lifelong dependence on multiple pharmaceutical drugs with adverse long-term health effects: http://www.dlife.com/diabetes/type-2/diabetes-treatment/drugs-that-raise-blood-glucose
  8. A 2015 study at Linkoping University in Sweden, headed by Dr. Johnny Ludvigsson, professor of pediatrics, proved in a large cohort study following over 10,000 families and children for 14 years, that childhood stress and trauma dramatically increase the risk for future diabetes type 1, and environmental factors such as diet, hygiene, poverty, viral infections, heavy metal toxins, and a genetic and epigenetic predispostion all play a role, with children evaluated with a predisposing set of factors perhaps 12 times as likely to acquire diabetes type 1 when the unresolved effects of childhood stress and trauma are seen. Clearly a holistic preventive approach is needed: http://www.liu.se/forskning/forskningsnyheter/1.629345?l=en
  9. A 2015 study at the University of Colorado Denver, Barbara Davis Center for Childhood Diabetes, showed that alterations in gut Microbiota with overgrowths of specific pathological bacteria are highly correlated with autoimmune reactions linked to susceptibility of Type 1 Diabetes. Such findings show that antibiotic overuse in infancy and childhood, as well as other medication use that damages the Biome, and early diet that could harm the balance of microbiota in the gut are potentially an integral part of diabetes pathology, not just a genetic propensity. Such study also shows that improving the healthy balance of the Biome later in adult life could play a significant role in the holistic treatment of diabetes: http://www.ncbi.nlm.nih.gov/pubmed/26068542
  10. A 2015 randomized human study Tel Aviv University dividing patients diagnosed predominantly with Type 2 Diabetes into 2 groups, with one group eating a large healthy breakfast and a small dinner in the evening, and the other a small breakfast and a large dinner, the usual human pattern today, showed that the habit of the large healthy breakfast and small dinner resulted in a 20 percent average decrease in postprandial blood sugar levels, and 20 percent improved levels of insulin, C-peptide (not CRP, the protein peptide links the insulin chains A and B to improve insulin metabolism), and GLP-1 (glucose-like peptide-1, the target of drugs that act as agonists to GLP-1 in diabetic treatment, or incretin mimics, such as Victoza, Trulicity etc.). This demonstrates that dietary habits could be more effective than the current drug protocols to control diabetes: https://english.tau.ac.il/news/timing_of_meals
  11. A 2015 study at Keralla University of Health and Allied Sciences, in India, found that an alcohol extract of the Chinese herb Citrus sinensis peel (similar to other citrus medicinal peels such as C. aurantium and reticulata, e.g. Zhi ke, Zhi shi, Qing pi, Chen pi) showed significant antimicrobial activity against Prevotella species, which are linked to unhealthy Biome and diabetes. Such study could find specific herbal extracts that could be invaluable to help prevent diabetes type 1 and other autoimmune diseases: http://www.ncbi.nlm.nih.gov/pubmed/26024407
  12. A 2013 discovery at the Harvard Stem Cell Project, by the postdoctoral researcher Peng Yi, under the guidance of the director of this project, Professor Doug Melton, a long-time research specialist in diabetic pathology, found that a newly discovered protein hormone, betatrophin, dramatically stimulates growth of new pancreatic beta cells, the main insulin producing cells in the body that are damaged or killed in Diabetes Type 1 and advanced Metabolic Syndrome, or Diabetes Type 2. This discovery lays to rest the notion that pancreatic beta cells may not regrow and reestablish normal function, leading to a lifetime dependency on synthetic insulin hormone, and the subsequent health problems that are often devastating in the long run: http://news.harvard.edu/gazette/story/2013/04/potential-diabetes-breakthrough/
  13. Research in 2001 at Massachusetts General Hospital, affiliated with Harvard Medical School, and finally published in the March 24, 2006 issue of Science, showed how beta cell regeneration was achieved in the laboratory by stimulating immune modulation with Complement Freund's Adjuvant and introducing donor spleen cells into diabetic laboratory animals. Such study demonstrates the potential for a holistic course of treatment to stimulate immune responses and spleen cell activity to potentially achieve reversal of diabetes and regrowth of functional beta cells: http://www.biologynews.net/archives/2006/11/23/new_data_from_nih_lab_confirms_protocol_to_reverse_type_1_diabetes_in_mice.html
  14. A 2006 study at Washington University School of Medicine, in St. Louis, Missouri, U.S.A. demonstrated that pancreatic beta cells could be regenerated even without stem cell growth if the autoimmune process was modulated at the right time during recovery. The prior studies were duplicated with injection of male splenocyte stem cells, but the regrowth occurred in the host normal cells as well in a percentage of the study animals: http://www.ncbi.nlm.nih.gov/pubmed/16556846
  15. A 2010 placebo-controlled human clinical trial of acupuncture in the treatment of diabetic peripheral neuropathy at Changchun University in China provided evidence that a 15-day treatment protocol significantly improved both motor and sensory function: http://www.ncbi.nlm.nih.gov/pubmed/20633522
  16. A 2015 article in the British Medical Journal (BMJ) describes the approved human clinical trial pilot study of acupuncture stimulation to determine the mechanisms by which this treatment has been able to reduce insulin resistance and improve insulin sensitivity. This approved clinical trial will use electroacupuncture stimulation for more than 6 months to prove that such adjunct care could reverse PCOS and Metabolic Syndrome, and will be conducted by experts at the Guangzhou Medical University, in China, and the Karolinska Institute, in Stockholm, Sweden. In a few years, this process of human clinical trials will provide evidence that demands integration of acupuncture for Metabolic Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/25941189
  17. A 2009 study of electroacupuncture showed that this treatment significantly improved lowering of circulating glucose levels when added to standard pharmaceutical treatment with rosiglitazone (Avandia). The diabetic drug did not show evidence of increasing insulin plasma concentrations until electroacupuncture stimulation was added. Since Avandia is shown to significantly increase cardiovascular risks, and now comes with stern FDA warnings, an integrative M.D. could lower the dosage, and the subsequent risk and harm, by incorporating electroacupuncture into the therapy, and utilizing the Complementary Medicine specialties of the Licensed Acupuncturist. A single acupuncture point, ST36, was used in the study to clarify the effects, but a more individualized and complex acupuncture treatment would be used in clinical practice, enhancing the effects even more: http://www.ncbi.nlm.nih.gov/pubmed/20633486
  18. A 2010 review of scientific studies by the Kanazawa Medical University in Ishikawa, Japan, found that ample proof of effectiveness, and a number of mechanisms by which acupuncture is effective for treatment of insulin resistance has been demonstrated with well-designed randomized clinical human trials, as well as physiological studies. 234 English-language scientific studies accepted by the U.S. PubMed database were reviewed: http://www.ncbi.nlm.nih.gov/pubmed/20590731
  19. A 2009 study at the International University of Health and Welfare in Otawara, Tochigi, Japan, reveals that electroacupuncture exerts very safe and modulatory improvement of insulin responsiveness, improving the glucose metabolism and cellular response to insulin without negatively affecting the circulating glucose balance. Unlike pharmaceutical treatment, acupuncture is shown to enhance and improve our normal physiological homeostatic mechanisms, not alter the mechanism. Diabetic drugs often induce hypoglycemic states and other negative imbalanced metabolic effects: http://www.ncbi.nlm.nih.gov/pubmed/19556171
  20. A 2005 study at China Medical University in Taichung, Taiwan, found that 2 Hz electroacupuncture bilaterally at ST36 in laboratory animals induced significant increases in adrenal beta-endorphin and circulating insulin, and that these effects were enhanced by increased serotonin. Use of a serotonin precursor such as L-Tryptophan or 5HTP (griffonia seed extract) could be helpful: http://www.ncbi.nlm.nih.gov/pubmed/15814202
  21. A 2012 study at the University of Otago in New Zealand found that electroacupuncture at ST36 and Ren12 for 30-90 minutes resulted in a significant reduction in blood glucose, with just one treatment. Future studies are being designed to check the results of Chinese studies that have demonstrated normalization of the insulin metabolism, lipids, fatty acids, and beta-endorphin. These stage one studies warrant progression to stage 2 and 3 studies involving human clinical trials : http://www.ncbi.nlm.nih.gov/pubmed/22309901
  22. A 1999 study at China Medical College in Taichung, Taiwan, found that a 15 Hz 10 mA electroacupuncture stimulation at a single point, Ren 12, induced adrenal beta-endorphins and reduced plasma glucose concentration in type 2 diabetic laboratory animals in an insulin-dependent manner. Subsequent laboratory studies demonstrated in animal studies that removal of the adrenal glands abolished this effect, proving that the effect was indeed adrenal, and that the health and function of the adrenals is important to the regulation of blood glucose in an insulin-dependent manner: http://www.ncbi.nlm.nih.gov/pubmed/10064107
  23. A 2014 study in China showed that electroacupuncture at the point GB26, or Dai mai, can reduce insulin resistance, regulate blood lipids, and lower blood glucose in laboratory animals with Metabolic Syndrome. This point has long been associated with the systemic endocrine system and metabolic regulation in TCM: http://www.ncbi.nlm.nih.gov/pubmed/25069196
  24. A 2013 review of the effects of adrenal stress and insufficiency on diabetic states, by the University of Buffalo, in New York, USA, showed that Cortin, or chemicals secreted by the adrenal cortex, when deficient, have a number of gradual effects on the human organism, with altered blood sugars, urea, and symptoms of fatigue, loss of appetite, asthenia, leg pain, insomnia, depression, poor memory, and muscle ache. When normal Cortin levels are regained, a gradual resolution to this syndrome of adrenal fatigue, or deficiency, termed Kidney Yang Qi Deficiency in TCM, occurs. These symptoms are commonly seen in diabetic syndromes, and can be relieved with a combination of adrenal cortex extract, specific herbal and nutrient chemicals, and acupuncture stimulation: http://press.endocrine.org/doi/abs/10.1210/endo-16-5-521?journalCode=endo
  25. A 2011 study at China Medical University in Taiwan found that electroacupuncture stimulation at the points ST36 and Ren12 in laboratory animals with induced Type 2 diabetes resulted in significant lowering of blood glucose levels, with effects attributed to cholinergic effects of the nervous regulation of insulin signaling proteins: http://www.ncbi.nlm.nih.gov/pubmed/21799686
  26. A 2009 study at Tungs Taichung Metro Harbor Hospital, Department of Endocrinology and Metabolism, in Taiwan, found that electroacupuncture at the point ST36 significantly improved glucose tolerance and insulin sensitivity in study animals with insulin resistance and diabetes induced by prednisone, a synthetic corticosteroid well known to induce hyperglycemic states: http://www.ncbi.nlm.nih.gov/pubmed/19646276
  27. A 2011 joint study at Hubei University of Chinese Medicine in Wuhan, China, Kanazawa Medical University in Daigaku, Japan, and Huazhong University of Science and Technology in Wuhan, China, found that electroacupuncture with 3 Hz milliamp stimulation for 10 weeks induced metabolic changes that reduced insulin resistance in laboratory animals by increasing SIRT1, PGC-1alpha, NRF1 and ACOX expressions. SIRT1 levels may increase in human tissues in response to caloric restriction and exercise as well, and with the use of the herbal chemical resveratrol, and a comprehensive treatment protocol, utilizing all of these methods concurrently is recommended: http://www.hindawi.com/journals/ecam/2011/735297/
  28. A 2012 review of clinical studies of electroacupuncture to treat diabetes found that studies with both humans and animals showed significant benefit, although with single point studies, longer treatment times, with electroacupuncture stimulation for 30 minutes per treatment were often needed to lower blood glucose. The points studied were ST36 and Ren12 most often. Future studies are being devised to study electroacupuncture more fully, measuring not only blood glucose, but insulin, lipids, fatty acids, and beta-endorphin: http://www.ncbi.nlm.nih.gov/pubmed/22309901
  29. A 2014 randomized controlled study in China demonstrated that electroacupuncture at points along the spine at the points Yi shu, UB20, and UB23 could reduce neurohormonal regulators, such as cortin (CORT), corticotropin releasing hormone (CRH), and improve insulin sensitivity, with electroacupuncture at Yi shu reducing the level of cortin (hormones and chemicals of the adrenal cortex) more than medication, showing how this type of stimulation could add to treatment success if integrated as well: http://www.ncbi.nlm.nih.gov/pubmed/25675573
  30. A 2011 randomized controlled study of the effects of electroacupuncture on various neurohormonal parameters, at the China Academy of Chinese Medical Sciences, in Beijing, China, found that electroacupuncture stimulation at Ren 4 is able to potentiate estrogen effects, and down-regulated the expression of Kiss-1, or kisspeptin-1, known as K1, which was found to be the missing link in the physiology of progression of Metabolic Syndrome to true diabetes in 2014, at the esteemed Johns Hopkins Medical School. Future study will surely show that such common acupuncture techniques may have a dramatic impact over time on Metabolic Syndrome and diabetes: http://www.ncbi.nlm.nih.gov/pubmed/?term=kisspeptin+acupuncture
  31. A 2012 study at the University of Texas Southwestern Medical School, in Dallas, Texas, found that leptin affects the metabolic regulation in the brain via the proopiomelano-cortin neurons (POMC), regulating glucose metabolism and homeostasis centrally independently of its effect on the energy metabolism. Restoring leptin receptor balance was shown to both normalize blood glucose and ameliorate insulin resistance in the liver and lipid imbalance. These problems are thus central to Metabolic Syndrome and diabetes, and research has revealed a number of herbal and nutrient chemicals that restores leptin homeostasis, and has shown that specific acupuncture stimulations may also modulate this leptin and cortin metabolism: http://www.ncbi.nlm.nih.gov/pubmed/22326958
  32. A 2014 study in China to further clarify acupuncture treatment protocols typed the female human patients into either Yin deficiency or Yang deficiency types, and showed that individualized treatments produced an 81 percent effectiveness in the Yin deficiency group and a 76 percent effectiveness in the Yang deficiency group, as measured with levels of fasting blood sugars, fasting insulin, insulin sensitivity, insulin resistance, pancreatic function, total cholesterol, triglycerides and cholesterol in both LDL and HDL. Greater efficacy was shown in younger patients, and such study both shows the broad effects of acupuncture as a Complementary and Integrative Medicine, as well as helping to refine guidelines in therapy: http://www.ncbi.nlm.nih.gov/pubmed/24673047
  33. A 2011 randomized controlled study, at the Nanjing General Hospital of the Nanjing Military Command, comparing acupuncture therapy to standard pharmaceutical medication in the treatment of diabetes type 2 showed that the acupuncture stimulation was more effective by far in lowering fasting leptin levels and improving insulin sensitivity, while fasting insulin and insulin resistance were improved in both therapies. Again, the benefits of integrating acupuncture into the treatment protocol are considerable: http://www.ncbi.nlm.nih.gov/pubmed/21942183
  34. A 2008 study of the effects of the herbal chemical resveratrol, obtained from the Chinese herb Polygonum cuspidatum, or Hu zhang, demonstrated that resveratrol may increase SIRT1 activity as well as SIRT2. Numerous studies now show that this herbal chemical may prove very valuable in the treatment of diabetes: http:/journal.9med.net/qikan/article.php?id=419372
  35. A 2007 study at the Second Military Medical University in Shanghai, China, together with Brown University in Providence, Rhode Island, found that chemicals in American Ginseng, or Panax quinquefolius, increases insulin production over time in Type 1 diabetes by improving beta cell function and immune reactivity, and improves postprandial sugar metabolism in Type 2 diabetes. The type and quality of ginseng has been found to be important in clinical utilization. Combination with Crepe Myrtle, another proven aid to postprandial sugar utilization is also recommended: http://www.cmjournal.org/content/2/1/11
  36. A 2007 study at the Chonbuk National University Medical School, in Jeonju, South Korea, found that the Chinese herb Coptidis (Huang lian) protects against cytokine-induced beta-cell death in the pancreas, a hallmark of Diabetes Type 1, by suppression of the cytokine NF-kappaB. Coptis or Huang lian is a source of Berberine, along with Mahonia: http://www.ncbi.nlm.nih.gov/pubmed/17464176
  37. A 2016 study at Xiamen University in China showed that the Chinese herb Rheum palmatum, or Da huang, was effective in helping to resolve fatty liver, or hepatic steatosis, and improved glucose tolerance, affecting specific pathways of gene expression to achieve these goals: http://www.ncbi.nlm.nih.gov/pubmed/27109162
  38. A 2013 randomized controlled study at the Chinese Academy of Medical Sciences in Beijing, China, found that a combination of Rheum palmatum (Da huang), Cordyceps (Dongchong xia cao), and Rhodiola crenulata (Hong jin tian) could significantly benefit and protect kidney function and health in diabetic laboratory animals, improving blood sugar levels as well as key measures of kidney function, and providing antioxidant effects: http://www.ncbi.nlm.nih.gov/pubmed/24558885
  39. A 2009 study at the Chonbuk National University Medical School, in Jeonju, South Korea, found that the Chinese herb Fructus Xanthii (Cang er zi) protects against cytokine-induced beta-cell death in the pancreas, a hallmark of Diabetes Type 1, by suppression of the cytokine NF-kappaB: http://www.ncbi.nlm.nih.gov/pubmed/19288032
  40. A 2014 study at Grangdong Pharmaceutical University, in Guangzhou, China, found with extensive testing of both metabolic parameters and actual genetic expression in liver and fat cells, that a typical Chinese Herbal Formula used to treat Metabolic Syndrome, or Type 2 Diabetes, called FTZ, actually reversed insulin resistance in liver and fat cells, as well as lowering circulating triglycerides, total cholesterol and fasting blood sugars. The formula consists of Ligustrum lucidum / Nu zhen zi, Salvia miltiorhiza / Dan shen, Coptis chinensis / Huang lian, Panax notoginseng / San qi, Eucommia ulmoides / Du zhong, Cirsium japonicum / Da ji, and Citrus medica / Zhi shi: http://www.translational-medicine.com/content/12/1/47 / or go to: http://www.ncbi.nlm.nih.gov/pubmed/24555840
  41. A 2008 study at the University of Verona, Verona, Italy, demonstrated that chemicals in St. John's wort, or Hypericum perforatum, such as hyperforin, target key mechanisms of cytokine-induced beta cell damage in the pancreas, and at low dosage serves to improve beta-cell function and survival, making it a valuable addition to therapy in true diabetes: http://www.ncbi.nlm.nih.gov/pubmed/18226577
  42. A 2007 study at the Dongduk Women's University in Seoul, South Korea, found that the Chinese herb silkworm extract (Bombix mori, or Jiang Can) significantly reduced circulating blood sugar levels in laboratory animals with induced diabetes and affected the hypothalamic regulation of vasopressin to treat and prevent diabetic neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/17359645?
  43. A 2013 study at the University of Kashmir, Srinagar, India, found that chemicals in the herb Urtica dioica, or Stinging nettle, significantly lowered blood sugar during a glucose tolerance test: http://www.ncbi.nlm.nih.gov/pubmed/?term=urtica+dioica+neuropathy
  44. A 2013 study at the Lakshmi Naraine College, in Bhopal, India, found that the herb Urtica dioica (Stinging Nettle) significantly relieved symptoms of both central and peripheral neuropathy in diabetes as well: http://www.ncbi.nlm.nih.gov/pubmed/23036051
  45. A 2015 study at the University of Copenhagen School of Medicine, in Denmark, showed that active chemicals in the Chinese herb Scutellaria baicalensis, or Huang qin, act effectively as aldose reductase inhibitors and alpha-glucosidease inhibitors, providing proven benefits for peripheral neuropathy. These studies use high resolution MRI spectroscopy to confirm these effects. Huang qin is already shown to be a significant anti-inflammatory and antioxidant herb, and is widely utilized in Chinese herbal formulas: http://www.ncbi.nlm.nih.gov/pubmed/26187760
  46. A 2008 study at Pukyong National University, in South Korea, identified the Chinese herb Sophora flavescens, or Ku shen, as a significant aldose reductase inhibitor in studies with laboratory animals, showing its potential within an integrated protocol to treat diabetic peripheral neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/18718128
  47. A 2009 study at the Chungnam National University College of Pharmacy, in Daejeon, South Korea, found that 2 chemicals in the Chinese herb Paeonia suffruticosa, or Mu dan pi, exerted significant benefits with aldose reductase inhibition and inhibition of Advanced Glycation Endproducts (AGEs), making this herb doubly effective within formulas to treat diabetic peripheral neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/19670875
  48. A 2011 randomized conrolled human study at Mt. Sinai School of Medicine, in New York, New York, U.S.A. showed that Advanced Glycation Endproducts (AGEs) are highly correlated with insulin resistance in diabetes, and decreasing AGEs in the diet showed remarkable improvement in Type 2 Diabetes with decrease in Leptin, inflammatory markers, and a healthy increase in adiponectin and insulin reactivity: http://www.ncbi.nlm.nih.gov/pubmed/21709297
  49. A 2005 review of scientific studies of Chinese herbs and the flavonoids that act as aldose reductase inhibitors and antioxidants, by the Beijing Institute of Technology, in China, shows that evidence points to a variety of herbal chemicals useful in this way to treat or prevent diabetic peripheral neuropathy, vasculopathy, and retinopathy, including quercetin, silymarin, peurarin, baicalein, berberine, and others: http://www.ncbi.nlm.nih.gov/pubmed/16335816
  50. A 2012 meta-review of all scientific studies and randomized controlled human clinical trials of the Chinese herbal chemical berberine in the treatment of type 2 diabetes or Metabolic Syndrome, by Tongji Medical College, Huazhong University, Hubei, China, found that berberine showed a comparable but not better control of high blood sugar to metformin, glipizide, or rosiglitazone, and a mild antidyslipidemic effect. Use of berberine with these common diabetic drugs showed greater control of blood sugar than the drugs alone, implying that a lower dosage to achieve control might be achieved, thus avoiding side effects. The conclusion of this review was that berberine appeared to be efficaceous for treating diabetes type 2 and high lipid cholesterol: http://www.ncbi.nlm.nih.gov/pubmed/23118793
  51. A 2011 study at Pusan National University School of Korean Medicine found that a Chinese herbal formula exerted multiple therapeutic effects for the treatment of type 2 diabetes, inhibiting NFkB signaling dysfunction stimulated by the inflammatory cytokine TNF-alpha, attenuated ER stress in liver cells, reduced fasting blood glucose levels, and reduced HbA1C levels, improving postprandial glucose levels, and enhancing insulin sensitivity. These findings in laboratory animals, which also found reduced free fatty acids, triglycerides and total cholesterol, shows the promise of Chinese herbal formulas in the Complementary treatment of type 2 diabetes. The formula consisted of ginseng (Xi yang shen), Pureria lobata (Ge gen), Dioscorea batatas (Shan yao), Rehmannia glutinosa (Sheng di huang), Amomum cadamomum (Sha ren), Poncirus fructus (Gou qi zi), and Evodia officialis (Wu zhu yu), which is a commonly used formula: http://www.ncbi.nlm.nih.gov/pubmed/21375727
  52. A 2015 study at the Gulhane Medical Academy, in Turkey, showed that the biomarker E-selectin, a regulator of cell adhesion and unhealthy atherosclerotic plaque, as well as chronic inflammation, and now highly specific for cardiovascular risk, is shown to increase to excess levels in parallel with high circulating glucose in pre-diabetic (Metabolic Syndrome) and early diabetic states, and is associated with arterial stiffness, or atherosclerosis: http://www.ncbi.nlm.nih.gov/pubmed/26201008
  53. A 2015 study at China Medical University and Asia University, in Taiwan, showed that an active chemical in the Chinese herb Zi cao, or Lithospermum erythrorhizon, called shikonin, signficiantly reduces the adhesion factors that are now key biomarkers for dangerous atheroscleratic plaque and cardiovascular risk, E-selectin and ICAM, by suppressing oxidant inflammatory levels, clearing or preventing oxidized low-density lipoproteins (oxLDL) and atherogenesis: http://www.ncbi.nlm.nih.gov/pubmed/25541286
  54. A 2014 study at China Medical University and Asia University, in Taiwan, also showed that an active chemical in the Chinese herb Chuan xin lian (Andrographis paniculata), called andrographolide, significantly inhibits key inflammatory mechanisms which induce enothelial artery adhesioin molecules (ICAM) linked to atherosclerosis: http://www.ncbi.nlm.nih.gov/pubmed/24998495
  55. A 2013 study at the Korea Institute of Oriental Medicine found that an alcohol extract of the Chinese herb Xia ku cao (Prunella vulgaris) suppresses chronic inflammatory induced expression of endothelial arterial adhesion molecules such as ICAM and E-selectin that are linked to dangerous atherosclerotic plaque: http://www.ncbi.nlm.nih.gov/pubmed/23884101
  56. A 2013 study at Kyungpook National University School of Medicine, Daegu, South Korea, found that the Chinese herbal chemical berberine, an alkaloid found in a number of herbs, but principally Coptis chinensis, or Huang lian, produced significant effects to relieve allodynia (sensitivity to pain) in diabetic neuropathy, exerting antioxidant, anti-inflammatory, and antidepressant activities in studies: http://www.ncbi.nlm.nih.gov/pubmed/23734996
  57. A 2012 study of integration of Chinese Herbal Medicine to treat diabetic retinopathy, by the University of Sydney, in Australia, provides a thorough explanation of the various aspects to this pathology, such as accumulation of advanced glycation endproducts (AGEs), inflammatory imbalance, metabolic dysfunctions etc. that can be helped with various Chinese herbs and formulas cited with scientific studies, as well as Western herbs such as Gingko and Bilberry: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252962/
  58. A 2015 study at the Korea Institute of Oriental Medicine, in Daejon, South Korea, found that Myricetin, a well studied flavonoid chemical in a number of Chinese herbs, as well as common foods in small amounts, very significantly reduced the accumulation of advanced glycation endproducts (AGEs) that are the hallmark of diabetic retinopathy. This is achieved via antioxidant and antiinflammatory pathways of phosphorylation of ERK and FAK (focal adhesion kinase). Accumulation of these glycation complexes that are central to diabetes (e.g. A1C) produces AGE receptor expression (RAGE) which activates these inflammatory pathways that eventually produce diabetic retinopathy and can cause symptoms to flare with stress. Myricetin is found in the Chinese herbs Huang lu (Cotinus coggygria cinerea), Gou mei (Murica rubra), and Man shan hong (Rhododendron dahuricum), which also contain Quercitin, a similar chemical that is much studied in diabetes treatment. Such flavonoids are found in minute amounts in fresh whole foods, especially berries, and some other fruits, nuts and vegetables, as well as red wine, and account for the beneficial effects of bilberry extract, which is rich in myricetin, quercetin and kaempferol. Studies have shown that slow thawing of frozen berries in the refrigerator increases the flavonoid content 6-fold over thawing in the microwave, and that fresh, local organic berries and fruits have a much higher content: http://www.ncbi.nlm.nih.gov/pubmed/25450667
  59. A 2012 meta-review of studies at Suzuka University of Medical Science, in Mie, Japan, found that the Indian herb Lagerstroemia speciosa, or Banaba, long used to treat diabetes in Ayurvedic medicine, contained active chemicals that exhibited significant antiglycemic effects, lowering blood sugar in 60 minutes, as well as significant antihyperlipidemic and antioxidant effects. The chemicals studied, including corolosic acid and eliagitannins were found to work via the PPAR pathway at both the liver and the fat cells: http://www.ncbi.nlm.nih.gov/pubmed/23082086
  60. A 2004 study at Yale University School of Medicine found that chronic Diabetes mellitus induces degeneration in the hypothalamus affecting vasopressin producing neurons, contributing to the pathology of diabetic peripheral neuropathy and other negative health effects: http://www.ncbi.nlm.nih.gov/pubmed/15006692
  61. A 2008 study at Joslin Diabetes Center and Harvard Medical School found that carbonic anhydrase II expressing pancreatic cells act as progenitors that give rise to new islest and acini after birth and after injury, and that this identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types shows that restoration of pancreatic hormone producing beta cells is possible: http://www.ncbi.nlm.nih.gov/pubmed/18481956
  62. A further 2009 study at Joslin Diabetes Center and Harvard Medical School found that within the exocrine (acinar and ductal) pancreas of the mouse in laboratory studies, that there are cells that can give rise to insulin-positive cells in vitro: http://www.ncbi.nlm.nih.gov/pubmed/19183938
  63. Cardioprotective effects of European Olive leaf tincture were identified in 2003, preventing high blood pressure and atherosclerosis, while also improving insulin metabolism and providing antioxidant clearing of arteries: http://www.ncbi.nlm.nih.gov/pubmed/12648829?
  64. Cardioprotective effects of the unique Chinese herb, Rhodiola rosea, or Hong Jin Tian, were reviewed in 2007: http://www.ncbi.nlm.nih.gov/pubmed/18074810
  65. A study published in 2013, headed by Harvard Public Health, and conducted at a number of University Medical Schools, showed that just 8 ounces of fresh walnuts a month provided significant benefits in prevention of Diabetes Type 2 and Metabolic Syndrome, primarily due to the quality of omega-3 and omega-6 essential fatty acids, but also due to other nutrients: http://jn.nutrition.org/content/143/4/512.full.pdf
  66. Cardioprotective effects of Omega-3 fatty acids, EPA and DHA, were reviewed in Europe in 1999, and have become standard therapy following a stroke or myocardial infarction (heart attack). Krill oil presents the high quality and most concentrated type of this supplement, with a natural preservative, unlike fish oils: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)07072-5/abstract
  67. Studies in 2010 presented by the American College of Cardiology showed that the array of medications commonly prescribed to reduce risk for patients with metabolic syndrome, or diabetes type 2, are not only ineffective, but actually increased cardiovascular risk for most patients: http://www.nytimes.com/2010/03/15/health/research/15heart.html
  68. Meta-analysis of research in 2009 at the Pennington Biomedical Research Center at Louisiana State University found that evidence supports the use of ginseng, coptis, and bitter melon extract in the treatment of Metabolic Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/18537696
  69. Studies in 2010 by the West China School of Pharmacy in Chengdu, confirmed that saponins in ginseng, combined with saponins in Siberian ginseng (notoginseng), do indeed decrease fasting blood glucose, improve glucose tolerance, and improves insulin and leptin sensitivity at a modest dosage over 12 to 30 days. NOTE: saponins are best extracted in alcohol and/or glycerin tincture: http://www.ncbi.nlm.nih.gov/pubmed/20435129
  70. Studies in 2009 at the Department of Pharmacologie of the University of Montreal found that silibin from Milk Thistle effectively counters the type of fatty liver disease commonly seen as a progressive disorder in metabolic syndrome, obesity and diabetes, by exerting potent antioxidant and anti-inflammatory activities (reducing TNF-alpha), as well as improving insulin metabolism, and aiding liver function (hepatoprotective): http://www.ncbi.nlm.nih.gov/pubmed/19884114
  71. Studies in 2009 at the College of Pharmacy at Chungnam National University found that triterpenes in the Chinese herb Mud dan pi (Moutan cortex, or Paeonia suffruticosa) improved glucose uptake and glycogen synthesis in insulin-resistant liver cells, in a dose-dependant manner. NOTE: triterpenes are best extracted in an alcohol and glycerite tincture: http://www.ncbi.nlm.nih.gov/pubmed/19716700
  72. Studies in 2006 at the Beijing Institute of Pharmacology found that extracts of Xuan fu hua (Inula japonica) exerted a significant hypoglycemic effect, lowering blood glucose levels better than the pharmaceutical drug glycazide and equal to the effects of Metformin in diabetic laboratory animals but only mildy in normal subjects. Lowering of triglycerides was also noted: http://www.ncbi.nlm.nih.gov/pubmed/16508145
  73. Studies in 2010 at the Tajen University Department of Pharmacy in Taiwan found that the Chinese herb Abelmoschus moschatus, a type of hibiscus, was effective in improving insulin sensitivity with 2 weeks of use, and was useful as an integrative medicine for patients with insulin sensitivity: http://www.ncbi.nlm.nih.gov/pubmed/19610024
  74. Studies in 2010 at Wenzhou University in China found that the Chinese herb Cirsium japonicum, or Da ji, produced significant antidiabetic effects, reducing circulating adiponectin, improving insulin resistance, and reducing high triglycerides and blood glucose: http://www.ncbi.nlm.nih.gov/pubmed/20361298
  75. Studies in 2010 at the University Montpellier Center for Pharmacology and Innovation related to Diabetes, in Montpelier, France, found that an herbal chemical quercetin potentiated glucose and insulin metabolism and protected pancreatic beta cells against oxidative damage. Quercetin and isoquercetin are found in the Chinese herbs Luo bu ma, Sang ji sheng, Sang ye, rhododendron dahuricum (man shan hong), Chai hu, Yu xing cao, Bian xu, Wei mao, and Fan shi liu, and in small quantities in shallots, garlic, steel cut oats, cranberries, cabbage, kale, kohlrabi, brussel sprouts, spinach, chives, and pears, as well a evening primrose leaf oil. A combination of resveratrol and quercetin, two important chemicals in Chinese herbs, is now available as Extension Resvertrol, from Vitamin Research Products: http://www.ncbi.nlm.nih.gov/pubmed/20860660
  76. Studies in 2010 at Chonnam National University in Korea found that propolis, a resinous polysaccharide collected by honey bees, may be a potential antidiabetic agent for the treatment of insulin-resistant or insulin-insentive diabetic states. Propolis showed both antioxidant capacity and inhibition of the enzyme glucose-6-phosphatase (G6Pase) that is implicated in insulin resistance: http:/www.ncbi.nlm.nih.gov/pubmed/20878710
  77. A July 13, 2010 article in the New York Times outlines the history of the hiding of serious cardiovascular risks associated with the drug Avandia, a class of glitazones designed to decrease insulin resistance and help with diabetes care. The scandal of hiding important research findings from the public and FDA by SmithKline Beecham (formerly GlaxoKline Smith) may signal a new era in FDA function: http://www.nytimes.com/2010/07/13/health/policy/13avandia.html?_r=1
  78. A July 15, 2010 article in the New York Times reveals that the FDA, once again, allowed a drug to remain on the market despite the history of illegally hiding risks in patient studies and the enormous payouts in product liability from patient harm admitted. GlaxoSmithKline stated that it was assuming a $2.36 billion loss in one quarter for legal liability for the diabetes drug Avandia as well as the antidepressant Paxil: http://www.nytimes.com/2010/07/16/business/global/16avandia.html?src=busln
  79. In 2010, the University of Cincinnati College of Medicine produced research demonstrating that an active chemical in American Ginseng, the ginsenoside Rb1, exerted both antihyperglycemic and antiobesity effects in a dose-dependent manner, affecting the hypothalamus, as well as the pancreas and insulin receptors and glucose transporters.: http://www.ncbi.nlm.nih.gov/pubmed/20682695
  80. In 2005, researchers at the Pritzker School of Medicine at the University of Chicago, Illinois, found that total ginsenosides, or active ingredients of American ginseng, extracted from the leaves and stem, have potential for treating diabetes. Most studies have focused on the traditional use of the plant root, and thousands of studies over the last decades have demonstrated the anti-hyperglycemic effects of chemicals in ginseng, especially in improving postprandial glucose utilization.: http://www.ncbi.nlm.nih.gov/pubmed/16115378
  81. In 2001, researchers at the College of Osteopathic Medicine in Athens, Ohio, found that extracts of Crepe Myrtle (Lagerstroemia speciosa) exerted significant beneficial effects on glucose uptake postprandially, and also inhibited the adipocyte differentiation that is induced by excess insulin, potentially aiding the diabetic patient in the long-term as well as the short: http://www.ncbi.nlm.nih.gov/pubmed/11533261
  82. In 2012, researchers at National Tsing Hua University in Taiwan found that Cordyceps, a unique medicinal plant root fungal combination in nature, called Dong Chong Xia Cao (winter bug summer herb) in China, exerted significant glucose lowering in diabetic animals in vivo, having a number of effects on insulin receptors and central controls: http://www.ncbi.nlm.nih.gov/pubmed/22821853
  83. In 2004, the University of Pittsburgh Dept. of Pediatrics studied the effects of R-lipoic acid to reduce oxidative stress and hyperglycemic diabetic progression in Metabolic Syndrome (Diabetes type 2). R-lipoic acid was found to prevent hyperglycemia, reduce insulin levels, and increase the free radical oxidant scavenging potential in animal studies: http://www.ncbi.nlm.nih.gov/pubmed/14749277
  84. In 2007, studies at the University of Heidelberg, Germany, Institute for Anatomy and Cell Biology, found that L-carnosine levels correlated with decreased pancreatic beta cell mass in diabetes, and that a genetic variant noted in diabetes resulted in the increased enzymatic clearance of L-carnosine, indicating that this amino acid would be recommended for all true diabetic states with decreased insulin capacity: http://www.ncbi.nlm.nih.gov/pubmed/17601992
  85. In 2010, studies at the China Medical University in Taichung, Taiwan, found that inorganic mercury in the environment causes pancreatic beta cell death and that this is significantly reversed with N-acetyl cysteine supplementation: http://www.ncbi.nlm.nih.gov/pubmed/20006636
  86. In 2012, studies at the Magyar Tudomanyos Academy in Budapest, Hungary, found that study animals with hyperlipidemia benefitted significantly from magnesium malate supplementation, with lowering of blood glucose, alkaline phosphatase and amylase activities (starch to sugar conversion), as well as reduced oxidative stress in red blood cells, as measured with chemiluminiscence: http://www.ncbi.nlm.nih.gov/pubmed/21676674
  87. In 2010, studies at the Hamner Institutes for Health Sciences in Research Triangle Park, North Carolina, found that chronic exposure to inorganic arsenic in the environment provoked an adaptive oxidative stress response that damaged pancreatic beta cell function. The researchers found that this chronic inorganic arsenic toxicity was highly associated with incidence of type 2 Diabetes. Chelation therapy may be a significant addition to treatment protocol to stop the onset of type 2 Diabetes in cases of Metabolic Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/20100676
  88. In 2011, studies at the University Putra Malaysia on laboratory animals induced with diabetes showed that Bitter Melon extract, or Momordica charantia (the Chinese herb Ku Gua), alleviated pancreatic damage and increased the number of beta cells, as well as exerting a hypoglycemic effect equal to the pharmaceutical drug glibenclamide (Glyburide, a sulfonylurea). This Chinese herb could thus be an important part of a long-term treatment in renewal of pancreatic beta-cell damage in Diabetes mellitus type 1: http://www.ncbi.nlm.nih.gov/pubmed/21117023
  89. In 2002, studies at the Kyoto Prefectural University of Medicine in Japan found that astaxanthin, a potent antioxidant carotenoid terpene found in arctic krill, microalgaes and sea cucumber, exerted potent beneficial and protective effects on pancreatic beta-cells in laboratory animals induced with diabetes (db/db), increasing the ability of the beta-cells to secrete insulin, and preserving beta-cell function: http://www.ncbi.nlm.nih.gov/pubmed/12688512
  90. In 2004, studies at the Kyoto Prefectural University of Medicine in Japan found that astaxanthin, a potent antioxidant carotenoid terpene found in arctic krill, microalgaes and sea cucumber, also was able to ameliorate the progression of diabetic kidney damage (nephropathy) in diabetic laboratory animals: http://www.ncbi.nlm.nih.gov/pubmed/15096660
  91. In 2012, a study at Yonsei University College of Medicine, in Seoul, South Korea, found that the omega-6 gamma linolenic acid (GLA) aided kidney function, inhibited key inflammatory mediators MCP-1 and ICAM-1, and decreased the fibrosis of extracellular matrix, to significantly inhibit or reverse kidney damage in diabetes. GLA is readily available in foods and herbs, or as a supplement derived from black currant seed oil: http://www.ncbi.nlm.nih.gov/pubmed/23074118
  92. In 2011, studies at Zhejiang University in China found that anthocyanins from the Chinese herb Yang mei (Myrica rubra or Chinese bayberry) demonstrated significant protective effects for pancreatic beta-cells from oxidative damage (other anthocyanins that may be applicable may include the bilberry extracts). These chemicals are derived from the fruit, leaves or root of the myrica rubra: http:/www.ncbi.nlm.nih.gov/pubmed/21166417
  93. In 2010, studies at the Hamner Institutes for Health Sciences in Research Triangle Park, North Carolina, found that persistent oxidative stress coupled with deficient endogenous antioxidant metabolism is highly associated with impaired pancreatic beta cell function and the creation of type 2 diabetic state in Metabolic Syndrome. Improvement in the key endogenous antioxidant metabolism in the body, the glutathione metabolism, may be the key to preventing the develpment of a true diabetes in a Metabolic Syndrome: http://www.ncbi.nlm.nih.gov/pubmed/19501608
  94. In 2011, studies at Tsinghua University in Shenzhen, China, found that many scientific studies show significant benefit of herbal medicine in TCM for lowering blood glucose and controlling inflammation. The authors noted that the 23 herbs that show hypoglycemic effects in study contain 12 active chemicals that all have potent anti-inflammatory actions, indicating that such study may imply that diabetes may be an inflammatory disease, and that such anti-inflammatory and antidiabetic herbal therapy as is seen in these commonly used Chinese herbs may be preventive of diabetes, or inhibiting of the progression of the disease: http://www.ncbi.nlm.nih.gov/pubmed/21205111
  95. A 2015 study at the Korea Institute of Oriental Medicine showed that the herbal chemical Myricetin could be an effective adjunct treatment for diabetic retinopathy, inhibiting AGE-induced migration of retinal pericytes through various anti-inflammatory pathways. Advanced glycation endproducts such as the now well-known A1C are implicated in the still poorly understood mechanisms that lead to visual degeneration in diabetes, causing migration of pericytes from the eye tissues of the retina. Myricetin is found in the Chinese herbs Huang lu (Cotinus coggygria leaf), Gou mei (Myrica rubra fruit), and Man shan hong (Rhododendron dahuricum): http://www.ncbi.nlm.nih.gov/pubmed/25450667
  96. A 2012 study at the Korea Institute of Oriental Medicine, in Daejeon, South Korea, found that a chemical in the Chinese herb Pueraria lobata, or Ge gen, commonly called Kudzu root, effectively inhibits retinal pericyte apoptosis induced by AGEs in diabetic retinal neuropathy, via a number of antioxidant and anti-inflammatory pathways:http://www.ncbi.nlm.nih.gov/pubmed/22609359
  97. A 2015 study at Shanghai University in China showed that the Chinese herb Dendrobium chrysotoxum (Shi hu) alleviated diabetic retinopathy by preventing retinal inflammation and tight junction protein decrease, decreasing the expression of pro-inflammatory cytokines that drive this disease. Such herbal medicine could prove to be a valuable adjunct in preventing the consequences of severe acute diabetic episodes, or the effects of chronic diabetes: http://www.ncbi.nlm.nih.gov/pubmed/25685822
  98. In 2008, a group of experts from Manchester University in the United Kingdom submitted this overview of the complex pathology of diabetic peripheral neuropathy, indicating that a complex treatment protocol is needed to reverse this pathology: http://www.academia.edu/295733/Pathophysiology_and_Treatment_of_Painful_Diabetic_Neuropathy
  99. In 2009, a large cohort study by the Institute for Health Research in Denver, Colorado, U.S.A., sponsored by Kaiser Permanente, showed that patients with painful diabetic peripheral neuropathy had significantly higher comorbities and healthcare utilization, with a 2.5 times greater likelihood of hospital admission, and increased healthcare costs estimated to average an additional $6000 per year over similar patients without a painful diabetic peripheral neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/19419344
  100. In 2013, a study at the University of Miami Miller School of Medicine showed that a low-dose CoQ10 supplement reduced painful diabetic neuropathy, allodynia and temperature sensitive hyperalgesia, as well as inflammatory cytokines and lipid peroxidation, in laboratory animals with induced painful diabetic peripheral neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/23334664
  101. In 2013, a study at Karolinska University, Rolf Luft Research Center for Diabetes and Endocrinology, found also that CoQ10 presented a promising adjunct treatment for diabetic peripheral neuropathy, alleviating allodynia, mechanical hyperalgesia, and sciatic nerve dysfunction, as well as dorsal root nerve damage, and downregulating pain signaling PLC after 6 months of treatment: http://www.ncbi.nlm.nih.gov/pubmed/23267110
  102. In 2010, a study of topical cannibinoids, called Cannabidiol, was shwon to relieve symptoms of painful diabetic peripheral neuropathy, by the University of Calgary, Alberta, Canada. Unfortunately, such topical cannibinoid cream has not been approved by the U.S. FDA. The combination of cannibidiol and capsaicin could potentially be an inexpensive and effective medicine for painful diabetic peripheral neuropathy, allowing millions of sufferers to perform normal work and exercise activities while treating their disease: http://www.ncbi.nlm.nih.gov/pubmed/20236533
  103. A 2012 study at the Chinese PLA General Hospital, Beijing, China, found that alpha lipoic acid (ALA) inhibited intermittent high glucose and high glucose induced oxidative stress and apoptosis in Schwann Cells of the peripheral nervous system: http://www.ncbi.nlm.nih.gov/pubmed/22796564
  104. A 2014 meta-review of all published scientific studies of Alpha lipoic acid (ALA) in the treatment of painful diabetic neuropathy, performed by the Democritus University of Thrace School of Medicine, in Alexandroupolis, Greece, concluded that ALA is a "valuable therapeutic option for diabetic neuropathy", better tolerated than chronic use of pain medication, and actually improves neural function: http://www.ncbi.nlm.nih.gov/pubmed/25381809
  105. A 2013 study at the G. d'Annunzio University, Chieti, Italy found that the nutritional supplement acetyl-L-carnitine, a molecule naturally produced in the mitochondria of cells, which enables Coenzyme A and antioxidant effects to occur, also induces neuroprotective, neurotrophic (growing new neural cells), and analgesic (pain relieving) effects in the peripheral nervous system. The effects of acetyl-L-carnitine in the central nervous system, or brain, have long been noted, with clinical trials demonstrating positive effects on memory and cognitive impairment, but now a number of sound studies demonstrate the effectiveness of acetyl-L-carnitine on various peripheral neuropathies as well. The analgesic effects were dependent on epigenetic changes and controls, suggesting a more holistic therapy is needed as well for significant relief of neuralgia : http://www.ncbi.nlm.nih.gov/pubmed/23965166
  106. A 2007 study at the University of Catania, Catania, Italy found that the nutritional supplement Acetyl-L-Carnitine (ALC) has clearly demonstrated significant effects in the treatment of neuralgia and peripheral neuropathy, as well as the prevention of neuropathic pain in a variety of diseases, including diabetes. These researchers noted that the effects are noted over time, implying that the neuro-restorative aspects of this molecule are what apparently provides pain and other symptom relief: http://www.ncbi.nlm.nih.gov/pubmed/17696591
  107. A 2012 study at the Chinese Academy of Medical Science and Peking Union Medical College found that a chemical in the Chinese herb Salvia miltiorrhiza (Dan shen) exhibited significant protective effects against diabetic peripheral neuropathy in laboratory animals, increasing motor nerve conduction velocity and pain threshold, nitric oxide synthase, and other markers of improvement: http://www.ncbi.nlm.nih.gov/pubmed/22996345
  108. A 2009 study at the University of California San Diego showed that a combination of Vitamins B1, B6 and B12 showed variable benefits in improving nerve conduction and relieving allodynia in painful diabetic peripheral neuropathy, although for each one used alone there was little or no benefit. This cocktail of B vitamins also did not address markers of oxidative stress and inflammation, suggesting that a larger treatment protocol is needed: http://www.ncbi.nlm.nih.gov/pubmed/19393643
  109. A 2009 human clinical trial Serbia noted that the combination of benfotiamine and P5P (B6) significantly reduced pain, allodynia, and hyperpathy in 22 patients, while improving motor nerve conduction and muscle action potentials, as well as sensory nerve conduction: http://www.ncbi.nlm.nih.gov/pubmed/20069914
  110. A 2001 study at the University of Michigan Medical Center, Ann Arbor, Michigan, found that supplementation with the amino acid taurine significantly improved markers of oxidative stress and inhibited depletion of glutathione metabolism in animals with painful diabetic peripheral neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/11681853
  111. A study in 2014 at the First People's Hospital of Foshan, in China, found that a standardized extract of curcumin, a key anti-inflammatory and antioxidant chemical in Chinese herbs, alleviated diabetic painful neuropathy better than a pharmaceutical drug apocynin derived from plant sources, or placebo of normal saline, in laboratory animals, working via the NADPH pathway and reduction of oxidative stress and cell toxicity (malaondialdehyde): http://www.ncbi.nlm.nih.gov/pubmed/24370596
  112. A study at the Kyungpook National University School of Medicine, in Daegu, South Korea, found that the active chemical in a number of Chinese herbs, berberine, now also standardized in medicines, could significantly relieve diabetic neuropathic pain and allodynia, with 20 mg/kg dosage of berberine similar in effect to 10 mg/kg of amitriptyline, a tricyclic antidepressant approved for this use, but which has considerable adverse side effects: http://www.ncbi.nlm.nih.gov/pubmed/23734996
  113. A 2013 study at the PSG College of Pharmacy, in Tamil Nadu, India, found that the aqueous extract of the Chinese herb Tribulus terristris (Ci li ji) significantly relieved diabetic painful peripheral neuropathy via antioxidant and anti-inflammatory pathways, in a randomized controlled clinical trial with laboratory animals: http://www.ncbi.nlm.nih.gov/pubmed/23280817
  114. a 2014 study at the Karnataka College of Pharmacy, in Bangalore, India, found that an active chemical in a species of bitter melon long used to treat diabetes in Ayurvedic medicine, Momordica cymbalaria, with a steroidal saponin, was effective in treating and preventing diabetic neuropathy, possessing significant antioxidant capacity, and improving demyelination and neuronal degeneration in laboratory animals: http://www.ncbi.nlm.nih.gov/pubmed/24550589
  115. A 2013 study at the University of Miami Miller School of Medicine, in Miami, Florida, U.S.A. found that the coenzyme Q10 (CoQ10-H2) could help significantly to relieve diabetic neuropathic pain and allodynia, reducing oxidative damage and inflammation to the peripheral nerves: http://www.ncbi.nlm.nih.gov/pubmed/23334664
  116. A 2012 study at Kuwait University Department of Medicine showed that the hormone Vitamin D deficiency is a significant risk factor for diabetic peripheral neuropathy, and that further study is needed to see if supplementation results in relief of the disease or prevention: http://www.ncbi.nlm.nih.gov/pubmed/22050401
  117. A 2010 study at the Changchun University of Chinese Medicine demonstrated that a short course of acupuncture could improve measures of motor and sensory nerve function in diabetic peripheral neuropathy, whereas the sham acupuncture in the randomized controlled trial produced no such results: http://www.ncbi.nlm.nih.gov/pubmed/20633522
  118. A 2010 randomized controlled study at Liaoning University of Traditional Chinese Medicine, in Liaoning, China, found that acupuncture produced an 87.5 percent effective rate compared to a 63.6 percent effective rate in the placebo acupuncture group in the treatment of painful peripheral neuropathy, with half of the patients receiving real acupuncture during a 3 month treatment period reporting that symptoms were markedly relieved: http://www.ncbi.nlm.nih.gov/pubmed/20397454
  119. A 2012 placebo controlled study of the effects of electroacupuncture on neuropathic pain showed that stimulation at just 2 points, GB30 and UB40 raised both mechanical and thermal pain thresholds, lowering sensitivity to pain, following a 7-day daily course of treatment. The pain thresholds were raised significantly on the 16th day, 9 days after the course of electroacupuncture, and the measurable expression of both neuronal nitric oxide synthase and mRNA were downregulated in the spinal cord, showing that simple electroacupuncture produced significant effects on neuropathic pain that were both peripheral and central, which were not duplicated in the control group : http://www.ncbi.nlm.nih.gov/pubmed/23342771
  120. A 2013 meta-review of studied nutrient medicine and pharmaceuticals to treat painful diabetic neuropathy, by the Iran University of Medical Sciences, shows that current databases present no defined cure or treatment, but that current clinical trials are exploring taurine, acetyl-L-carnitine, alpha lipoic acid, advanced glycation endproduct inhibitors such as benfotiamine and aminoguanidine, and the Vitamin B3 nicotinamide, as well as ruboxistaurin (protein kinase C inhibitor), fidarestat (aldose reductase inhibitor), and trandolapril (angiotensin-converting enzyme inhibitor): http://www.ncbi.nlm.nih.gov/pubmed/23738033
  121. A 2010 clinical trial at Keio University in Tokyo, Japan found that the aldose reductase inhibiting drug Epairastat suppressed the deterioration in diabetic peripheral neuropathy of the lower extremities, probably by its effects on the polyol pathway, as well as suppression of AGEs: http://www.ncbi.nlm.nih.gov/pubmed/19716319
  122. A 2008 study at Pukyong National University, Busan, South Korea, found that the Chinese herb Sophora flavescens (Ku shen) contained flavonoids that exerted significant aldose reductase inhibition, and is thus applicable to treatment of Diabetic peripheral neuropathy by affecting the polyol pathway and reducing accumulation of Advanced Glycation Endproducts (AGEs): http://www.ncbi.nlm.nih.gov/pubmed/18718128
  123. A 1997 study at Toyama Medical and Pharmaceutical University, Japan, found that chemicals in the Chinese herb Salvia miltiorrhiza (Dan shen) exerted significant effects as an aldose reductase inhibitor, explaining positive effects of this herb in the treatment of diabetic peripheral neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/9377780
  124. A 2007 study at the Korea Institute of Oriental Medicine, Daejeon, South Korea, found that the Chinese herb Cassia tora (Jue ming zi) exerted signficant aldose reductase inhibition and clearance of AGEs to treat diabetic complications. This seed has long been used to treat diabetic retinopathy, but may also be applicable to diabetic peripheral neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/17978503
  125. A 2013 study at Kyoto Pharmaceutical University in Kyoto, Japan found that an alcohol tincture of the flowers of the Chinese herb Prunus Mume (a fruit tree that produces Wu mei) exerted significant effects of aldose reductase inhibition: http://www.ncbi.nlm.nih.gov/pubmed/23546004
  126. A 2011 study at Central South University, in Changsha, Hunan Province, China, found that the Chinese herb Eucommia ulmoides (Du zhong) contained lignans that reversed hypertensive vascular remodeling as well as the aldose reductase inhibiting drug Epairestat, suggesting that this herbal medicine may enhance the effects of Epairestat treatment for diabetic peripheral neuropathy: http://www.ncbi.nlm.nih.gov/pubmed/20817083