Free Shipping on All Orders $75 Or More! Ends January 31st.

Your Trusted Brand for Over 35 Years

Life Extension Magazine

<< Back to April 2017

Will Metformin Become the First Anti-Aging Drug?

April 2017

By Raegan Linton

A committed group of scientists is seeking to validate metformin as the first-ever anti-aging medication.1,2

In this day of staggering drug prices, metformin is available as a low-cost generic.

One mechanism by which metformin works is by activating AMPK, an enzyme inside cells that lowers blood sugar by promoting energy utilization.

Activating AMPK has broad-ranging effects that extend far beyond blood sugar control. Studies show that boosting AMPK activity can prevent—and even reverse—the life-shortening effects of aging, such as cardiovascular disease, diabetes, neurodegenerative diseases, cancer, and more.3

In this article, we’ll review data that persuaded the FDA to allow metformin to be studied in humans as the first anti-aging drug.1

Broad-Spectrum Effects

Broad-Spectrum Effects  

The most commonly prescribed antidiabetic drug is metformin. It has been in use in England since 1958 and in the United States since 1995.

Derived from a compound found in the French Lilac, metformin has a track record of safety and effectiveness at routine doses of up to 2,000 mg daily.4-7

So what evidence is there for the FDA to consider this drug as an anti-aging medication? The reason is simple:

Metformin can block or diminish many of the fundamental factors that accelerate aging.8-12

These include protecting against DNA damage glycation, poor mitochondrial function, and chronic inflammation. Metformin has been shown to facilitate DNA repair, which is critical for cancer prevention.

By attacking these fundamental degenerative processes, metformin can prevent the development of aging’s most troubling diseases.

Metformin has also been shown to increase the production of known longevity-promoting signaling molecules in cells, such as mTOR and AMPK—all of which reduce fat and sugar storage and increase youthful functioning at the cellular level.11,13

Studies have shown that by activating AMPK, metformin specifically impacts lifespan. For example, roundworms treated with metformin have higher AMPK activity and live about 20% longer than untreated control animals.14 Mice treated with metformin have been found to live nearly 6% longer than controls.11 And most impressively, diabetics taking metformin were shown to live 15% longer than healthy individuals without diabetes!15

AMPK activity declines with age,16 making us more vulnerable to many of the diseases associated with aging. Fortunately, a wealth of recent studies show that by activating AMPK, metformin plays a major role in preventing age-related disorders including cancer, cardiovascular disease, obesity, and neurocognitive decline.

By combatting many of the underlying causes of aging—and by activating AMPK—metformin can be considered a broad-spectrum anti-aging drug.

What You Need to Know
Metformin as an Anti-Aging Drug

Metformin as an Anti-Aging Drug

  • Metformin has been a staunch workhorse against diabetes for more than 50 years.
  • Studies show that metformin acts by boosting the activity of AMPK, a master metabolic regulator that favors fat- and sugar-burning and prevents their accumulation.
  • Because AMPK is relevant in all tissues, this makes metformin extremely important in reducing metabolic imbalances in the entire body.
  • Strong evidence suggests that metformin, through its protective effects and AMPK-activating properties, can help prevent cancer, cardiovascular disease, obesity and its consequences, and even neurodegenerative disorders.

Cancer Protective Effects of Metformin

Diabetics have an increased risk of cancer. In a study of head and neck cancers, researchers were surprised to find that diabetic patients had a 46% reduction in risk of developing these cancers compared to non-diabetic patients.17 What was the reason for this unexpected reduction? The diabetic patients were taking metformin.

Similar effects have been seen for the risk of gastric (stomach) cancers as well, with metformin users experiencing a 55% decrease in the risk of stomach cancer compared with nonusers.18 Important studies like these have helped to confirm a decade-long trend suggesting that metformin has anti-cancer properties.17

While these studies show that metformin has the potential to reduce the risk of developing cancer, others show its benefits for those who already have cancer.

A study encompassing 27 clinical trials representing more than 24,000 patients found that in people with early-stage cancers of the colon and rectum, metformin use improved recurrence-free survival by 37%, overall survival by 31%, and cancer-specific survival by 42%.19

The same study reported similar results for men with early-stage prostate cancer, with metformin use increasing recurrence-free survival by 17%, overall survival by 18%, and cancer-free survival by 42% compared with non-metformin users.19

By now, metformin has been studied in the context of total tumor incidence in 17 different target organs, 21 strains of mice, and four strains of rats. It has been studied in cancers that occur spontaneously, and in those induced by 16 different chemical carcinogens from multiple classes, ionizing radiation, viruses, genetic modifications, and high-fat diets, using five different routes of administration.20

A whopping 86% of such studies showed that metformin clearly inhibited cancer development and showed zero evidence of cancer stimulation by the drug.20

Indeed, as one expert recently put it, maybe it’s time “to make this long story short” about metformin: It works to prevent cancer.20

Metformin Prevents Cardiovascular Disease

Despite billions of dollars spent on drugs such as Crestor and Lipitor, cardiovascular disease remains the single biggest killer in America. While there are multiple causes of cardiovascular disease, most boil down to the development of atherosclerosis, or “hardening of the arteries.”

Atherosclerosis is promoted by factors such as oxidation of LDL cholesterol, accumulation of that oxidized fat in arterial walls, and damage to the endothelium, which is the thin layer of cells lining those arterial walls.21

Metformin is now known to prevent these early steps in atherosclerosis development.

One of the key ways it does this is by activating the metabolic regulator AMPK. By activating AMPK, metformin:

  • Mitigates LDL oxidation and the resulting endothelial dysfunction, which slows the development of atherosclerosis.21
  • Reduces the conversion of harmless immune system cells (monocytes) into fat-laden macrophages, an action that reduces their accumulation in vessel walls.22 It also increases cholesterol export out of those cells, while also suppressing the inflammatory stimulus they normally produce.23,24
  • Offers critical protection to endothelial cells that line coronary arteries, which supply blood to the heart muscle itself. Specifically, metformin enhances the resistance of endothelial cells to “fat poisoning,” the death of endothelial cells in the presence of high fat concentrations.25 This is highly protective against heart attacks, which occur when coronary arteries, blocked by atherosclerotic plaques laden with fat and inflammatory cells, fail to provide enough blood to the hard-working heart muscle.

Metformin has also been shown to prevent the fragmentation of mitochondria in endothelial cells.26 Such fragmentation is closely associated with the dysfunction of endothelial cells and is now considered an important precursor of atherosclerosis.26

The results of these protective effects have been seen in numerous human studies. In one study, heart attack patients taking metformin had a significant 75% reduction in the risk of dying after 30 days, and a 68% reduction in their risk of dying 12 months after the attack.27

Several studies have also demonstrated that metformin reduces the risk of heart attack, and is associated with reduction in stroke, atrial fibrillation (an arrhythmia), and death from all causes.28

Finally, a 2016 study showed significant reductions in systolic (top number) blood pressure in nondiabetic people taking metformin. The largest reductions were seen in those having impaired glucose tolerance or obesity.29

Obesity itself appears ready to yield to metformin treatment, as we’ll now see.

FDA Approves First Anti-Aging Study
FDA Approves First Anti-Aging Study

The FDA has approved a study that will determine if metformin can do more than lower blood sugar—it will evaluate metformin’s ability to slow aging. This is the first ever anti-aging study approved by the FDA.

Studies have shown that metformin can block or diminish many of the underlying factors that accelerate aging, and it has also been shown to extend lifespan in animals. Dr. Nir Barzilai from the Albert Einstein College of Medicine, along with researchers from the American Federation for Aging Research (AFAR), want to find out if metformin can extend lifespan in humans as well.

The study, called Targeting Aging with Metformin (TAME), will evaluate 3,000 people over a course of six years. Half of the participants will receive metformin, and the other half will receive a placebo. Since aging is largely characterized by the development of disease, the success of the study will be determined by whether or not the drug delays the onset of typical age-related diseases, such as cardiovascular disease, cancer, and cognitive decline.

This groundbreaking study has the potential to change the future of how we treat disease. Developing a single drug designed to treat multiple conditions would dramatically reduce the number of drugs a typical person would need, which would reduce overall drug side effects, eliminate contraindications, and of course, save money.

None of this is good for Big Pharma’s bottom line—which is likely why no company has agreed to fund the study. Until that happens, this important study is on hold.

But you can help. AFAR is seeking individual contributions to get the TAME study started. To learn more, and make a donation if you like, visit www.afar.org/donate/

Metformin Reduces Body Weight and Fat Mass

Metformin Reduces Body Weight and Fat Mass  

Metformin’s ability to activate AMPK makes it especially beneficial in combatting obesity. This is because AMPK is a metabolic regulator that stimulates youthful cellular behaviors such as burning fat (instead of storing it), taking sugar out of the blood, and recycling cellular contents to eliminate toxic proteins.30

As a result, metformin can be expected to have important effects on body weight and fat deposits. And indeed, studies show that metformin fights obesity and reduces body fat mass, even in non-diabetic patients.

This is true in some of the most challenging populations, such as women with polycystic ovary syndrome, a major cause of obesity and endocrine problems in premenopausal women.

In one study, women with polycystic ovary syndrome were treated with 850 mg of metformin or a placebo twice daily for 6 months. During that time, those in the placebo group experienced increases in weight and blood sugar, as expected. Those taking metformin, on the other hand, had significant decreases in weight and blood sugar—with metformin-treated women losing an average of 9.24 pounds. The metformin group also had significant increases in beneficial HDL cholesterol.31

Metformin has been found to significantly reduce body weight, body mass index (BMI), and insulin resistance in patients taking modern antipsychotic medications such as olanzapine, aripiprazole, risperidone, and quetiapine.32-35 These are impressive results, since major side effects of these drugs include rapid weight gain, loss of insulin sensitivity, and other features of metabolic syndrome.36

But by far, the largest group of people fighting obesity are simply aging individuals who are otherwise healthy (nondiabetic). Metformin shows promise for this population as well.

An important study in a group of such people—all women with midlife weight gain but normal blood sugars—showed that taking metformin for 12 months reduced mean body weight by 11.6 pounds.37 In addition, treated subjects had significant decreases in their body fat percentage, a favorable change that can reduce many of the long-term consequences of obesity.

Metformin is showing promise in obese but otherwise healthy young people as well. A group of 10-16- year-olds took 2,000 mg of metformin per day or a placebo for 18 months. Those taking metformin lost nearly half a pound in fat mass. By contrast, the placebo group gained almost 4.5 pounds in fat mass.38

Metformin as Neuroprotectant

There is rapidly growing literature on metformin’s potential role in preventing neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Once again, much of this literature focuses on metformin’s ability to activate AMPK, the youth-promoting energy regulator in all of our cells.

One major effect of AMPK activation is the cleanup of accumulated misfolded proteins in brain cells. The accumulation of proteins, such as tau and beta-amyloid, contributes to brain cell death and dysfunction in neurodegenerative diseases.

Thus, it makes sense that metformin might be effective in preventing disorders associated with those proteins. Numerous animal and laboratory studies show that metformin does indeed have such effects. These studies demonstrate that metformin:

  • Reduces levels of an enzyme that generates beta-amyloid proteins32
  • Decreases the harmful effect of beta-amyloid on brain cell function39-41
  • Reduces levels of alpha synuclein, another protein that accumulates and causes damage in Parkinson’s disease42
  • Prevents the loss of dopamine-producing brain cells in a model of Parkinson’s disease43,44
  • Improves motor coordination in a mouse model of Parkinson’s45

In 2016, a human study showed that taking 1,000 mg of metformin twice daily for 12 months improved memory recall in a group of older adults with a condition called amnestic mild cognitive impairment (a memory-stealing predecessor of Alzheimer’s).39

Given the close connections between Alzheimer’s and diabetes (it’s been called “Type III diabetes”), there is every reason to believe that metformin, through its AMPK-activating properties, will help in the long fight to retain our minds and personalities as we age.

Precautions and Useful Suggestions with Metformin Use
Precautions and Useful Suggestions with Metformin Use

Although metformin has an outstanding track record in the fight against diabetes, cancer, obesity, neurodegenerative and cardiovascular diseases, there are some precautions to be aware of with its use.

Metformin is known to interfere with the absorption of B12, increasing the risk of vitamin B12 deficiency.46,47 Low B12 levels contribute to higher concentrations of artery-clogging homocysteine—an independent risk factor for cardiovascular disease.48,49 The tiny amounts of vitamin B12 and other B-vitamins found in commercial supplements is usually not enough to offset this problem. Individuals using metformin should ensure that they are taking higher doses of B-vitamins (at least 300 mcg of methylcobalamin, the active form of vitamin B12) and checking their homocysteine levels to ensure proper protection.

Some studies have shown that metformin reduces free and total testosterone levels in men.50 Testosterone is especially important in male diabetics as it enhances insulin sensitivity.51 Life Extension has previously published clinical data on the importance of maintaining youthful testosterone levels in diabetic men to improve glucose utilization.52

If a blood test shows low testosterone, applying a topical testosterone cream can restore levels of this vital hormone to youthful ranges.

Side effects associated with metformin use include gastrointestinal distress or a slight taste disturbance, usually a metallic taste. Rarely, metformin may cause a potentially serious lactic acidosis, a buildup of lactic acid in the blood.53

If you use or are considering metformin, consult your physician, take your B-vitamins, and periodically check your kidney function, homocysteine levels, and in men, free and total testosterone.

Summary

The world’s first clinical trial of a true “anti-aging” drug may be about to begin.  

The world’s first clinical trial of a true “anti-aging” drug may be about to begin. But while the study is new, the drug is more than half a century old.

Metformin has been used for more than 50 years to treat type II diabetes. A wealth of recent studies now supports a major role for metformin in preventing age-related disorders including cancer, cardiovascular disease, obesity, and neurocognitive decline.

The American Federation for Aging Research (AFAR) has a long uphill road to get this study (called TAME, or the Targeting Aging with Metformin trial) started. They face almost-certain opposition from Big Pharma companies for whom treating—not preventing—aging is a lucrative business.

The good news is that we don’t have to wait for this new metformin study to get off the ground. Metformin is already available as a prescription medication. And many thoughtful physicians who are presented with the evidence will prescribe it based on its recognized benefits against specific age-related disorders.

There are also nutrients that have been shown to boost AMPK activity and function to lower blood glucose similar to metformin.54-57

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Available at: http://www.afar.org/natgeo/. Accessed 24 October, 2016.
  2. Barzilai N, Crandall JP, Kritchevsky SB, et al. Metformin as a Tool to Target Aging. Cell Metab. 2016;23(6):1060-5.
  3. Coughlan KA, Valentine RJ, Ruderman NB, et al. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes. 2014;7:241-53
  4. Available at: https://www.drugs.com/dosage/metformin.html. Accessed 25 February, 2016
  5. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50(2):81-98
  6. Hadden DR. Goat’s rue - French lilac - Italian fitch - Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection. J R Coll Physicians Edinb. 2005;35(3):258-60
  7. Perla V, Jayanty SS. Biguanide related compounds in traditional antidiabetic functional foods. Food Chem. 2013;138(2-3):1574-80
  8. Formoso G, De Filippis EA, Michetti N, et al. Decreased in vivo oxidative stress and decreased platelet activation following metformin treatment in newly diagnosed type 2 diabetic subjects. Diabetes Metab Res Rev. 2008;24(3):231-7
  9. Garg G, Singh S, Singh AK, et al. Metformin Alleviates Altered Erythrocyte Redox Status During Aging in Rats. Rejuvenation Res. 2016
  10. Cameron AR, Morrison VL, Levin D, et al. Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status. Circ Res. 2016;119(5):652-65
  11. Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192
  12. Lee YS, Doonan BB, Wu JM, et al. Combined metformin and resveratrol confers protection against UVC-induced DNA damage in A549 lung cancer cells via modulation of cell cycle checkpoints and DNA repair. Oncol Rep. 2016;35(6):3735-41
  13. de Kreutzenberg SV, Ceolotto G, Cattelan A, et al. Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. Nutr Metab Cardiovasc Dis. 2015;25(7):686-93
  14. De Haes W, Frooninckx L, Van Assche R, et al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc Natl Acad Sci U S A. 2014;111(24):E2501-9
  15. Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014;16(11):1165-73
  16. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012;11(2):230-41
  17. Figueiredo RA, Weiderpass E, Tajara EH, et al. Diabetes mellitus, metformin and head and neck cancer. Oral Oncol. 2016;61:47-54
  18. Tseng CH. Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus. Aging (Albany NY). 2016;8(8):1636-49
  19. Coyle C, Cafferty FH, Vale C, et al. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol. 2016;27(12):2184-95
  20. Anisimov VN. Metformin for cancer and aging prevention: is it a time to make the long story short? Oncotarget. 2015;6(37):39398-407
  21. Dong Y, Zhang M, Wang S, et al. Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo. Diabetes. 2010;59(6):1386-96
  22. Vasamsetti SB, Karnewar S, Kanugula AK, et al. Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes. 2015;64(6):2028-41
  23. Wan X, Huo Y, Johns M, et al. 5’-AMP-activated protein kinase-activating transcription factor 1 cascade modulates human monocyte-derived macrophages to atheroprotective functions in response to heme or metformin. Arterioscler Thromb Vasc Biol. 2013;33(11):2470-80
  24. Buldak L, Labuzek K, Buldak RJ, et al. Metformin affects macrophages’ phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages. Pharmacol Rep. 2014;66(3):418-29
  25. Eriksson L, Nystrom T. Activation of AMP-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis. Cardiovasc Diabetol. 2014;13:152
  26. Wang Q, Zhang M, Torres G, et al. Metformin Suppresses Diabetes-Accelerated Atherosclerosis via the Inhibition of Drp1-Mediated Mitochondrial Fission. Diabetes. 2017;66(1):193-205
  27. Abualsuod A, Rutland JJ, Watts TE, et al. The Effect of Metformin Use on Left Ventricular Ejection Fraction and Mortality Post-Myocardial Infarction. Cardiovasc Drugs Ther. 2015;29(3):265-75
  28. Anabtawi A, Miles JM. Metformin: Nonglycemic Effects and Potential Novel Indications. Endocr Pract. 2016;22(8):999-1007
  29. Zhou L, Liu H, Wen X, et al. Effects of metformin on blood pressure in nondiabetic patients: a meta-analysis of randomized controlled trials. J Hypertens. 2017;35(1):18-26
  30. Luo T, Nocon A, Fry J, et al. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity. Diabetes. 2016;65(8):2295-310
  31. Trolle B, Flyvbjerg A, Kesmodel U, et al. Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled cross-over trial. Hum Reprod. 2007;22(11):2967-73
  32. Wang M, Tong JH, Zhu G, et al. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophr Res. 2012;138(1):54-7
  33. Wu RR, Jin H, Gao K, et al. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2012;169(8):813-21
  34. Chen CH, Huang MC, Kao CF, et al. Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2013;74(5):e424-30
  35. Peng PJ, Ho PS, Tsai CK, et al. A Pilot Study of Randomized, Head-to-Head of Metformin Versus Topiramate in Obese People With Schizophrenia. Clin Neuropharmacol. 2016;39(6):306-10
  36. Komossa K, Depping AM, Gaudchau A, et al. Second-generation antipsychotics for major depressive disorder and dysthymia. Cochrane Database Syst Rev. 2010(12):CD008121
  37. Mogul H, Freeman R, Nguyen K. Metformin-Sustained Weight Loss and Reduced Android Fat Tissue at 12 Months in Empowir (Enhance the Metabolic Profile of Women with Insulin Resistance): A Double Blind, Placebo-Controlled, Randomized Trial of Normoglycemic Women with Midlife Weight Gain. Endocr Pract. 2016;22(5):575-86
  38. van der Aa MP, Elst MA, van de Garde EM, et al. Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial. Nutr Diabetes. 2016;6(8):e228
  39. Luchsinger JA, Perez T, Chang H, et al. Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial. J Alzheimers Dis. 2016;51(2):501-14
  40. Chen B, Teng Y, Zhang X, et al. Metformin Alleviated Abeta-Induced Apoptosis via the Suppression of JNK MAPK Signaling Pathway in Cultured Hippocampal Neurons. Biomed Res Int. 2016;2016:1421430
  41. Chiang MC, Cheng YC, Chen SJ, et al. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction. Exp Cell Res. 2016;347(2):322-31
  42. Perez-Revuelta BI, Hettich MM, Ciociaro A, et al. Metformin lowers Ser-129 phosphorylated alpha-synuclein levels via mTOR-dependent protein phosphatase 2A activation. Cell Death Dis. 2014;5:e1209
  43. Bayliss JA, Lemus MB, Santos VV, et al. Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons. PLoS One. 2016;11(7):e0159381
  44. Lu M, Su C, Qiao C, et al. Metformin Prevents Dopaminergic Neuron Death in MPTP/P-Induced Mouse Model of Parkinson’s Disease via Autophagy and Mitochondrial ROS Clearance. Int J Neuropsychopharmacol. 2016;19(9)
  45. Patil SP, Jain PD, Ghumatkar PJ, et al. Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience. 2014;277:747-54
  46. Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012;97(3):359-67
  47. de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. Bmj. 2010;340:c2181
  48. Carlsen SM, Folling I, Grill V, et al. Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Scand J Clin Lab Invest. 1997;57(6):521-7
  49. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015;14:6
  50. Ozata M, Oktenli C, Bingol N, et al. The effects of metformin and diet on plasma testosterone and leptin levels in obese men. Obes Res. 2001;9(11):662-7
  51. Grossmann M, Thomas MC, Panagiotopoulos S, et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab. 2008;93(5):1834-40
  52. Available at: http://www.lifeextension.com/magazine/2007/7/report_diabetes/Page-01. Accessed January 26, 2017
  53. Available at: http://www.diabetes.co.uk/diabetes-medication/metformin-side-effects.html. Accessed January 26, 2017
  54. Nguyen PH, Gauhar R, Hwang SL, et al. New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum. Bioorg Med Chem. 2011;19(21):6254-60
  55. Shi L, Qin N, Hu L, et al. Tiliroside-derivatives enhance GLUT4 translocation via AMPK in muscle cells. Diabetes Res Clin Pract. 2011;92(2):e41-6.
  56. Nagatomo A, Nishida N, Matsuura Y, et al. Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma. Prev Nutr Food Sci. 013;18(2):85-91.
  57. Goto T, Teraminami A, Lee JY, et al. Tiliroside, a glycosidic flavonoid, ameliorates obesity-induced metabolic disorders via activation of adiponectin signaling followed by enhancement of fatty acid oxidation in liver and skeletal muscle in obese-diabetic mice. J Nutr Biochem. 2012;23(7):768-76.