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Life Extension Magazine February 2012
As We See It

Proven Methods to Reduce Fasting and Postprandial Glucose Levels

By William Faloon
Proven Methods to Reduce Fasting and Postprandial Glucose Levels

Scientific studies indicate that any amount of fasting glucose over 85 mg/dL incrementally adds to heart attack risk.1

Postprandial glucose surges over 140 mg/dL lead to diabetic complications, even in those who are not diabetic.

If you can choose an ideal fasting glucose reading, it would probably be around 74 mg/dL.2 We know, however, that some people are challenged to keep their glucose under 100 mg/dL. What this means is that it is critically important for aging individuals to follow an aggressive program to suppress excess glucose as much as possible.

The good news is that many approaches that reduce glucose also lower insulin,3,4 LDL,3,5-7 triglycerides,3,8-10 and C-reactive protein,11 thereby slashing one’s risk of vascular disease,9,12-14 cancer,15-18 dementia,19-23 and a host of other degenerative disorders.

This month’s issue featured an in-depth review of green coffee bean extract that has been shown to reduce postprandial glucose levels by an average of 32%.24 It functions by inhibiting the glucose-6-phosphatase enzyme that enables the body to create new surplus glucose and inappropriately release stored glucose from tissues.

To achieve optimal glucose levels, some people will need to take steps to impede glucose absorption and improve insulin sensitivity. In this section, we succinctly describe drugs, hormones, nutrients, and lifestyle changes that facilitate healthy glucose levels.

Nutrient Options

Since Life Extension® members know it is best to take dietary supplements with meals, it should not be difficult for them to make it a routine practice to shield their bloodstream from excessive calorie absorption by taking the proper nutrients before most meals.

An efficient way of obtaining nutrients that can impede the impact of carbohydrate and fat foods when taken before meals is a powdered drink mix that provides the nutrients in the box below.

Nutrients that Reduce the Impact of Excess Calorie Intake

Propolmannan 2,000 mg
Mechanism(s): Slows gastric emptying to delay rapid carbohydrate absorption. It also provides a viscous barrier that binds bile acids that normally facilitate fat absorption.25-27

Phaseolus vulgaris 445 mg
Mechanism(s): Inhibits the amylase digestive enzyme used to break down carbohydrate foods for eventual absorption into the blood as glucose.10,28

Irvingia gabonensis 150 mg
Mechanism(s): Inhibits amylase and functions via three additional mechanisms to internally regulate glucose and triglyceride metabolism.29-31

Green Tea Extract 100 mg and higher
Mechanism(s): Inhibits the lipase digestive enzyme used to break down fatty foods and boosts internal utilization of glucose by boosting resting metabolic rate.32,33

We suggest taking a powdered drink mix containing these ingredients before the two heaviest meals of the day.

For Sugar Addicts

For those whose glucose levels remain unacceptably high despite taking the powdered drink mix, there are encapsulated nutrients that work to specifically block the sucrase and glucosidase digestive enzymes. Sucrase breaks down sucrose to fructose and glucose, and glucosidase catalyzes the hydrolysis of the glycosidic linkage to all carbohydrates to release smaller sugars. Blocking these enzymes reduces the amount of glucose absorbed from dietary sources. One capsule containing L-arabinose and a special brown seaweed extract should be taken before eating sucrose (table sugar)-containing foods.34-36

Enhancing Insulin Sensitivity

Aging causes a loss of insulin sensitivity, which means that glucose that would normally be utilized by energy-producing cells instead either remains in the blood or converts to storage as triglycerides (in blood and fat cells) or glycogen in the liver.

A cinnamon extract has been developed to enhance the ability of insulin to drive blood glucose into muscle cells. This cinnamon compound that enhances insulin sensitivity is combined with brown seaweed extract (to inhibit the glucosidase enzyme) to provide additive control over glucose levels.36-42

Drug Options

Drug Options
Atherosclerosis

An anti-diabetic drug that Life Extension suggests normal aging people consider taking to lower glucose is metformin (refer to article on page 56 of this month’s issue about metformin and cancer risk reduction). It is available in low-cost generic form.

Metformin has a long history of safe human use, plus intriguing data to suggest that it may possess anti-aging properties.43,44 We think that those with excess fasting blood glucose (above 80-85 mg/dL) should ask their doctor about metformin even if they are not diagnosed as diabetic.

Some of the side benefits of metformin include weight loss45-47 and triglyceride reduction,48-50 which are in themselves proven heart attack risk-reducers.

Metformin Dosing and Precautions

The dose of metformin varies considerably. The starting dose may be as low as 250-500 mg once a day with a meal. If hypoglycemia (low blood sugar) does not manifest, the dose of metformin may be increased to 500-850 mg taken before two or three meals, all under the supervision of your physician, of course. One side effect of metformin is that it can cause homocysteine levels to elevate.51 This is less likely to happen to Life Extension members who already take nutrients that suppress homocysteine. Those with impaired kidney function or congestive heart failure may not be able to take metformin.

Metformin functions to reduce absorption of ingested carbohydrates,52-54 suppress appetite,55,56 enhance insulin sensitivity,57-59 and most uniquely, metformin inhibits the release of stored liver glucose (glycogen) back into the blood.60-63

One of the problems that frustrates so many people who follow a low-calorie diet, yet have persistently elevated glucose levels, is that the liver improperly dumps too much glucose into the blood. This of course is a vital life function in a starvation state, but for aging individuals, excess hepatic release of glycogen (called gluconeogenesis) causes them to suffer chronically high glucose and insulin levels. Metformin inhibits gluconeogenesis.64,65

Another low-cost drug that lowers glucose levels is acarbose, which reduces the absorption of ingested carbohydrates by inhibiting the glucosidase and other sugar absorbing-enzymes in the small intestine. A typical dose is 50-100 mg of acarbose taken before each meal. Some people experience intestinal side effects, but otherwise, acarbose is highly efficacious in reducing blood glucose levels and reducing several cardiac risk markers in the blood.9,12,13

There are of course other FDA-approved drugs that will lower your glucose levels. Many of these drugs, however, function by mechanisms that carry side effect risks.

Life Extension stands on solid scientific ground in recommending that those with impaired glucose tolerance follow an aggressive program that involves eating healthier and smaller meals, exercising, and taking nutrients before meals that deflect the impact of excess calorie intake. Drugs like metformin may be considered for its multiple benefits that extend beyond mere glucose control. Acarbose should be utilized if glucose levels remain stubbornly high.

Methods to Reduce Postprandial Glucose Levels
Methods to Reduce Postprandial Glucose Levels
Cinnamon, White Bean, Green Tea
  • Fasting blood glucose levels over 85 mg/dL increase heart attack risk.
  • Postprandial glucose levels over 140 mg/dL may lead to complications associated with diabetes—even in those who are not diabetic.
  • Nutritional, hormonal, dietary, and lifestyle methods that lower blood glucose can reduce cardiovascular risk factors, lessen cancer risk, and improve markers associated with longevity.
  • Plant extracts such as propolmannan, irvingia extract, Phaseolus vulgaris (white bean) extract, green tea, and cinnamon can help reduce glucose levels and promote healthy insulin sensitivity.
  • The anti-diabetes drug metformin helps promote healthy blood glucose and lipid levels while supporting weight loss efforts.
  • Optimizing DHEA levels in men and women and testosterone levels in men may help promote optimal glucose levels and insulin sensitivity.
  • Healthy lifestyle choices such as calorie restriction, exercise, consuming a Mediterranean diet, and avoiding dietary sugars further support healthy blood glucose levels.

     

Hormone Options

Hormone Options

Normal aging is accompanied by a sharp decline in hormones that are involved in maintaining insulin sensitivity and hepatic glucose control.

Restoring DHEA (dehydroepiandrosterone) levels to youthful ranges in men and women may help enhance insulin sensitivity and glucose metabolism in the liver.66-70

Progressive doctors are realizing that in men, a testosterone deficiency can induce a serious reduction of insulin sensitivity. For men, restoring youthful levels of testosterone has been shown to be particularly beneficial in facilitating glucose control.71 Blood tests can assess your hormonal status so a man can replenish testosterone (and DHEA) to more youthful ranges. Optimal free testosterone blood levels in men are between 20-25 pg/mL.72

Life Extension has published articles showing that diabetic men can derive enormous benefits by restoring testosterone to youthful ranges, as opposed to overloading the body with excess insulin as mainstream doctors continue to do.73-75

Dietary Options

People can achieve remarkable control over glucose levels by altering their diet and exercising more. Below are three dietary options to consider:

  • 1. Consume a low-calorie diet (often less than 1,400-1,800 calories a day). Most people cannot adhere to this kind of low-calorie diet.76
  • 2. Consume a Mediterranean diet, with lots of fresh fruits and vegetables, fish and beans as protein sources, and omega-3 and monounsaturated fats (olive oil), while avoiding saturated fats, refined carbohydrates, cholesterol-laden foods, excess omega-6 fats, and most animal products. An increasing percentage of health-conscious Americans are adopting this kind of diet.77-79
  • 3. Avoid sugary fruit juices (almost all fruit juices contain too many sugars) and beverages spiked with fructose,80-84 sucrose,85-89 and/or high-fructose corn syrup.90-94 Consume a low-glycemic index and low-glycemic load diet.95.96

Summary

From a practical standpoint, achieving optimal glucose readings on your next blood test will probably involve a combination of the various approaches described in this section. Each individual will respond differently.

For some, a modest reduction in calorie intake and an increase in physical activity will sufficiently lower fasting and after-meal glucose levels. Most aging individuals, however, will need to take nutrients such as green coffee berry extract and other carbohydrate-enzyme inhibitors before heavy meals to impede the impact of ingested calories. Others should ask their doctor about prescription drugs such as metformin.

When one questions the importance of doing all this, please know that the incidence of pre-diabetes, metabolic syndrome, and type 2 diabetes is increasing at alarming rates. In fact, diseases related to glucose impairment are skyrocketing everywhere in the world that adopts unhealthy Western eating habits.

A medical catastrophe is predicted for the United States as the vast majority of the population is now overweight and suffers frighteningly high levels of glucose, insulin, and triglycerides.

The single most important component of one’s longevity program may be the steps taken before meals to neutralize the toxic effects of excess calories most of us invariably ingest.

Life Extension urges all members to enact a personal program designed to suppress fasting glucose levels to ranges below 86 mg/dL and keep two-hour after-meal glucose surges below 120-140 mg/dL. Fortunately, there is a wide range of options that enable aging humans to accomplish this profoundly effective anti-aging feat.

Hormone Precautions

Men with pre-existing prostate cancer should avoid testosterone until their cancer is cured. Women with certain types of hormone-related cancers are advised to avoid DHEA until their cancer is cured. Men who replace testosterone are advised to test their blood within 60 days to make sure that their estrogen (estradiol) levels and prostate- specific antigen (PSA) are not increasing. Some men convert (aromatize) testosterone into estradiol. If this happens, there are drugs (like anastrozole) or nutrients that inhibit the aromatase enzyme to keep estradiol in the safe range of between 20-30 pg/mL. These blood tests, taken 60 days after testosterone therapy is initiated, can also detect liver or blood count abnormalities that in rare cases can be exacerbated by testosterone.

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

References

1. Bjornholt JV, Erikssen G, Aaser E, et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care. 1999 Jan;22(1):45-9.

2. Walford RL, Harris SB, Gunion MW. The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11533-7.

3. Lucas CP, Boldrin MN, Reaven GM. Effect of orlistat added to diet (30% of calories from fat) on plasma lipids, glucose, and insulin in obese patients with hypercholesterolemia. Am J Cardiol. 2003 Apr 15;91(8):961-4.

4. Behall KM, Scholfield DJ, Hallfrisch JG, Liljeberg-Elmståhl HG. Consumption of both resistant starch and beta-glucan improves postprandial plasma glucose and insulin in women. Diabetes Care. 2006 May;29(5):976-81.

5. Sood N, Baker WL, Coleman CI. Effect of glucomannan on plasma lipid and glucose concentrations, body weight, and blood pressure: systematic review and meta-analysis. Am J Clin Nutr. 2008 Oct;88(4):1167-75.

6. Ngondi JL, Oben JE, Minka SR. The effect of Irvingia gabonensis seeds on body weight and blood lipids of obese subjects in Cameroon. Lipids Health Dis. 2005 May 25;4:12.

7. Anderson JW, Allgood LD, Turner J, Oeltgen PR, Daggy BP. Effects of psyllium on glucose and serum lipid responses in men with type 2 diabetes and hypercholesterolemia. Am J Clin Nutr. 1999 Oct;70(4):466-73.

8. Nizami F, Farooqui MS, Munir SM, Rizvi TJ. Effect of fiber bread on the management of diabetes mellitus. J Coll Physicians Surg Pak. 2004 Nov;14(11):673-6.

9. Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J. 2004 Jan;25(1):10-6.

10. Udani J, Hardy M, Madsen DC. Blocking carbohydrate absorption and weight loss: a clinical trial using Phase 2 brand proprietary fractionated white bean extract. Altern Med Rev. 2004 Mar;9(1):63-9.

11. Derosa G, Maffioli P, Ferrari I, et al. Acarbose actions on insulin resistance and inflammatory parameters during an oral fat load. Eur J Pharmacol. 2011 Jan 25;651(1-3):240-50.

12. Zeymer U. Cardiovascular benefits of acarbose in impaired glucose tolerance and type 2 diabetes. Int J Cardiol. 2006 Feb 8;107 (1):11-20.

13. Oyama T, Saiki A, Endoh K, et al. Effect of acarbose, an alpha-glucosidase inhibitor, on serum lipoprotein lipase mass levels and common carotid artery intima-media thickness in type 2 diabetes mellitus treated by sulfonylurea. J Atheroscler Thromb. 2008 Jun;15(3):154-9.

14. Vasdev S, Gill V, Singal P. Role of advanced glycation end products in hypertension and atherosclerosis: therapeutic implications. Cell Biochem Biophys. 2007;49(1):48-63.

15. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005 Jun 4;330(7503):1304-5.

16. Wu WT, Chen HL. Effects of konjac glucomannan on putative risk factors for colon carcinogenesis in rats fed a high-fat diet. J Agric Food Chem. 2011 Feb 9;59(3):989-94.

17. Bravi F, Edefonti V, Bosetti C, et al. Nutrient dietary patterns and the risk of colorectal cancer: a case-control study from Italy. Cancer Causes Control. 2010 Nov;21(11):1911-8.

18. Zhang ZJ, Zheng ZJ, Kan H, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care. 2011 Oct;34(10):2323-8.

19. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009 Apr 15;301(15):1565-72.

20. Yaffe K, Blackwell T, Whitmer RA, Krueger K, Barrett Connor E. Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. J Nutr Health Aging. 2006 Jul-Aug;10(4):293-5.

21. Xu W, Qiu C, Winblad B, Fratiglioni L. The effect of borderline diabetes on the risk of dementia and Alzheimer’s disease. Diabetes. 2007 Jan;56(1):211-6.

22. Hsu CC, Wahlqvist ML, Lee MS, Tsai HN. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis. 2011;24(3):485-93.

23. Luchsinger JA. Type 2 diabetes, related conditions, in relation and dementia: an opportunity for prevention? J Alzheimers Dis. 2010;20(3):723-36.

24. Nagendran MV. Effect of Green Coffee Bean Extract (GCE), High in Chlorogenic Acids, on Glucose Metabolism. Poster presentation number: 45-LB-P. Obesity 2011, the 29th Annual Scientific Meeting of the Obesity Society. Orlando, Florida. October 1-5, 2011.

25. McCarty MF. Glucomannan minimizes the postprandial insulin surge: a potential adjuvant for hepatothermic therapy. Med Hypotheses. 2002 Jun;58(6):487-90.

26. Vuksan V, Jenkins DJ, Spadafora P, et al. Konjac-mannan (glucomannan) improves glycemia and other associated risk factors for coronary heart disease in type 2 diabetes. A randomized controlled metabolic trial. Diabetes Care. 1999 Jun;22(6):913-9.

27. Gonzalez Canga A, Fernández Martínez N, Sahagún AM, et al. Glucomannan: properties and therapeutic applications. Nutr Hosp. 2004 Jan-Feb;19(1):45-50.

28. Celleno L, Tolaini MV, D’Amore A, Perricone NV, Preuss HG. A dietary supplement containing standardized Phaseolus vulgaris extract influences body composition of overweight men and women. Int J Med Sci. 2007 Jan 24;4(1):45-52.

29. Oben JE, Ngondi JL, Momo CN, Agbor GA, Sobgui CS. The use of a Cissus quadrangularis/Irvingia gabonensis combination in the management of weight loss: a double-blind placebo-controlled study. Lipids Health Dis. 2008 Mar 31;7:12.

30. Ngondi JL, Etoundi BC, Nyangono CB, Mbofung CM, Oben JE. IGOB131, a novel seed extract of the West African plant Irvingia gabonensis, significantly reduces body weight and improves metabolic parameters in overweight humans in a randomized double-blind placebo controlled investigation. Lipids Health Dis. 2009 Mar 2;8:7.

31. Oben JE, Ngondi JL, Blum K. Inhibition of Irvingia gabonensis seed extract (OB131) on adipogenesis as mediated via down regulation of the PPARgamma and leptin genes and up-regulation of the adiponectin gene. Lipids Health Dis. 2008 Nov 13;7:44.

32. Juhel C, Armand M, Pafumi Y, Rosier C, Vandermander J, Lairon D. Green tea extract (AR25) inhibits lipolysis of triglycerides in gastric and duodenal medium in vitro. J Nutr Biochem. 2000 Jan;11(1):45-51.

33. Bose M, Lambert JD, Ju J, Reuhl KR, Shapses SA, Yang CS. The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr. 2008 Sep;138(9):1677-83.

34. Preuss HG, Echard B, Bagchi D, Stohs S. Inhibition by natural dietary substances of gastrointestinal absorption of starch and sucrose in rats and pigs: 1. Acute studies. Int J Med Sci. 2007 Aug 6;4(4):196-202.

35. Available at: http://www.naturalproductsinsider.com/news/2011/10/insea2-studies-accepted-for-publication.aspx. Accessed November 7, 2011.

36. Available at: http://www.naturalproductsinsider.com/news/2009/12/insea2-reduces-glycemic-response.aspx#. Accessed October 28, 2011.

37. Zhang J, Tiller C, Shen J, et al. Antidiabetic properties of polysaccharide- and polyphenolic-enriched fractions from the brown seaweed Ascophyllum nodosum. Can J Physiol Pharmacol. 2007 Nov;85(11):1116-23.

38. Lamela M, Anca J, Villar R, Otero J, Calleja JM. Hypoglycemic activity of several seaweed extracts. J Ethnopharmacol. 1989 Nov;27(1-2):35-43.

39. Hlebowicz J, Darwiche G, Bjorgell O, Almer LO. Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects. Am J Clin Nutr. 2007 Jun;85(6):1552-6.

40. Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Cinnamon extract prevents the insulin resistance induced by a high-fructose diet. Horm Metab Res. 2004 Feb;36(2):119-25.

41. Khan A, Safdar M, Muzaffar Ali Khan M, Nawak Khattak K, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003 Dec;26(12):3215-8.

42. Broadhurst CL, Polansky MM, Anderson RA. Insulin-like biological activity of culinary and medicinal plant aqueous extracts in vitro. J Agric Food Chem. 2000 Mar;48(3):849-52.

43. Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle. 2008 Sep 1;7(17):2769-73.

44. Onken B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010 Jan 18;5(1):e8758.

45. Fontbonne A., Charles MA, Juhan-Vague I, et al. The effect of metformin on the metabolic abnormalities associated with upper body fat distribution. Results of the BIGPRO 1 trial. Diabetes Care. 1996 Sept; 19:920-6.

46. Guthrie R. Treatment of non-insulin-dependent diabetes mellitus with metformin. J Am Board Fam Pract. 1997 May-Jun;10(3):213-21.

47. Paolisso G, Amato L, Eccellente R, et al. Effect of metformin on food intake in obese subjects. Eur J Clin Invest. 1998 Jun;28(6):441-6.

48. Emral R, Koseoglulari O, Tonyukuk V, Uysal AR, Kamel N, Corapcioglu D. The effect of short-term glycemic regulation with gliclazide and metformin on postprandial lipemia. Exp Clin Endocrinol Diabetes. 2005 Feb;113(2):80-4.

49. Lund SS, Tarnow L, Frandsen M, et al. Impact of metformin versus the prandial insulin secretagogue, repaglinide, onfasting and postprandial glucose and lipid responses in non-obese patients with type 2 diabetes. Eur J Endocrinol. 2008 Jan;158(1):35-46.

50. Hollenbeck CB, Johnston P, Varasteh BB, Chen YD, Reaven GM. Effects of metformin on glucose, insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria. Diabete Metab. 1991 Sep-Oct;17(5):483-9.

51. Carlsen SM, Følling I, Grill V, Bjerve KS, Schneede J, Refsum H. Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Scand J Clin Lab Invest. 1997 Oct;57(6):521-7.

52. Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med. 1997 Jan;102(1):99-110.

53. Wilcock C, Bailey CJ. Reconsideration of inhibitory effect of metformin on intestinal glucose absorption. J Pharm Pharmacol. 1991 Feb;43(2):120-1.

54. Ikeda T, Iwata K, Murakami H. Inhibitory effect of metformin on intestinal glucose absorption in the perfused rat intestine. Biochem Pharmacol. 2000 Apr 1;59(7):887-90.

55. Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998 Jan;6(1):47-53.

56. McCarty MF. A proposal for the locus of metformin’s clinical action: potentiation of the activation of pyruvate kinase by fructose-1,6-diphosphate. Med Hypotheses. 1999 Feb;52(2):89-93.

57. Moon RJ. The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being. Diabetes Obes Metab. 2007 Jan;9(1):143-5.

58. Sir T, Castillo T, Munoz S, Lopez G, Calvillan M. Effects of metformin on insulin resistance in obese and hyperandrogenic women. Rev Med Chil. 1997 Dec;125(12):1457-63.

59. Giugliano D, De Rosa N, Di Maro G, et al. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care. 1993 Oct;16(10):1387-90.

60. Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002966.

61. Wiernsperger NF, Bailey CJ. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs. 1999;58 Suppl 1:31-9; discussion 75-82.

62. Mithieux G, Guignot L, Bordet JC, Wiernsperger N. Intrahepatic mechanisms underlying the effect of metformin in decreasing basal glucose production in rats fed a high-fat diet. Diabetes. 2002 Jan;51(1):139-43.

63. Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med. 1997 Jan;102(1):99-110.

64. Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000 Dec;49(12):2063-9.

65. Otto M, Breinholt J, Westergaard N. Metformin inhibits glycogen synthesis and gluconeogenesis in cultured rat hepatocytes. Diabetes Obes Metab. 2003 May;5(3):189-94.

66. Dhatariya K, Bigelow ML, Nair KS. Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes. 2005 Mar;54(3):765-9.

67. Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA. 2004 Nov 10;292(18):2243-8.

68. Boudou P, Sobngwi E, Ibrahim F, et al. Hyperglycaemia acutely decreases circulating dehydroepiandrosterone levels in healthy men. Clin Endocrinol (Oxf). 2006 Jan;64(1):46-52.

69. Diamond P, Cusan L, Gomez JL, Bélanger A, Labrie F. Metabolic effects of 12-month percutaneous dehydroepiandrosterone replacement therapy in postmenopausal women. J Endocrinol. 1996 Sep;150 Suppl:S43-50.

70. Yamashita R, Saito T, Satoh S, Aoki K, Kaburagi Y, Sekihara H. Effects of dehydroepiandrosterone on gluconeogenic enzymes and glucose uptake in human hepatoma cell line, HepG2. Endocr J. 2005 Dec;52(6):727-33.

71. Kapoor D, Malkin CJ, Channer KS, Jones TH. Androgens, insulin resistance and vascular disease in men. Clin Endocrinol (Oxf). 2005 Sep;63(3):239-50.

72. Faloon W. Physician’s guide: Using blood tests to safely induce weight loss. Life Extension Magazine®. 2009 Jun;15(6):42-63.

73. Bain J. The many faces of testosterone. Clin Interv Aging. 2007; 2(4):567-76.

74. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006 Mar;91(3):843-50.

75. Traish AM, Saad F, Guay AT. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl. 2009 Jan-Feb;30(1):23-32.

76. Lefevre M, Redman LM, Heilbronn LK, et al. Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis. 2009 Mar;203(1):206-13.

77. Paniagua JA, de la Sacristana AG, Sánchez E, et al. A MUFA-rich diet improves posprandial glucose, lipid and GLP-1 responses in insulin-resistant subjects. J Am Coll Nutr. 2007 Oct;26(5):434-44.

78. Tzima N, Pitsavos C, Panagiotakos DB, et al. Mediterranean diet and insulin sensitivity, lipid profile and blood pressure levels, in overweight and obese people; the Attica study. Lipids Health Dis. 2007 Sep 19;6:22.

79. Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA Study. J Am Coll Cardiol. 2004 Jul 7;44(1):152-8.

80. Gaby AR. Adverse effects of dietary fructose. Altern Med Rev. 2005 Dec;10(4):294-306.

81. Hallfrisch J, Ellwood KC, Michaelis OE 4th, Reiser S, O’Dorisio TM, Prather ES. Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men. J Nutr. 1983 Sep;113(9):1819-26.

82. Tokita Y, Hirayama Y, Sekikawa A, et al. Fructose ingestion enhances atherosclerosis and deposition of advanced glycated end-products in cholesterol-fed rabbits. J Atheroscler Thromb. 2005;12(5):260-7.

83. Beck-Nielsen H, Pedersen O, Lindskov HO. Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects. Am J Clin Nutr. 1980 Feb;33(2):273-8.

84. McPherson JD, Shilton BH, Walton DJ. Role of fructose in glycation and cross-linking of proteins. Biochemistry. 1988 Mar 22;27(6):1901-7.

85. Van Wymelbeke V, Beridot-Therond ME, de La Gueronniere V, Fantino M. Influence of repeated consumption of beverages containing sucrose or intense sweeteners on food intake. Eur J Clin Nutr. 2004 Jan;58(1):154-61.

86. Palmer JR, Boggs DA, Krishnan S, Hu FB, Singer M, Rosenberg L. Sugar-sweetened beverages and incidence of type 2 diabetes mellitus in African American women. Arch Intern Med. 2008 Jul 28;168(14):1487-92.

87. Yudkin J, Eisa O. Dietary sucrose and oestradiol concentration in young men. Ann Nutr Metab. 1988;32(2):53-5.

88. Tjaderhane L, Larmas M. A high sucrose diet decreases the mechanical strength of bones in growing rats. J Nutr. 1998 Oct;128(10):1807-10.

89. Torronen R, Sarkkinen E, Tapola N, Hautaniemi E, Kilpi K, Niskanen L. Berries modify the postprandial plasma glucose response to sucrose in healthy subjects. Br J Nutr. 2010 Apr;103(8):1094-7.

90. Moeller SM, Fryhofer SA, Osbahr AJ 3rd, Robinowitz CB; Council on Science and Public Health, American Medical Association. The effects of high fructose syrup. J Am Coll Nutr. 2009 Dec;28(6): 619-26.

91. Angelopoulos TJ, Lowndes J, Zukley L, et al. The effect of high-fructose corn syrup consumption on triglycerides and uric acid. J Nutr. 2009 Jun;139(6):1242S-1245S.

92. Stanhope KL, Havel PJ. Endocrine and metabolic effects of consuming beverages sweetened with fructose, glucose, sucrose, or high-fructose corn syrup. Am J Clin Nutr. 2008 Dec;88(6):1733S-1737S.

93. Forshee RA, Storey ML, Allison DB, et al. A critical examination of the evidence relating high fructose corn syrup and weight gain. Crit Rev Food Sci Nutr. 2007 47(6):561-82.

94. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008 Jun;48(6):993-9.

95. Willcox DC, Willcox BJ, Todoriki H, Suzuki M. The Okinawan diet: health implications of a low-calorie, nutrient-dense, antioxidant-rich dietary pattern low in glycemic load. J Am Coll Nutr. 2009 Aug;28 Suppl:500S-516S.

96. Brand-Miller J, McMillan-Price J, Steinbeck K, Caterson I. Dietary glycemic index: health implications. J Am Coll Nutr. 2009 Aug;28 Suppl:446S-449S.