Type 2 Diabetes

What is Type 2 Diabetes?

Diabetes mellitus is a disorder in which blood sugar (glucose) levels are abnormally high because the body does not produce enough insulin to meet its needs. In type 2 diabetes (formerly called non-insulin-dependent diabetes or adult-onset diabetes), the pancreas continues to produce insulin, sometimes even at higher-than-normal levels. However, the body develops resistance to the effects of insulin, resulting in not enough insulin to meet the body’s needs.

Causes and Symptoms

Type 2 diabetes, once rare in children and adolescents, has recently become more common. However, it typically begins in people older than 30 and becomes progressively more common with age. About 26% of people older than 65 have type 2 diabetes. Obesity is the chief risk factor, with an estimated 80 to 90% of people with this chronic disease being overweight or obese. Certain race and ethnic groups are also at increased risk such as: African Americans, American Indians, and Latinos who live in the United States – all have a twofold to threefold increased risk. Type 2 diabetes is also hereditary and tends to run in families[1].

People with type 2 diabetes may not experience any symptoms for years or decades before they are diagnosed. Initial symptoms may be subtle and include:

  • Increased urination and thirst
  • Fatigue
  • Blurred vision
  • Dehydration

Diagnosis

Diagnostic criteria by the American Diabetes Association (ADA) include the following [2]:

  • A fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher, or
  • A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
  • A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis
  • A hemoglobin A1c (HbA1c) level of 6.5% or higher can also be used as a diagnostic criterion.

Management

The goals of type 2 diabetes management and treatment include reducing the risk of both micro and macrovascular disease risk. Goals of treatment are as follows:

  • Microvascular (i.e., eye and kidney disease) risk reduction through control of blood sugar and blood pressure
  • Macrovascular (ie, coronary, cerebrovascular, peripheral vascular) risk reduction through control of blood lipids and hypertension, smoking cessation
  • Metabolic and neurologic risk reduction through control of blood sugar

Approaches to help prevent diabetic complications include the following:

  • HbA1c every 3-6 months
  • Yearly dilated eye examinations
  • Annual microalbumin checks
  • Foot examinations at each visit
  • Blood pressure < 130/80 mm Hg, lower in diabetic nephropathy
  • Statin therapy to reduce low-density lipoprotein cholesterol

What is the Conventional Treatment?

Diet, exercise, and education are the cornerstones of treatment of diabetes and often among the first recommendations for people with mild diabetes. Because complications are less likely to develop if blood sugar levels are tightly controlled, the goal of treatment is to keep blood glucose levels within a normal range as much as possible. In addition, the treatment of high blood pressure and high cholesterol levels are also an important part of preventing diabetes complications such as having a heart attack and/or stroke.

Diet: A healthy diet is important for controlling blood sugar levels and preventing diabetes complications. Eating a consistent, well-balanced diet high in fiber and low in saturated fats and concentrated sweets is recommended. Carbohydrates tend to have the greatest effect on blood sugar therefore to control blood sugar individuals should know which foods contain carbohydrates, the size of “a serving” of different foods and how many carbohydrate servings to eat each day. A registered dietitian can help individuals work out a diet/meal plan that works best for them. For more detailed information about nutrition therapy recommendations set forth by the American Diabetes Association go to Nutrition Therapy Recommendations for the Management of Adults With Diabetes.

A low glycemic diet which focuses on foods that are low on the glycemic index have been shown to lower postprandial glucose and insulin levels and improve lipid profiles and are thought to reduce the risk of both diabetes and cardiovascular risk. As of yet, no intervention studies have been performed, but evidence available from epidemiological studies suggest a protective effect to lower glycemic diets.[3]

Exercise and Weight Control: Regular exercise, in any form, can help reduce the risk of developing diabetes. Physical activity helps move sugar from the blood into the cells of the body. The more active the individual, the lower the blood sugar level. Physical activity can also help reduce the risk of diabetes complications such as heart disease, stroke, kidney failure, blindness and leg ulcers. As little as 20 minutes of walking, three times a week has found to be beneficial. Individuals taking insulin may need to lower their insulin dose before exercising. Working with a doctor will help determine if medication adjustments are necessary. If an individual is overweight, modest weight loss (i.e. 10 lbs.) can reduce the risk of developing diabetes and help normalize blood sugars and/or reduce the need for diabetes medication.

Self-Monitoring Blood Glucose: Careful monitoring of blood sugar levels is the only way to make sure blood sugar levels remain within recommended target levels. Checking blood sugar levels using a glucometer is generally recommended before each meal and again at bedtime. A range of 90-130 mg/dl before meals is suggested for most people with diabetes. However individuals should work with their doctor to set their particular target.

Pharmacologic therapy

Early initiation of pharmacologic therapy is associated with improved glycemic control and reduced long-term complications. However there are many different types of medications that may be used alone or in combination to treat diabetes[4]. Examples include:

  • Biguanides – help lower blood sugar by making sure the liver does not make too much. They also help lower the amount of insulin in the body. Metformin is an example of a biguanide.
  • Sulfonylureas– help the pancreas make more insulin, which then lowers blood glucose. They also help the body make use of the insulin it already makes. Glimepiride, glyburide, glipizide are all sulfonylureas.
  • Meglitinide derivatives-help the pancreas make more insulin right after meals and is often used in combination with metformin. Repaglinide is a meglitinide.
  • Alpha-glucosidase inhibitors– these work by decreasing the absorption of carbohydrate from the intestines, slowing the absorption and lowering the rise of blood sugar throughout the day. Acarbose and miglitol are alpha-glucosidase inhibitors.
  • Thiazolidinediones (TZDs) – help make cells more sensitive to insulin. Examples of TZD’s include piogliazone and rosiglitazone.
  • Incretin mimetics- work by mimicking incretins such as GLP-1. GLP-1 is a hormone that increases insulin secretion by the pancreas, slows absorption of glucose from the gut and reduces the action of glucagon. All three actions reduce blood sugar levels. Exenatide (Byetta®) is an injectable medication that mimics GLP-1.
  • Dipeptidyl peptidase IV (DPP-4) inhibitors- works by inhibiting the body’s ability to control blood sugar. After eating, this medication reduces the amount of sugar produced by the liver. Sitagliptin (Januvia®) is a DPP-4 inhibitor.
  • Insulin – acts like the insulin produced by the body and may be necessary in patients with type 2 diabetes to overcome insulin resistance. There are several types of insulin classified by how soon and how long they act. Premixed combinations are also available. For more information about the different types of insulin available, go to: diabetes.org

Natural Approaches

Banaba

Banaba (Lagerstroemia speciosa) is an herbal medicine traditionally used in the Philippines for blood sugar stabilization. The hypoglycemic effect, which pre-clinical trials have suggested is due to insulin-mimetic and anti-adipogenic properties, is thought to be attributed to corosolic acid and ellagitannins.[5][6] Clinical trials of Banaba, though, are lacking. A small (n=31) study of diabetics and non-diabetics, using 10mg of corosolic acid before a glucose tolerance test, showed reduction of blood glucose levels at 60, 90, and 120 minutes, but only reached significance at 90 minutes. [7]

Bitter melon

Bitter Melon (Momordica charantia) is both a food and a medicine native to South America, Africa, and Asia. Active ingredients appear to be charantin, vicine, and polypeptide-p. These ingredients appear to have effects on insulin secretion, glucose uptake, and gluconeogenesis in pre-clinical studies.[8] A 2009 review found few clinical trials of good quality to comment on effectiveness, but thought pre-clinical data was intriguing enough to call for more trials.[9] A 2012 Cochrane review found four clinical trial involving 479 participants, two were uncontrolled and open-label. They found no significant effect for Bitter melon on blood glucose parameters.[10]

Carnitine

L-carnitine is an amino acid that plays a role in metabolism as a modulator of fuel utilization in cells through insulin-mediated glucose disposal. [11] Carnitine appears to assist in the removal of fatty acyl CoA derivatives/metabolites that are present in muscle mitochondria and lead to inhibition of both insulin signaling and glucose oxidation (leading to insulin insensitivity).[12] A 2012 review suggests that carnitine’s actions are especially present in insulin-resistant states.[13] The acetylated version (acetyl-L-carnitine) is the version seen most often in research.

Chromium

Chromium is a trace element that has an active role to play in both carbohydrate and lipid metabolism, it is also a component of glucose tolerance factor.[14] Chromium deficiency has been known for a long time to cause a reversible insulin resistance and diabetes (especially during parenteral feeding).[15] A 2007 meta-analysis reviewed 41 trials (N = 1198) at dosages ranging from 200 to 1000 mcg/day. Fourteen of these trials (N = 431) investigated type 2 diabetics with HbA1c levels between 7.0-10.2 and were able to show a 0.6 percent drop in HbA1c over the study periods.[16] A 2014 Review analyzed 25 studies that met inclusion criteria and concluded that chromium (especially chromium picolinate) using dosages of or greater than 200 mcg/day improved glycemic control (as evidenced by HbA1c and fasting blood glucose levels) along with improve triglyceride levels in diabetics.[17]

 

In other studies, when chromium in combined with biotin (2mg/day), the results were better (1.76 percent reduction in HbA1c level) for a sub-set of patients with levels above 10 (poorly controlled).[18] Although other studies using biotin and chromium combination showed no results.[19]

Cinnamon

Cinnamon (Cinnamomum cassia) is a commonly used spice, but it also has medical properties. Pre-clinical trials have demonstrated cinnamon’s ability to activate insulin receptors and increase glycogen synthase activity.[20] [21] A 2008 meta-analysis of five clinical trial (n=282) evaluated doses of cinnamon from 1 to 6 grams daily and reported no changes in hemoglobin A1C, or lipid parameters,[22] although one of the studies did show a decrease in fasting blood glucose.[23] A 2012 Cochrane review of ten randomized controlled trials found a high degree of potential for bias, and could not recommend cinnamon for use in diabeteics.[24] A 2013 review of 10 randomly controlled trials (n=543) of 120mg -6g dose for 4-18 weeks showed an overall reduction of fasting plasma glucose (-24.59 mg/dl), total cholesterol (-15.60 mg/dl), LDL-C (-9.42 mg/dl), triglycerides (-29.59 mg/dl) and increased HDL-C (1.66 mg/dl) but no significant effect on hemoglobin A1c levels.[25]

Fenugreek

Fenugreek (Trigonella foenum-graecum) is a spice and an herbal medicine. Preliminary trials suggest hypoglycemic and antihyperlipidemic properties.[26] A 2014 meta-analysis of 10 randomly controlled trials, in patients with diabetes, demonstrated a pooled response of significant changes in blood glucose 0.96 mmol/l, 2 hour postload glucose by -2.19 mmol/l and HbA1c by -0.85% as compared to control interventions.[27]

Fiber

Epidemiological and cohort studies have long suggested an association between cereal grain fiber and reduced incidence of type 2 diabetes.[28] A 2000 study published in New England Journal of Medicine evaluated a high fiber diet (50 grams) and concluded that soluble fiber, especially, helps to improve glycemic control, while decreasing hyperinsulinemia, and lowering plasma lipid concentrations in patients with type 2 diabetes.[29] A 2001 Review of patients with type 2 diabetes who consumed a diet high in fiber (50 g fiber/day) for six weeks showed significant improvements in glycemic control and lipid panels when compared with patients who consumed a diet with moderate amounts of fiber (25 g fiber/day) but they questioned whether the diet could be maintained long-term because of compliance issues.[30] A recent (2013) systematic review/meta-analysis of randomly controlled trials for effect of fiber on glycemic control, chose 11 trials that met inclusion criteria, (n=605). They concluded that high fiber diets (up to 42.5 g/day) or supplements containing soluble fiber (up to 15.0 g/day), were able to reduce reduced HbA1c, by 0.55% and fasting plasma glucose by 9.97 mg/dL.[31]

Fish oil

Most pre-clinical and epidemiological studies support an association between fish oil/fish intake and reduction in incidence of type 2 diabetes, although in some cases, negative associations are present.[32] Omega-3 fatty acids have a known beneficial association in heart disease,[33] including improvement in blood lipids (especially triglycerides – which have an association with glycemic control and inflammation[34]). These associations, however, have not translated into positive clinical trials in persons with diabetes or metabolic syndrome using fish oil supplements. In humans, the majority of randomly controlled studies have failed to show improvements in glycemic control or insulin sensitivity.[35] [36]

Garlic

While traditional use along with pre-clincal studies have suggested garlic (Allium sativum), and garlic extracts may have an effect on both insulin and glycemic parameters, no large randomly controlled trial exists in the treatment of type-2 diabetics. Garlic does contain volatile sulfur compounds (alliin, allicin, diallyl disulfide, diallyl trisulfide, diallyl sulfide, S-allyl cysteine, ajoene and allyl mercaptan, among others) that appear to have effects on insulin resistance.[37] Garlic also has known antioxidative, anti-inflammatory, and antiglycative properties. [38] One randomly controlled trial (which demonstrated the most dramatic effect on glycemic parameters) was designed to examine thrombocyte aggregation in non-diabetic populations.[39]

Green Tea

The polyphenol catechins (especially epigallocatechin gallate, EGCG) has been the focus of numerous studies. These catechins appear to improve both insulin sensitivity and reduce beta-cell damage in per-clinical trials.[40] [41] Caffeine, also present in green tea, is known to initially impair glucose metabolism, but longer use stimulates lipolysis and increases basal energy expenditure along with mobilizing glycogen from muscle stores.[42] Population studies suggest a reduction of Type 2 Diabetes risk of up to 48 percent for regular tea consumers.[43] [44] To date, few clinical trials have taken place to test the association. A small randomly controlled trial (n = 49) supplemented green tea catechins for three months and reported no changes in Hemoglobin A1c levels.[45] Another crossover study followed sixty borderline diabetics who received a green tea-extract powder containing 544 mg polyphenols (456 mg catechins) daily for 2 months and then were crossed over to the non-intervention arm for a 2-month period. A significant reduction in hemoglobin A1c levels were reported.[46]

Ginseng

Ginseng has been investigated in pre-clinical trials that have demonstrated reduced carbohydrate absorption, increased glucose transport, and modulation of insulin secretion.[47] The saponins (panax notoginseng saponins – PNS) are thought to be anti-inflammatory and help decrease postprandial glycemic response. [48] [49] A few short clinical trials have been performed to assess American ginseng’s effects on the glucose tolerance test in both diabetic and non-diabetics participants and was found to significantly reduce GTT.[50] [51] In a longer trial, decreases in both fasting blood glucose and Hemoglobin A1c levels have been reported.[52]

Gymnema

Gymnema (Gymnema sylvestre) has found use in Ayurvedic medicine to help diabetes, high cholesterol, and obesity. In pre-clinical trials, Gymnema has been shown to decrease the uptake of glucose from the small intestine. [53] Several components present in Gymnema appear to prevent the accumulation of triglycerides in muscle and liver. [54] A few small clinical trials have shown significant effects on fasting blood glucose and HemoglobinA1c levels. An unpublished trial used 200 mg of an ethanolic extract daily for 18 months in 22 persons with type 2 diabetes showed improvements in blood sugar control.[55] Two, uncontrolled trials (n=65 and n=27), using 400-800 mg for 3-12 months also showed significant improvements.[56] [57] A 2007 review suggested that none of these trails meet standard inclusion criteria, but pre-clinical research is very promising and, therefore, warrant further investigation. [58]

Magnesium

Magnesium is a co-factor in many enzymatic pathways involved in glucose regulation including glucose oxidation and modulation of glucose transport across cellular membranes. Hypomagnesemia is a common presentation in diabetics (especially those with glycosuria), and magnesium deficiency is known to increase insulin resistance.[59] A review of epidemiological studies suggests a strong role for magnesium in the prevention of diabetes and metabolic syndrome.[60] Clinical trials have been mixed, with some showing improvements in fasting blood glucose[61] [62] and fructosamine levels,[63] but most showing no response. A 2012 review cites the strong observational studies, but points out that good clinical data are lacking, perhaps due to length (years) and cost of such studies.[64] Magnesium also may play a role complications of diabetes such as retinopathy, neuropathy, thrombosis and hypertension.[65]

Vanadium

In pre-clinical trials, vanadium appears to exert an insulinomimetic effect. [66] A 2008 meta-analysis discovered 150 potential trials, but non met inclusion criteria, they then considered five uncontrolled trials (N= 48), using 50-300 mg vanadium for 3-6 weeks that demonstrated significant reductions in fasting blood glucose levels and suggested that, while promising, must be interpreted with caution.[67]

Vitamin E

Vitamin E has well known antioxidant activities, with potential influences of protein glycation, lipid oxidation, as well as insulin sensitivity and secretion,[68] but whether this translates into effective treatment or prevention of diabetes is unknown. A 2011 review of nine clinical trial (N = 418) vitamin E supplementation appeared to help a sub-set of diabetes (those with poor glycemic control and whose baseline vitamin E levels were low). [69] Further trials are needed to understand vitamin E’s role in blood sugar regulation and control.

Other Professional Resources:

American Diabetes Association’s Standards of Medical Care in Diabetes

American Diabetes Association Nutrition Therapy Recommendations

References

[1] National Diabetes Statistics Report, 2014

[2] Standards of Medical Care in Diabetes—2013 Diabetes Care 2013 Jan; 36 (Supp 1): S11-S66. PMID: 23264422

[3] Riccardi G, Rivellese AA, Giacco R. Role of glycemic index and glycemic load in the healthy state, in prediabetes, and in diabetes. Am J Clin Nutr. 2008 Jan;87(1):269S-274S. PMID: 18175767.

[4]Bennett WL, Wilson LM, Bolen S, et al. Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update:   Agency for Healthcare Research and Quality (US); 2011 Mar. (Comparative Effectiveness Reviews, No. 27.) PMID: 21735563.

[5] Miura T, Takagi S, Ishida T. Management of Diabetes and Its Complications with Banaba (Lagerstroemia speciosa L.) and Corosolic Acid. Evid Based Complement Alternat Med. 2012;2012:871495. PMID: 23082086.

[6] Klein G, Kim J, Himmeldirk K, Cao Y, Chen X. Antidiabetes and Anti-obesity Activity of Lagerstroemia speciosa. Evid Based Complement Alternat Med. 2007 Dec;4(4):401-7. PMID: 18227906.

[7] Fukushima M, Matsuyama F, Ueda N, Egawa K, Takemoto J, Kajimoto Y, Yonaha N,

Miura T, Kaneko T, Nishi Y, Mitsui R, Fujita Y, Yamada Y, Seino Y. Effect of corosolic acid on postchallenge plasma glucose levels. Diabetes Res Clin Pract. 2006 Aug;73(2):174-7. Epub 2006 Mar 23. PMID: 16549220.

[8] Akhtar MS, Athar MA, Yaqub M. Effect of Momordica charantia on blood glucose level of normal and alloxan-diabetic rabbits. Planta Med. 1981 Jul;42(3):205-12. PMID: 7280086.

[9] Leung L, Birtwhistle R, Kotecha J, Hannah S, Cuthbertson S. Anti-diabetic and hypoglycaemic effects of Momordica charantia (bitter melon): a mini review. Br J Nutr. 2009 Dec;102(12):1703-8. PMID: 19825210.

[10] Ooi CP, Yassin Z, Hamid TA. Momordica charantia for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2012 Aug 15;8:CD007845. PMID: 22895968.

[11] Mingrone G. Carnitine in type 2 diabetes. Ann N Y Acad Sci. 2004 Nov;1033:99-107. PMID: 15591007.

[12] Mynatt RL. Carnitine and type 2 diabetes. Diabetes Metab Res Rev. 2009 Sep;25 Suppl 1:S45-9. PMID: 19662615.

[13] Ringseis R, Keller J, Eder K. Role of carnitine in the regulation of glucose homeostasis and insulin sensitivity: evidence from in vivo and in vitro studies with carnitine supplementation and carnitine deficiency. Eur J Nutr. 2012 Feb;51(1):1-18. PMID: 22134503.

[14] SCHWARZ K, MERTZ W. Chromium(III) and the glucose tolerance factor. Arch Biochem Biophys. 1959 Nov;85:292-5. PMID: 14444068.

[15] Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson A. Chromium deficiency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition. Am J Clin Nutr. 1977 Apr;30(4):531-8. PMID: 192066.

[16] Balk EM, Tatsioni A, Lichtenstein AH, Lau J, Pittas AG. Effect of chromium supplementation on glucose metabolism and lipids: a systematic review of randomized controlled trials. Diabetes Care. 2007 Aug;30(8):2154-63. Epub 2007

May 22.. PMID: 17519436.

[17] Suksomboon N, Poolsup N, Yuwanakorn A. Systematic review and meta-analysis of the efficacy and safety of chromium supplementation in diabetes. J Clin Pharm Ther. 2014 Jun;39(3):292-306. PMID: 24635480.

[18] Albarracin CA, Fuqua BC, Evans JL, Goldfine ID. Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to

obese patients with type 2 diabetes. Diabetes Metab Res Rev. 2008 Jan-Feb;24(1):41-51. PMID: 17506119.

[19] Geohas J, Daly A, Juturu V, Finch M, Komorowski JR. Chromium picolinate and biotin combination reduces atherogenic index of plasma in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Am J Med Sci. 2007 Mar;333(3):145-53. PMID: 17496732.

[20] Cao H, Polansky MM, Anderson RA. Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes. Arch Biochem Biophys. 2007 Mar 15;459(2):214-22. Epub 2007 Jan 25. PMID: 17316549.

[21] Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y. Cinnamon extract (traditional herb) potentiates in vivo insulin-regulated glucose utilization via enhancing insulin signaling in rats. Diabetes Res Clin Pract. 2003 Dec;62(3):139-48. PMID: 14625128.

[22] Baker WL, Gutierrez-Williams G, White CM, Kluger J, Coleman CI. Effect of cinnamon on glucose control and lipid parameters. Diabetes Care. 2008 Jan;31(1):41-3. Epub 2007 Oct 1. PMID: 17909085.

[23] Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003 Dec;26(12):3215-8. PMID: 14633804.

[24] Leach MJ, Kumar S. Cinnamon for diabetes mellitus. Cochrane Database Syst Rev. 2012 Sep 12;9:CD007170. PMID: 22972104.

[25] Allen RW, Schwartzman E, Baker WL, Coleman CI, Phung OJ. Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. Ann Fam Med. 2013 Sep-Oct;11(5):452-9. PMID: 24019277

[26] Baquer NZ, Kumar P, Taha A, Kale RK, Cowsik SM, McLean P. Metabolic and

molecular action of Trigonella foenum-graecum (fenugreek) and trace metals in experimental diabetic tissues. J Biosci. 2011 Jun;36(2):383-96. PMID: 21654091.

[27] Neelakantan N, Narayanan M, de Souza RJ, van Dam RM. Effect of fenugreek (Trigonella foenum-graecum L.) intake on glycemia: a meta-analysis of clinical trials. Nutr J. 2014 Jan 18;13:7. PMID: 24438170.

[28] Murakami K, Okubo H, Sasaki S. Effect of dietary factors on incidence of type 2 diabetes: a systematic review of cohort studies. J Nutr Sci Vitaminol (Tokyo). 2005 Aug;51(4):292-310. PMID: 16262005.

[29] Chandalia M, Garg A, Lutjohann D, von Bergmann K, Grundy SM, Brinkley LJ. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. N Engl J Med. 2000 May 11;342(19):1392-8. PMID: 10805824.

[30] McIntosh M, Miller C. A diet containing food rich in soluble and insoluble fiber improves glycemic control and reduces hyperlipidemia among patients with type 2 diabetes mellitus. Nutr Rev. 2001 Feb;59(2):52-5. PMID: 11310776.

[31] Silva FM, Kramer CK, de Almeida JC, Steemburgo T, Gross JL, Azevedo MJ. Fiber intake and glycemic control in patients with type 2 diabetes mellitus: a systematic review with meta-analysis of randomized controlled trials. Nutr Rev. 2013 Dec;71(12):790-801. PMID: 24180564.

[32] Wallin A, Di Giuseppe D, Orsini N, Patel PS, Forouhi NG, Wolk A. Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies. Diabetes Care. 2012 Apr;35(4):918-29 PMID: 22442397.

[33] von Schacky C. Omega-3 fatty acids and cardiovascular disease. Curr Opin Clin Nutr Metab Care. 2007 Mar;10(2):129-35. PMID: 17284999.

[34] Guadarrama-López AL, Valdés-Ramos R, Martínez-Carrillo BE. Type 2 diabetes, PUFAs, and vitamin D: their relation to inflammation. J Immunol Res. 2014;2014:860703. PMID: 24741627.

[35] Yanai H, Hamasaki H, Katsuyama H, Adachi H, Moriyama S, Sako A. Effects of intake of fish or fish oils on the development of diabetes. J Clin Med Res. 2015 Jan;7(1):8-12. PMID: 25368695.

[36] Flachs P, Rossmeisl M, Kopecky J. The effect of n-3 fatty acids on glucose homeostasis and insulin sensitivity. Physiol Res. 2014;63 Suppl 1:S93-118.PMID: 24564669.

[37] Padiya R, Banerjee SK. Garlic as an anti-diabetic agent: recent progress and patent reviews. Recent Pat Food Nutr Agric. 2013 Aug;5(2):105-27. PMID: 23270395.

[38] Liu CT, Sheen LY, Lii CK. Does garlic have a role as an antidiabetic agent? Mol Nutr Food Res. 2007 Nov;51(11):1353-64.PMID: 17918164.

[39] Kiesewetter H, Jung F, Pindur G, Jung EM, Mrowietz C, Wenzel E. Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxicol. 1991 Apr;29(4):151-5. PMID: 2071264.

[40] Anderson RA, Polansky MM. Tea enhances insulin activity. J Agric Food Chem. 2002 Nov 20;50(24):7182-6. PMID: 12428980.

[41] Sabu MC, Smitha K, Kuttan R. Anti-diabetic activity of green tea polyphenols and their role in reducing oxidative stress in experimental diabetes. J Ethnopharmacol. 2002 Nov;83(1-2):109-16. PMID: 12413715.

[42] Robinson LE, Savani S, Battram DS, McLaren DH, Sathasivam P, Graham TE. Caffeine ingestion before an oral glucose tolerance test impairs blood glucose management in men with type 2 diabetes. J Nutr. 2004 Oct;134(10):2528-33. PMID: 15465742.

[43] Iso H, Date C, Wakai K, Fukui M, Tamakoshi A; JACC Study Group. The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults. Ann Intern Med. 2006 Apr 18;144(8):554-62. PMID: 16618952.

[44] Polychronopoulos E, Zeimbekis A, Kastorini CM, et al. Effects of black and green tea consumption on blood glucose levels in non-obese elderly men and women from Mediterranean Islands (MEDIS epidemiological study). Eur J Nutr. 2008 Feb;47(1):10-6. PMID: 18204918.

[45] Mackenzie T, Leary L, Brooks WB. The effect of an extract of green and black tea on glucose control in adults with type 2 diabetes mellitus: double-blind randomized study. Metabolism. 2007 Oct;56(10):1340-4. PMID: 17884442.

[46] Fukino Y, Ikeda A, Maruyama K, Aoki N, Okubo T, Iso H. Randomized controlled trial for an effect of green tea-extract powder supplementation on glucose abnormalities. Eur J Clin Nutr. 2008 Aug;62(8):953-60. Epub 2007 Jun 6. PMID: 17554248.

[47] Shane-McWhorter, Laura. Biological complementary therapies: a focus on botanical products in diabetes. Diabetes Spectrum 14.4 (2001): 199-208.

[48] Mucalo I, Rahelić D, Jovanovski E, Bozikov V, Romić Z, Vuksan V. Effect of American ginseng (Panax quinquefolius L.) on glycemic control in type 2 diabetes. Coll Antropol. 2012 Dec;36(4):1435-40. PMID: 23390846.

[49] Uzayisenga R, Ayeka PA, Wang Y. Anti-diabetic potential of Panax notoginseng saponins (PNS): a review. Phytother Res. 2014 Apr;28(4):510-6. PMID: 23846979.

[50] Vuksan V, Sievenpiper JL, Koo VY, Francis T, Beljan-Zdravkovic U, Xu Z, Vidgen E. American ginseng (Panax quinquefolius L) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2 diabetes mellitus. Arch Intern Med. 2000 Apr 10;160(7):1009-13. PMID: 10761967.

[51] Vuksan V, Stavro MP, Sievenpiper JL, Beljan-Zdravkovic U, Leiter LA, Josse RG, Xu Z. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes. Diabetes Care. 2000 Sep;23(9):1221-6. PMID: 10977009.

[52] Sotaniemi EA, Haapakoski E, Rautio A. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care. 1995 Oct;18(10):1373-5. PMID: 8721940.

[53] Porchezhian E, Dobriyal RM. An overview on the advances of Gymnema sylvestre: chemistry, pharmacology and patents. Pharmazie. 2003 Jan;58(1):5-12.PMID: 12622244.

[54] Pothuraju R, Sharma RK, Chagalamarri J, Jangra S, Kumar Kavadi P. A systematic review of Gymnema sylvestre in obesity and diabetes management. J Sci Food Agric. 2014 Mar 30;94(5):834-40. PMID: 24166097.

[55] Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K, Shanmugasundaram ER. Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin-dependent diabetes mellitus patients. J Ethnopharmacol. 1990 Oct;30(3):295-300. PMID: 2259217.

[56] Joffe D. Gymnema sylvestre lowers HbA1c Diabetes Control Newsl 2001. 761. Available from: www.diabetesincontrol.com/studies/gymnema1_2.shtml. Accessed 2/11/2015

[57] Shanmugasundaram ER, Rajeswari G, Baskaran K, et al. Use of Gymnema sylvestre leaf extract in the control of blood glucose in insulin-dependent diabetes mellitus. J Ethnopharmacol. 1990 Oct;30(3):281-94. PMID: 2259216.

[58] Leach MJ. Gymnema sylvestre for diabetes mellitus: a systematic review. J Altern Complement Med. 2007 Nov;13(9):977-83. PMID: 18047444.

[59] Paolisso G, Scheen A, D’Onofrio F, Lefèbvre P. Magnesium and glucose homeostasis. Diabetologia. 1990 Sep;33(9):511-4. PMID: 2253826.

[60] Dong JY, Xun P, He K, Qin LQ. Magnesium intake and risk of type 2 diabetes: meta-analysis of prospective cohort studies. Diabetes Care. 2011 Sep;34(9):2116-22. doi: 10.2337/dc11-0518. PMID: 21868780.

[61] Paolisso G, Sgambato S, Gambardella A, Pizza G, Tesauro P, Varricchio M, D’Onofrio F. Daily magnesium supplements improve glucose handling in elderly subjects. Am J Clin Nutr. 1992 Jun;55(6):1161-7. PMID: 1595589.

[62] Paolisso G, Sgambato S, Pizza G, Passariello N, Varricchio M, D’Onofrio F. Improved insulin response and action by chronic magnesium administration in aged NIDDM subjects. Diabetes Care. 1989 Apr;12(4):265-9. PMID: 2651054.

[63] de Lordes Lima M, Cruz T, Pousada JC, Rodrigues LE, Barbosa K, Canguçu V. The

effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. Diabetes Care. 1998 May;21(5):682-6. PMID: 9589224.

[64] Hruby A, McKeown NM, Song Y, Djoussé L. Dietary magnesium and genetic

interactions in diabetes and related risk factors: a brief overview of current knowledge. Nutrients. 2013 Dec 6;5(12):4990-5011. PMID: 24322525.

[65] Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care. 2003 Apr;26(4):1277-94.PMID: 12663610.

[66] Pandey SK, Anand-Srivastava MB, Srivastava AK. Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation. Biochemistry. 1998 May 12;37(19):7006-14. PMID: 9578588.

[67] Smith DM, Pickering RM, Lewith GT. A systematic review of vanadium oral supplements for glycaemic control in type 2 diabetes mellitus. QJM. 2008 May;101(5):351-8. PMID: 18319296.

[68] Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care. 2003 Apr;26(4):1277-94.PMID: 12663610.

[69] Suksomboon N, Poolsup N, Sinprasert S. Effects of vitamin E supplementation on glycaemic control in type 2 diabetes: systematic review of randomized controlled trials. J Clin Pharm Ther. 2011 Feb;36(1):53-63. PMID: 21198720.