For the health-conscious,prediabetic, and diabetic:This article focuses on 22 potent glucose-lowering agents with strong supporting evidence for their usefulness. In addition,3 extra agents are discussed that also can lower glucose but carry harmful risks.
Alpha lipoic Acid:
In 1999, a placebo controlled study involving seventy-four patients with type 2 diabetes found significantly more patients in the treatment group receiving 600 mg, 1200mg, or 1800mg of alpha lipoic acid revealed an increase in insulin sensitivity and subsequent decreases in glucose. (1) A later human study in 2012 corroborated ALA’s anti-diabetic effects by revealing a dose-dependent suppression of fasting glucose in subjects taking 300mg,600mg,900mg, or 1200mg ALA daily during the six month double-blind placebo controlled trial. (2) In a separate Italian study, subjects treated with almost half the dose of metformin (1.7g) plus alpha lipoic and myo-inositol faired better than subjects taking a higher dose of metformin (3g). (3)
It is postulated that alpha lipoic acid is able to act as a formidable anti-diabetic agent by facilitating insulin stimulation through enhancing muscle GLUT4 protein content, and additionally increasing GLUT4 translocation to cell membranes. As a result of these modes of action, glucose uptake is upregulated into muscle and fat cells, effectively lowering blood glucose.
One Major Caveat***
In obese diabetic subjects without exercise, alpha lipoic acid was shown to increase oxidation of LDLs (low density lipoproteins) (4), which could lead to the development of atherosclerosis. In those who exercised, however, antioxidant capacity was significantly increased and no atherogenic effect was observed. If taking alpha lipoic acid, it is recommended that is combined with exercise. The exercises that the otherwise sedentary subjects participated in involved only brisk walking on a treadmill for thirty minutes for 5 days a week, so intense exercise is by no means necessary. It is also worthy to note that ALA did not seem to improve insulin sensitivity in these diabetic patients with or without exercise, and that brings us to the last point …
Alpha lipoic acid consists of two forms known as “R” or “S” isomers. R-alpha lipoic acid is the biologically active native form to the body while S-alpha lipoic acid is a product of chemical synthesis and inactive by itself. Most commercial ALA products are sold are R/S racemic mixtures. Purchasing pure R-alpha lipoic acid is encouraged as it appears to confer a more potent effect on regulating glucose. (5)
Astaxanthin is another antioxidant one may want to include to ensure proper glucose metabolism. While astaxanthin is an antioxidant like the others mentioned, its hypoglycemic effect is achieved through a separate mode of action, meaning supplementing astaxanthin and other antioxidants will work to control blood sugar in different ways, unlike attempting to lower glucose with more of the same thing. Astaxanthin opposes the harmful effects of high fat and high sugar by maintaining insulin signaling and glucose metabolism. While dietary sugar and excess fat usually promote serine phosphorylation of IRS (insulin receptor substrate) proteins, astaxanthin decreases this activity, in addition to its modulatory role on metabolic enzymes that would otherwise lead to a worsening of glucose control under said dietary conditions. (64)
Just as the other antioxidants preserve damage to beta cells, astaxanthin also confers protection to vulnerable beta cells not only by inhibiting lipid peroxidation, but by preventing detrimental effects on these insulin-secreting cells mediated by glucose toxicity. (65)
This trace mineral can improve glucose regulation resistance in those with insulin resistance who are also deficient in this key mineral. It is now known that chromium increases insulin receptor kinase activity, which stimulates the insulin response. (33) Before the biological effects of chromium could be ascertained, chromium was long regarded as an anti-diabetic agent.
Since the 1950s, brewer’s yeast – which is abundant in chromium – has been known to prevent diabetes in experimental animals. (34) In diabetic humans (type I and type II), administration of chromium has strikingly enhanced glucose status and lowered insulin requirements in doses anywhere from 200mcg to 1000mcg. (35-38) In corticosteroid-induced diabetes, chromium at 600mcg per day reversed the condition. (39)
Null results are garnered from normoglycemic individuals with normal insulin production (people without diabetes), and supplementation may even have adverse effects in disease-free groups. (40) Ineffectiveness in normal individuals is simply because there is no faulty carbohydrate metabolism to correct and likely no chromium deficiency. Relatively healthy people often have normal levels of chromium compared to diabetics, so the divergence in results is not only not worrisome, but expected. (41) There are a few studies that could not detect any benefit from chromium in lowering blood sugar in diabetic subjects, but valid criticisms include using forms with poor bioavailability (chromium chloride) and doses that are too low (≤250mcg), in most cases, to achieve clinical benefit. (42-44)
Chromium picolinate is the form used in most experiments as well as the most popular form people supplement with due to its high bioavailability. There is, however, a serious concern that long term use of chromium picolinate will generate DNA damage based on unsettling responses both in cell cultures and animal models, especially in therapeutic dosages. (45) For that reason, it is advised to seek other forms with similar bioavailability such as chromium GTF (glucose tolerance factor) or chromium chelate.
Coffee consumption is linked to a “substantially lower risk” of type II diabetes, and decaffeinated – not caffeinated – seems to be largely responsible. (86-87) Caffeine by itself actually disrupts glucose metabolism by interfering with insulin sensitivity in both normal and diabetic individuals. (88)
The compound that is behind coffee’s strong anti-diabetic association is chlorogenic acid. In mice given Svetol, a decaffeinated green coffee bean extract, deficits in glucose tolerance that would otherwise occur under a high-diet were significantly prevented by supplementation. (89) Cholorogenic acid operates by promoting the absorption of glucose in liver cells and in skeletal muscle, as well as inhibiting glucose-6-phosphatase activity so glucose is not released in high amounts from the liver. (90) In a human study, a trial with 600mg of green coffee bean extract divided amongst 3 doses daily led to significantly lowered postprandial (after-meal) glucose scores after 40 days. There was also a modest effect on weight loss in the supplemented group, despite not changing their normal diets. (91) Besides inhibiting glucose-6-phosphatase to help curb fat accumulation, clorogenic acid inhibits glucose uptake in the small intestine, so as less glucose is absorbed, fat can be broken down, hence the weight loss. A normal weight is critical in maintaining normal glucose levels as excess fat prevents insulin release through numerous mechanisms (e.g., cellular stress, inflammation, dysregulation of hormones, etc). (143-144)
Because green coffee has a higher amount of chlorogenic acid than brown or roasted coffee (145), green coffee extract is preferred over the alternative to reap the anti-diabetic benefits.
This exercise supplement has proven to lower glucose in both normal and diabetic subjects. In normal sedentary men undergoing moderate aerobic training, those assigned to take creatine – approximately 10g per day for 3 months – glucose tolerance improved over the control group who received dextrose during aerobic training. (15) Similar results occurred when football players were supplemented with 15g of creatine for one week, followed by 3g daily for the remaining 49 days. After 8 weeks, serum glucose decreased, indicating glucoregulation by creatine. (16)
In 25 type I diabetics who received 5g of creatine per day for 12 weeks with concurrent exercise (twice a week), glucose control was significantly enhanced based on the reduction of HbA1c (glycated hemoglobin) levels, which serve as a marker for long term glycemic status. (17)
Interestingly, creatine works through a mechanism shared by metformin, an anti-diabetic drug heralded as the top-performing diabetes medication. Through stimulating AMPK-alpha activation, GLUT4 translocation is induced in skeletal muscles, more so than with exercise alone. In other words, creatine encourages glucose uptake in the muscles, effectively lowering plasma levels. This is one of the ways metformin operates to lower glucose levels, but creatine can be made to do the same as long as it is accompanied by exercise.
Astoundingly, taking 750mg of curcumin twice daily prevented progression to diabetes by 100% in pre-diabetics compared to the placebo group where 16.4% progressed to type II diabetes over the course of 9 months in a randomized double-blinded placebo-controlled trial. (135) Additionally, subjects who took curcumin showed improved overall function of beta cells, which is probably due to the fact that curcumin is potently anti-inflammatory.
While there seems to be a dearth of studies evaluating curcumin’s abilities to lower glucose in those already with fully developed diabetes, it has performed very well in animal studies (137) and did work to lower blood sugar and reduce the amount of insulin needed in human diabetics over 40 years ago. (136)
In healthy participants lacking the need to lower glucose, 6 grams of turmeric, which can contain 2%-8% of the curcumin, stimulated the postprandial/ post-meal insulin response (139), likely indicating that curcumin helps to lower glucose by boosting beta cell function and thereby enhancing insulin secretion.
At least 500mg of curcumin would be needed to protect against or control a diabetic condition, but curcumin is notoriously difficult to absorb. Newer formulations are available and while they are more expensive, bioavailability is dramatically increased. (146) Curcumin supplements with added piperine, in liposomal form, in a phospolipid complex, and/or micronized will provide reliably high bioavailability. (139-142)
Folate & B Vitamins:
A deficiency in folate/folic acid impairs glucose tolerance. (46) Folic acid is needed to maintain insulin sensitivity through activating AMPK (AMP-activated protein kinase), a regulator in energy homeostasis. (47) A low folate diet or a diet high in factors that enhance folate depletion (e.g. oral contraceptives, hormone replacement, smoking, and metformin) will prevent insulin from working to the best of its ability if the folate deficit is not corrected. Since 40%-60% of the population have genetic defects interfering with the needed conversion of inactive folate (folic acid) to its active form (methylfolate), it is prudent to supplement instead with ‘methylfolate’ rather than the more popular ‘folic acid’ supplements. (48)
Thiamine (vitamin B1) aids in controlling glucose by acting as a coenzyme for transketolase (Tk), which is an enzyme involved in glucose metabolism that diabetics seem to have reduced levels of. On top of that, thiamine is also serves as a cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes to maintain proper glucose utilization. Once again, these thiamine-dependant activities are reduced in diabetics. (49) A thiamine deficiency is linked with poorer glucose tolerance and impaired beta cell function. (50)
Theoretically, then, treating low thiamine levels with thiamine supplementation should result in better glucose control. Expectedly, data corroborates with that commonsense prediction. In 12 hyperglycemic subjects (10 with impaired glucose tolerance and 2 with newly diagnosed type II diabetes), high-dose thiamine supplementation (3 × 100 mg/day) led to a significant decrease in 2 hr plasma glucose levels whereas the placebo group received no such change in that measure, but did, however, experience increases in fasting glucose and insulin resistance. (51)
Vitamin B6 deficiency is associated with decreased plasma concentrations of insulin in mice. (52) In humans, a deterioration of glucose tolerance was reported under the same condition. In normal healthy people, glucose tolerance did not seem to be affected at all by a subclinical vitamin B6 deficiency, probably because the severe B6 deficiencies in animal models rarely occur in humans. (53) On the other hand, glucose tolerance was impaired in women who were B6 deficient who were concomitantly taking oral contraceptives. This impairment was successfully reversed with vitamin B6 supplementation. (54)
During pre-diabetes and diabetes where pancreatic beta cells are malfunctioning, vitamin B6 has been demonstrated to come to the aid in ameliorating this indirect detrimental effect on glucose levels. Vitamin B6 regenerates and improves the function of these crucial beta cells in in vitro studies and in animal models. (55-56)
Due to differing rates of efficacy in the conversion to active B6 (pyridoxal-5′-phosphate), it is best to supplement with the active form itself, keeping mind to look for ‘pyridoxal-5′-phosphate’ on the ingredient label of B6 supplements.
(References in last section)