Berberine, Banaba (Corosolic Acid), Rauwolfia Serpentina, (Apple Cider) Vinegar, Chromium. Supplements to Improve and Restore Insulin Sensitivity - Serving #2

Setbacks are part of the process. Don't be mad at yourself. Get back on the wagon and identify what triggered them.

Before we tie into serving #2 of our list of insulin sensitizing supplements, let me just briefly remind you of the imperative to have your lifestyle changes in place before even thinking about spending or, in the case you did not give up the laziness and gluttony, wasting money on dietary supplements, if you ever want to send your insulin resistance, pre- or full-blown diabetes to remission. There is no way you achieve that by leading the same life that caused it, in the first place (re-read Part I).

Lifestyle changes are more powerful than supplements, and psychology more important than physiology

So, enough of the lecturing - at least as far as the lifestyle changes are concerned, let's rather check out what "must have" [A], "may have" [B], "could have" [C] and "should not have" [D] supplements have found their way into today's installment of this series (learn more about the rating system):

• Berberine [B]: I must say that I was quite surprised that not just one but four of you insisted on including berberine in this list. Probably partly due to the fact that the euphoric reviews on some website did not take into account what a recent review rightly says about this supplement: "The evidence of berberine for treating T2DM [type 2 diabetes] should be carefully interpreted due to the low methodological quality, small sample size, limited number of trials, and unidentified risks of bias" (Dong. 2012).
  Remember: Just because it's "natural", berberine is not necessarily safe! The LD 50 (50% of animals die; please note that this is for 100% pure alkaloid content and not the amount of an extract) is 713.57mg/kg i.e. ca. 12mg/kg or <1g for human beings (Yi. 2013)! It has also been reported to cause bradycardia (Cannillo. 2013) and messes with the hepatic cytochrome metabolism (Guo. 2012) and who knows what side effects this may cause in conjunction with pharmacological drugs and other supplements. Against that background it's actually counter-intuitive that it's administration to human subjects in a 2010 study by Zhang et al. lead not just to improvements in blood glucose, but also n ALT and AST, both of which are generally regarded as markers of liver damage (Zhang. 2010)
  So while the evidence is accumulating, its quality is still questionable. This does not mean berberine does not work - on the contrary - you could even argue that this makes it "dangerous" to investigate. After all, studies like Chen (2010), Jeong (2009), Kim (2009), and Lee (2006) appear to suggest that it acts via multiple pathways including AMPK (see metforming and ALA in previous installment) to improve both the glucose and lipid metabolism in mice and men in a way that would make many of the currently available redundant.
  
  

  Insulin sensitivity is not the be-all-and-end-all of ultimate leanness. These 20 agents in this list could help you "conserve" weight loss results, keep you lean on a bulk and/or avoid the hazardous Yoyo effect. Berberine with its pronounced anti-ppar-gamma effect is one of them, check out the rest!

  What is particularly interesting for the non-diabetic user is however its suppressive effects on PPAR-gamma (learn more about PPAR-g and body fat gain), and it's direct beneficial effects on the expression of insulin receptors in type II diabetics. Just as the PPAR-gamma effect this is a berberine exclusive trick and nothing ALA or metformin - let alone of of the std. "just makes you fat" diabetes drugs could do (Zhang. 2010)
  
  So, although there is evidence that berberine can effectively compete with regular diabetes meds (e.g almost identical effects on HbA1c in Dong. 2010). The number of quality human studies is still low. This is particularly worrying because of the lack of reliable long-term safety studies and information on optimal dosages (currently extracts are usually administered in 2-3 doses at a total amount of 0.5g and 1.5g per day; cf. Dong. 2010).
  
  Berberine certainly has the potential for an "A" rating, but at the for now, it's still only a "B". Despite additional benefits on cancer and its potential ability to improve body compositon via PPAR-gamma suppression which is an effect current top dog, metformin, does not have to offer (e.g. Wei. 2012). 
• Corosolic acid from Banaba = Lagerstroemia speciosa [C]: It is quite funny that corosolic acid, which is actually a "brother" to ursolic acid (with a 2-alpha-hydroxy attachment to it), has very much in common with berberine. It increases GLUT-4 activity + glucose activity (unfortunately not tissue specific, i.e. in fat cells, as well) and it inhibits the activity of the fattening (spec. increase in fat cells) PPAR-gamma activity (Liu. 2001) - unfortunately only in the petri dish. Still, in a study in diabetic mice its anti-diabetic qualities sucked compared to malted barley extract which had much more pronounced effects on the glucose levels of the diabetic rodents (Hong. 2004).
  
  

  Instead of banaba, you better try "6 Bananas à day" - well at least if you are still insulin sensitive (learn why)

  Other studies, such as Park, Lee & Sung (2005), also suggest that the in vivo effects may differ from what Liu et al. observed in the petri dish (Park. 2005). The observations Park et al. made, i.e. the increase, not decrease in the pro-obesogenic PPAR-gamma activity, is however of little use, as banaba was just used as one of three compounds in their study, which shares this downside with a whole host of other studies that are often cited in support of the effects of corosolic acid.
  
  A study by Klein et al. from 2007 even suggests that it's not the corsolic acid in banaba, but rather one of the gallotannin from banaba water extracts, namely Penta-O-galloyl-glucopyranose (PGG) that's responsible for the anti-diabetic effects. Much more so than for berberine there is thus a lack of reliable data on the efficacy and potency of corosolic acid / banaba. In conjunction with the existing counter-evidence, Banaba is thus only a [C], as in "a candidate when you've tried all other things, already".

• Effects of different dosages of the anti-diabetes drug gilbenclamide and rauwolfia methanol extract on haemoglobin (Hb) and HbA1C levels in rodent model of diabetes (Azmi. 2012)

  Rauwolfia serpentina [C]: While I did actually not intend to have rauwolfia in this list, I stumbled upon a pertinent study and was surprised that the purported fat burner (due to its yohimbine content) has beneficial effects on glucose metabolism, as well.
  
  Pretty impressive ones, as you can see in the figure on the right. It reduces the HbA1c levels in alloxan-induced diabetic Wister male mice (DIA in the figure) to (almost) normal levels and is thus exactly as potent as 5mg/kg of the FDA approved anti-diabetes drug glibenclamide.
  
  The mere fact that we do only have data from rodent studies (see figure above), does yet probably suffice as an explanation why the herb that is among the top 50 fundamental herbs of Chinese Traditional Medicine did only get a "C" rating. In this case probably "C" as in "compound you don't have to avoid if you get it for free as part of fat burner you use anyway ;-)
• Vinegar (apple cidar and other) [C]: While it is one of those anti-diabetic supplements everyone knows about, it's not an insulin sensitizer or wonder drug, but a glycemic index (GI) reducer. In other words, the addition of vinegar will reduce the glycemia mainly (*) by modulating the absorption kinetics of high GI carbs. No wonder that it has no proven effect in low GI foods (Liatis. 2010).
  
  

  Glucose levels (mg/dL) of healthy normal-weight volunteers after a serving of instant mashed potatoes during oral octreotide/insulin suppression test w/ or w/out 20 mL apple cider vinegar [5% g acetic acid] (Salbe. 2009)

  If you don't believe that, because you have been exposed to Internet brain-washing for too long, check this out: In a 2009 study Salbe et al. observed that as soon as the insulin release is controlled for, the co-ingestion of vinegar loses it's effect and ...
  

  "[...] the rise of glucose [in response to a mashed potato meal] was modestly but significantly (P = .01) greater after vinegar ingestion compared to placebo, suggesting that vinegar does not act to decrease glycemia by interference with enteral carbohydrate absorption." (Salbe. 2009)

  Don't get me wrong that's not necessarily bad, but if you follow the advice in part I of this series, you are not consuming significant amounts of these foods (in the Liatis study, mashed potatoes with low fat milk), anyway.
  
  Vinegar is thus not a real means to improve insulin sensitivity, but a tool like low carbing which will simply make it less important to be insulin sensitive. Consequently, I am rating it with a "C" as in "continues to be useful, but the mechanism of action does not allow us to list it as an 'insulin sensitizer' in the narrow sense". As long as you are aware of that you can obviously still use it "strategically", whenever you are indulging a high GI meal (and actually don't want it to be high GI) - 2 tablespoons is what you see usually being used for this purpose (ca. 30ml).
  
  (*) It should be mentioned though that there are a couple of rodent studies that show improved insulin release in diabetic rats after prolonged treatement (e.g. Abu-Zaiton. 2011). That is however a downstream effect that would also occur if you work out and get rid of the simple sugars in your diet. Your pancreas will after all start to heal if you stop beating it to death day in and day out.
• Chromium [B]: Yes it helps, the evidence is there - in full-blown diabetics (!) who happen to have elevated serum, but lowered cellular chromium levels (Rükgauer. 2002). In their relatively recent review Wang et al. point out:
  

  I am not going to list it here, but actually all of you who have read the SuppVersity Science Round-Up Special on DHEA will know it can increase insulin sensitivity, as well (learn more).

  "[...] patient selection may be an important factor in determining clinical response, as it was concluded that a clinical response to chromium (ie, decreased glucose and improved insulin sensitivity) may be more likely in insulin-resistant individuals with type 2 diabetes who have more elevated fasting glucose and hemoglobin A(1c) levels." (Wang. 2010)

  The mechanism of action is actually a facilitative one, as trivalent chromium (that's very different from its toxic industrially used cousins that have no place in your body!) is involed in (Hua. 2012):
  
  • GLUT-4 expression,
  • control of oxidative damage
  • insulin action & signalling,
  • insulin receptor expression,
  • AMPK expression,
  Effective dosages range from 200mcg to 1,000mcg and I personally would suggest to start low and go for doses of max. 600mcg per day of either chromium picolinate or niacin bound chromium, which were the most potent formulations in a 2009 study by Preuss et al.
  
  Why not more? Well, you must have missed previous post "Chromium Picolinate Worsens Insulin Sensitivity in Healthy, Non-Diabetic, Non-Obese Individuals by Up to 25%" (learn more). You did miss it and you have been taking 2mg each day for the last 12 months? Well, at least you do now know why you're insulin resistant ;-)

  Insulin sensitivity measured in previously healthy individuals before and after the 16 week on high dose chromium (left); change in insulin sensitivity of the subjects vs. serum chromium levels (read more)

  The potential negative side effect of chromium in those who do not need it, as well as the overall mixed results from clinical trial make it a "B" choice for all of you who are actually insulin resistant. For those who want to avoid becoming insulin resistant or dream of the disproven anabolic + body composition improving effects of chromium (Vincent. 2003) it's clearly an "D" as in "DON'T take more than the RDA of 150mcg".

Yes you are right, that's not it - there is still more on the todo-list, but obviously my days have - just as yours - only 24h and since I am not willing to ruin my insulin sensitivity by working all night (there are better things to do not sleeping on the weekend, trust me), you will have to wait till next Sunday for another update - sorry ;-)

Ah, and in case you missed either Part I or Part II of this series, this would be the right moment to go back and read them.
References:

• Abu-Zaiton AS. Effect of apple vinegar on physiological state of pancreas in normal and alloxan induced diabetic rats. World Journal of Zoology. 2011; 6(1), 7-11.
• Azmi MB, Qureshi SA. Methanolic Root Extract of Rauwolfia serpentina Benth Improves the Glycemic, Antiatherogenic, and Cardioprotective Indices in Alloxan-Induced Diabetic Mice. Adv Pharmacol Sci. 2012;2012:376429. doi: 10.1155/2012/376429. Epub 2012 Dec 18.
• Cannillo M, Frea S, Fornengo C, Toso E, Mercurio G, Battista S, Gaita F. Berberine behind the thriller of marked symptomatic bradycardia. World J Cardiol. 2013 Jul 26;5(7):261-4.
• Chen C, Zhang Y, Huang C. Berberine inhibits PTP1B activity and mimics insulin action. Biochemical and Biophysical Research Communications. 2010;397(3):543–547.
• Golubnitschaja O, Yeghiazaryan K. Opinion controversy to chromium picolinate therapy's safety and efficacy: ignoring 'anecdotes' of case reports or recognising individual risks and new guidelines urgency to introduce innovation by predictive diagnostics? EPMA J. 2012 Oct 7;3(1):11.
• Dong H, Wang N, Zhao L, Lu F. Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evid Based Complement Alternat Med. 2012;2012:591654.
• Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol. 2012 Feb;68(2):213-7. 
• Hong H, Jai Maeng W. Effects of malted barley extract and banaba extract on blood glucose levels in genetically diabetic mice. J Med Food. 2004 Winter;7(4):487-90. 
• Hua Y, Clark S, Ren J, Sreejayan N. Molecular mechanisms of chromium in alleviating insulin resistance. J Nutr Biochem. 2012 Apr;23(4):313-9.
• Jeong HW, Hsu KC, Lee JW, et al. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. American Journal of Physiology. 2009;296(4):E955–E964. 
• Kim WS, Lee YS, Cha SH, et al. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. American Journal of Physiology. 2009;296(4):E812–E819.
• 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.
• Lee YS, Kim WS, Kim KH, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006;55(8):2256–2264. 
• Liatis S, Grammatikou S, Poulia KA, Perrea D, Makrilakis K, Diakoumopoulou E, Katsilambros N. Vinegar reduces postprandial hyperglycaemia in patients with type II diabetes when added to a high, but not to a low, glycaemic index meal. Eur J Clin Nutr. 2010 Jul;64(7):727-32.
• Liu F, Kim J, Li Y, Liu X, Li J, Chen X. An extract of Lagerstroemia speciosa L. has insulin-like glucose uptake-stimulatory and adipocyte differentiation-inhibitory activities in 3T3-L1 cells. J Nutr. 2001 Sep;131(9):2242-7.
• Park MY, Lee KS, Sung MK. Effects of dietary mulberry, Korean red ginseng, and banaba on glucose homeostasis in relation to PPAR-alpha, PPAR-gamma, and LPL mRNA expressions. Life Sci. 2005 Nov 12;77(26):3344-54.
• Preuss HG, Echard B, Perricone NV, Bagchi D, Yasmin T, Stohs SJ. Comparing metabolic effects of six different commercial trivalent chromium compounds. J Inorg Biochem. 2008 Nov;102(11):1986-90. doi: 10.1016/j.jinorgbio.2008.07.012. Epub 2008 Jul 31. 
• Rükgauer M, Zeyfang A. Chromium determinations in blood cells: clinical relevance demonstrated in patients with diabetes mellitus type 2. Biol Trace Elem Res. 2002 Jun;86(3):193-202.
• Salbe AD, Johnston CS, Buyukbese MA, Tsitouras PD, Harman SM. Vinegar lacks antiglycemic action on enteral carbohydrate absorption in human subjects. Nutr Res. 2009 Dec;29(12):846-9. 
• Stearns DM, Silveira SM, Wolf KK, Luke AM. Chromium (III) tris (picolinate) is mutagenic at the hypoxanthine (guanine) phosphoribosyltransferase locus in Chinese hamster ovary cells. Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 2002; 513(1), 135-142.
• Wang ZQ, Cefalu WT. Current concepts about chromium supplementation in type 2 diabetes and insulin resistance. Curr Diab Rep. 2010 Apr;10(2):145-51. doi: 10.1007/s11892-010-0097-3. Review.
• Wei W, Zhao H, Wang A, Sui M, Liang K, Deng H, Ma Y, Zhang Y, Zhang H, Guan Y. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012 Jan;166(1):99-105. 
• Vincent JB. The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent. Sports Med. 2003;33(3):213-30.
• Yi J, Ye X, Wang D, He K, Yang Y, Liu X, Li X. Safety evaluation of main alkaloids from Rhizoma Coptidis. J Ethnopharmacol. 2013 Jan 9;145(1):303-10.
• Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, Wang SK, Zhou ZX, Song DQ, Wang YM, Pan HN, Kong WJ, Jiang JD. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 2010 Feb;59(2):285-92.