Maintain & Increase Your Insulin Sensitivity - Wrap-Up: Overview + 3 Stacks. Plus: AMPK & PPAR-γ Revisited

It's not about exercise or nutrition, it's about both of them. And as long as it is not about the former it should not be about supplements either.

It's Sunday and finally time for the wrap up of the "Maintain & Increase Your Insulin Sensitivity" Series (read all previous installments). It took me quite some time to get through all the compounds on my and your list and the outcome is far from being a "complete" list of all the agents that can have beneficial effects on your insulin sensitivity. Still, if there is at least one agent, one fact or one take home message for each of the 6 previous articles of which you would say: "Ok, I guess that was worth wasting some of my valuable time on", I would be happy.

For myself it was by the way yet another occasion to learn more  about many of the agents, I reviewed in this series.

And if you listened to the SuppVersity Science Round-Up on Thursday, you will probably remember that I said that I was at least a cautiously excited about the potential of berberine... but I am wasting your time here. Let's start with the wrap up.

Lifestyle changes are more powerful than supplements: So don't forget that it's imperative to realize the lifestyle changes described in the first installment of this series. Otherwise the best you can hope to achieve with supplements (and drugs) is to slow the progression from insulin resistance to full-blown diabetes.

Before we take a look at the three stacks I have compiled, I do just briefly want to get you up to speed as far as the major underlying mechanisms of the supplements are concerned:

• AMPK: Some people in the medical establishment think of it as the good counter-part to mTOR. The fairy that will put an end to the pro-carcinogenic reign of the evil mTOR-witch, so to say. Others, who are mostly part of the "muscle head" community, think of AMPK as their fiercest enemy and mTOR as their brother in crime... It goes without saying that neither of these views is accurate. AMPK and mTOR are not even necessarily antagonistic - at least not for people like you - people who work out regularly. The mTOR expression after a workout does after all occur in the presence of increased an expression of AMPK. What else could you possibly ask for, if you want to "recomp" (i.e. lose fat and gain muscle to improve your physical appearance)?
  
  

  

  Few people know that there are two different iso-forms of AMPK. The alpha-2 isoform is the one that's expressed during a workout and it works hand in hand with mTOR and not against it (learn more)

  What may at first look like a paradox is actually easily explained if we don't look at the characteristic downstream effects of mTOR and AMPK, but rather at the circumstances in which they are activated. Outside of the previously mentioned exercise context those are in fact antagonist. With mTOR being triggered by the abundance of nutrients - specifically protein, and even more specifically leucine - you would not expect to see increases of AMPK at the same time. The latter is after all, expressed, when a cell senses a lack of nutrients in form of an increase in ADP (~used ATP) and a decrease in ATP levels. The reaction, i.e. an increased expression of AMPK will then have downstream effects on the uptake of glucose and the oxidation of fatty acids, both of which contribute to a restoration of normal ATP levels in the cell.
  
  Both AMPK and mTOR act highly localized. The exercise induced glucose uptake is thus muscle-specific - that should be obvious, since exercise will raise the ADP levels only in the muscle. Supplemental agents that mimic this effect, on the other hand, act systemically. Agents like alpha lipoic acid will therefore increase glucose uptake in both muscle and adipose tissue (Moini. 2002). After a workout and at other time points, where the glucose uptake is already high and, more importantly, muscle specific, it is thus not necessarily the best idea to try to "escalate" the effects by using a class of supplements that is often mislabeled as "insulin mimetics". 
• A note on the PPAR-effects of CLA, fish oil, TTA & co: I guess as a well-read SuppVersity reader you will know that CLA is a supplemental non-starter. In human studies the outstanding results from rodent trials have never been successfully replicated. This could be - at least in parts - a result of the dosage and the ratio of t10c12 CLA to it's c9t11 counterpart, which has the exact opposite effects on the PPAR-gamma receptor (Toomey. 2005).
  

  

  Some of you will probably also remember my articles about the pertinent effects of TTA and fish oil in the. Of those only the latter has a significant PPAR-gamma activity. TTA, on the other hand is predominantly a PPAR-delta and -alpha agonist and thus more a "true fat burner" than a general "fat handler", which is probably the best way to describe fish oil (learn more).
  PPAR-gamma: If you listened to the Science Round-Up last Thursday you will have heard me say that blocking PPAR-gamma will inhibit the storage of energy in the adipose tissue. That's true, but by no means as beneficial as you may be thinking. It is, for example, pretty likely that the CLA induced PPAR-gamma blockade is also responsible for the increased propensity to develop non-alcoholic fatty liver disease in CLA fed rodents.
  
  The results Fedor et al. present in a 2012 paper, show that these effects can be ameliorated if the PPAR-gamma suppressor (i.e. trans-10, cis-12-conjugated linoleic acid) is combined with a supplement that exerts the opposite effects in the liver - a supplement you all know pretty well: DHA, as in "fish oil". It is, just like many of the "older" diabetes drugs, an (allegedly less) potent PPAR-G agonist (=activator; cf. Neschen. 2006).
  
  Whether the blockade of PPAR-gamma is a good or a bad thing does thus obviously depend on the scenario we are talking about. For the lean individual, who is working out regularly and wants to defend his leanness in the absence of (un-)wanted eating orgies and "mass building regimen" it is probably a good thing. He or she will not have an energetic surplus that could end up clogging up the liver. And while the same goes for the average obese individual who has finally gotten his act together, PPAR-gamma inhibitors would seem clearly counter-indicated for sedentary individuals on the high calorie, high sugar, high fat diet so many people consider "normal", these days.
  
  As paradox as it may seem, the anti-diabetic effects of PPAR-gamma activating thiazolidinediones (TZDs) which are still used to "treat" (I should rather write "manage") diabetes mellitus and other diseases that feature insulin resistance will thus come at the expense of increased body fat storage. The latter can be pretty pronounced,as the data from pre-diabetic individuals Bray et al. published only recently goes to show you (figure 1).
  
  Despite their anti-inflammatory effects and their (limited) use in highly inflamed type II diabetics you will therefore not find any of the herbal PPAR-gamma agonists like pomegranate, pumpkin, mellisa officinalis, morus alba, artemisia capillaris, bitter melon, guggul, banaba or mulberry (cf. Huang. 2009) in the stacks below. And that despite the fact that they have anti-inflammatory activities.

Ok, I guess you are either fed up of theoretical details by now, or were so before and just scrolled down to the "stacks" in the first place.

There is a reason there is no "athlete's stack" here: Since I know you will be asking, I thought I will say it right away. The reason that there is no "athlete's stack" in the list is that athletes are either "normal-weight insulin resistant" or they are insulin sensitive and don't need any supplements on top of the lifestyle changes from episode I. You got your workouts, folks: There is no better muscle specific insulin sensitizer out there! If you are looking for agents to stay lean try berberine, it's anti-ppar-gamma effects may help and if you want more, stack it with taurine, of which you should by now know that its benefits go well beyond "glucose sensitizing" / You don't? Well, then take a look at the previous articles about taurine.

I guess I will not make you wait any longer, then... I have come up with three scenarios, the "insulin resistant obese / overweight individual", "the normal-weight insulin resistant individual" and the "cheater" (explanations follow below the stacks):

• 

  Table 1: List of the most important supplements discussed in the series; more details on each of them, as well as on those I did not include in this overview can be found in the individual installments.

  The insulin resistant obese / overweight individual will have to target weight and fat loss and increases in insulin resistance; a stack that could facilitate all three would contain.
• ALA (or metformin) - 3x 300-500mg 
• Berberine - 3x 200-400mg
• Fucoxanthin - 3x 5mg
• Taurine - 3x 2-3g
• Chromium - 1x 200mcg (*)
• The normal-weight insulin resistant individual will have to take care of inflammation, (usually) a beginning fatty liver and not taking the next step to the obese diabetic.
• Berberine - 3x 200-400mg 
• Chlorogenic acid - 3x 200-300mg
• Taurine - 3x 2-3g
• Milk thistle - 3x 200-400mg
• The cheater can be either of the former or a healthy perfectly insulin sensitive individual who wants to reduce the sudden rise in blood glucose after a meal.
• Cinnamon - 1-6g (Ceylon cinnamon)
• Vinegar - 2x tablespoons
• Green tea - 1-2 cups

The insulin resistant obese / overweight individual needs relieve most urgently, therefore he will also trial fucoxanthin, which has some impressive, but not exactly reliable weight loss data. He will either have a script for metformin or will use alpha lipoic acid (ALA) as a substitute and he will make sure that he gets adequate chromium by taking 200mcg of chromium picoliante or niacin-bound chromium per day *if this is not already in a multi he or she is taking.

The normal-weight insulin resistant individual has slightly different needs than his overweight comrade. He or she is almost certainly suffering from chronic inflammation and beginning or existing NAFLD (the obese will have that, as well, but for him it's only part of the problem). With it's effects on both AMPK and PPAR-gamma berberine will make sure that the body fat levels remain low. Just like taurine (read more), chlorogenic acid (Panchal. 2012) and milk thistle (read more), it will also help "revive" the liver and sooth the inflammation by promoting the bodies own antioxidant defense system.

The cheater, on the other hand, could be everyone who wants to undo (or fore-do, if you will) a high GI carb meal. The ingredients of this stack will ameliorate the blood sugar response and could thus potentially reduce any damage you could do to your pancreas... but let's be honest. With the occasional cheat you are not going to do any damage and if cheating becomes common practice you violate the "lifestyle-changes first!" principle and won't get away healthily no matter how much supplements you take.

Browse previous articles:

Lifestyle Changes

ALA, GABA, Taurine & Co.

Berberine, Banaba & Co.

Cinnamon, Curcumin & Co.

Lemon, Starch, Coffee & Co.

Chlorogenic acid, fucoxanthin & Co.

References:

• Fedor DM, Adkins Y, Mackey BE, Kelley DS. Docosahexaenoic acid prevents trans-10, cis-12-conjugated linoleic acid-induced nonalcoholic fatty liver disease in mice by altering expression of hepatic genes regulating fatty acid synthesis and oxidation. Metab Syndr Relat Disord. 2012 Jun;10(3):175-80.
• Huang TH, Teoh AW, Lin BL, Lin DS, Roufogalis B. The role of herbal PPAR modulators in the treatment of cardiometabolic syndrome. Pharmacol Res. 2009 Sep;60(3):195-206.
• Moini H, Tirosh O, Park YC, Cho KJ, Packer L. R-alpha-lipoic acid action on cell redox status, the insulin receptor, and glucose uptake in 3T3-L1 adipocytes. Arch Biochem Biophys. 2002 Jan 15;397(2):384-91.
• Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline GW, Sono S, Gillum M, Shulman GI. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes. 2006 Apr;55(4):924-8. 
• Panchal SK, Poudyal H, Waanders J, Brown L. Coffee extract attenuates changes in cardiovascular and hepatic structure and function without decreasing obesity in high-carbohydrate, high-fat diet-fed male rats. J Nutr. 2012 Apr;142(4):690-7.
• Toomey S, Harhen B, Roche HM, Fitzgerald D, Belton O. Profound resolution of early atherosclerosis with conjugated linoleic acid. Atherosclerosis. 2006 Jul;187(1):40-9. Epub 2005 Sep 22.

Cholorgenic Acid, Fucoxanthin and Irvingia Gabonensis - Supplements to Improve & Restore Insulin Sensitivity #4.1

In case you are wondering about the potatoes on the bottom right - they shall remind you that the caffeic acid ester is not a prerogative of green coffee beans.

As my buddy Sean Casey from www.caseperformance.com let me know I did actually overlook three suggestions to the "Maintain & Improve Your Insulin Sensitivity" series I had promised to include (sorry Tom!). Well, I am a man of my word and will make good for that today.

Before I begin discussing chlorogenic acid, fucoxanthin and irvingia gabonensis, I do just briefly want to point out that I deliberately postponed this post to Thursday, because it fits in quite nicely with one of the two hot topics of today's installment of the SuppVersity Science Round-Up on the Super Human Radio Network [brace yourselves, some sleazy self-promotion is about to follow ;]

The Science Round-Up airs every other Thursday, 12PM (EST)

SVSR - Sneak Peak: Airing at 12PM (EST) is today's installment of the SuppVersity Science Round-Up (listen live!). Scheduled topics for today are (1) "Are statins protecting us from Dementia? I thought it was the other way around!" - a discussion of the recent mainstream media news on "breakthrough science" and (2) a summary of the most interesting agents from the "Maintain & Improve Your Insulin Sensitivity Series" (read it). The latter will include a list of supplements that can be used to improve your insulin sensitivity and a discussion of the important and often overlooked question: "Which supps work for whom?"

Ok, that's it for the "advertisment break" ;-) Let's get back to the science of supplemental insulin sensitivity improvements. What works, what doesn't?

• Chlorogenic acid [A]: Actually I did not really overlook chlorogenic acid, I did only forget to mention that I would not discuss it on its own, because it is one of the main active ingredients in coffee. In fact it is one of those that are held responsible for effects such as those Kelly L Johnston and her colleagues observed in a 2003 study on the effects of coffee consumptions on the release of gastrointestinal hormone and glucose tolerance in humans (Johnston. 2003).
  
  What the scientists observed in their 9 healthy fasted volunteers who consumed 25 g glucose in either 400 mL water (control) or 400 mL caffeinated or decaffeinated coffee (equivalent to 2.5 mmol chlorogenic acid/L) a decade ago stands in line with the results of more recent studies that confirm that cholorogenic acid, which can also be found in herbs like dandelion and a whole host of other foods, like potatoes (10-14mg/100g; Dao. 1992), or broccoli (60mg/kg; Clifford. 2000), has potent anti-diabetic effects of which Ong et al. found only recently that they are - how else could it be - mediated by the activation the metabolic fuel gauge AMPK (Ong. 2013).
  
  Now all that would suggest that chlorogenic acid was an "A", as in "all of you should at least drink plenty of coffee", but if it was just for the chlorogenic acid content of the dark brew, a recent study by Mubarak et al. does actually question whether this may not have the exact opposite effect.

  

  A recent study on CGA supplementation with high fat diets raises a huge questionmark wrt to the effects of CGA on body fatness and - even more so - insulin sensitivity (Mubarak. 2013)

  As you can see in the figure above, the researchers from the University of Western Australia made an observation that stands in stark contrast with the results presented by Ong et al. earlier this year. The co-administration of a "physiologically obtainable dose" (1 g/kg of diet) of chlorogenic acid as part of the high fat diet the mice in the study were exposed to lead to a down-regulation of AMPK in the liver and, subsequently, an increase in NAFLD risk (learn more about the connection between NAFLD and diabetes).
  
  

  

  Effects of 329mg of CGA on substrate oxidation after determined during 3h postprandial phase (Soga. 2013)

  The underlying reasons of this discrepancy will still have to elucidated and I want to emphasis that they stand in conflict with evidence from both epidemiological studies and controlled trials (Vinson. 2012). The most recent of the latter is a paper by Soga et al. which confirms that the supplementation of a beverage containing 329 mg of chlorogenic for 4 weeks will increase both the postprandial energy expenditure (+5% vs. control) and fatty acid oxidation (+5% vs. baseline) in - and this is important - 16 healthy normal weight guys with a BMI of ~22kg/m² and a body fat percentage of only 16.7%.
  
  While it will have to be elucidated whether the negative effects Mubarak et al. observed in their recent study are related to the metabolism of CGA by different bacteria in the gut (cf. Nicolson. 2005) or specific dietary co-factors, cholorogenic acid still deserves an "A", as in "almost certainly beneficial". The suggested dosage for an adult is somewhere between 200-1,000mg/day and it is best taken with foods. This is particularly true if you get your cholorogenic acid from some sort of an extract (e.g. green coffee bean). These often contain other agents that are not exactly easy on your digestive tract. 
• Fucoxanthin [A-]: It has the word "thin" in it and has actually some promising data as a weight loss adjuvant. At first it looks as if it was "just" another powerful anti-oxidant with second / third line effects on insulin sensitivity that are mediated by an amelioration of whole body inflammation and as of now somewhat dubious weight loss effects. If we go beyond the few non-sponsored human trials and include the results of in-vitro studies, it does yet appear, as if fucoxanthin could also exert direct effects on your insulin sensitivity. The mechanisms?
  

  • 

    6-gingerol is probably a more reliable PPAR-gamma antagonist and it is only one out of 20 agents I discussed in a previous article - alongside vitamin A, curcumin, resveratrol, artimesia, glucosamine, and co.

    Fuco reduces the glucose uptake in mature fat cells (PPAR-gamma blockade), and facilitates the growth on new ones (Kang. 2011). Ok, that's not beneficial for someone who does not intend to remain fat, but it would allow you to become a "healthy obese" individual, who have a high number of small fat cells. In the presence of a caloric deficit, when new fat cells are not going to be formed it could also have a repartitioning effect.
  • Foco increases muscular GLUT-4 expression and interacts with PGC1-alpha; this is something you will usually see after a workout - not bad right (Kang. 2012)?
  In conjunction with its purported anti-cancer, antioxidant, anti-inflammatory, antiangiogenic and antimalarial activities (Peng. 2011), it may sound as if Fuco was a definite "A" as in "all of you should be on it", but with the few and not exactly extremely credible human trials, I am not willing to award more than a "B" as in "B-uy if you got money to spare and want to try something new". Why? Well, I don't have to tell you that you are the ones who constantly remind me that "rodents are no little men" - 99% of the subjects in the few existing in-vivo studies were however just that: rodents. The available information on optimal dosing regimen is correspondingly scarce and the best I can say is that sponsored studies on combination products suggests that 1.5-3.0mg per day would be necessary to actually see results, my calculation based on a rodent study by Jeon et al. (2010), on the other hand, says that you'd need ~16mg per day.
• Active ingredients, standardization and extracts While this does not apply for irvingia supplements only, the use of a specific (patented) extract in the Ngondi study reminds me to remind you that ostensibly identical products with say 200mg of irvingia in it may well have totally different effects. This is the case for irvingia and all other herbals, for which we do not really know the active ingredients and you cannot - even if you wanted - produce a standardized extract.
  

  Similarly, any 1:10 extract can - in the worst case - be less potent than the raw material, if the active ingredient was lost or at least significantly reduced during the extraction process. Keep that in mind, whenever you shop for herbal supplements.
  Irvingia gabonensis [B]: The number of human studies for irvingia is similarly low as for many of the other hyped anti-obesity drugs and looking at the few credible studies we do have it does not appear as if the seed extracts from the traditional West African food plant would have any direct effect on glucose management.
  
  In a 2009 study by Ngondi et al., for example, the adminstration of 150mg of a standardized irvingia extract did lead to impressive weight and "waist loss" of 12.8kg and 17cm in only 10 weeks. The corresponding reduction in fasting blood glucose is however a result of the weight loss and not vice versa. In other words, irvingia, which appears to act on both PPAR-gamma and leptin (Oben. 2008), improves glucose metabolism by reducing body fat (if we believe what the few existing studies are telling us)
  
  In view of the fact that irvingia works its still under-researched weight loss magic via leptin- and not insulin / blood glucose related mechanisms, irvingia gabonensis is only a "C" as in "C-an be used to get rid of body weight" (I would not put too much faith into the results of the existing studies, by the way). What appears to be quite certain, though, it that irvingia doe not have any direct insulin sensitizing effects - at least none that have been reliably documented in peer-reviewed studies. In addition, it is highly questionable that the next best supplement you buy will have a similar active ingredient composition as the IGOB13 (patented) extract that was used in the study by Ngondi et al.

So, these were the items that were missing from the previous installments of the "Maintain and Increase Your Insulin Sensitivity" series (read all articles).

Come back for more! The complete summary with some more general comments and three suggested stacks is going to be up next Sunday, as planned.

If you do not want to wait for that, I highly suggest you listen to the live show today at 12PM (EST) or download the podcast from the SuppVersity Science Round-Up: Seconds tomorrow.

References: 

• Clifford, MN, Chlorogenic acids and other cinnamates: nature, occurrence, dietary burden,
  absorption and metabolism. J. Sci. Food Agric. 2000, 80, 1033–1043
• Dao L, Mendel F. Chlorogenic acid content of fresh and processed potatoes determined by ultraviolet spectrophotometry. Journal of Agricultural and Food Chemistry. 1992; 40(11): 2152-2156.
• Jeon SM, Kim HJ, Woo MN, Lee MK, Shin YC, Park YB, Choi MS. Fucoxanthin-rich seaweed extract suppresses body weight gain and improves lipid metabolism in high-fat-fed C57BL/6J mice. Biotechnol J. 2010 Sep;5(9):961-9.
• Johnston KL, Clifford MN, Morgan LM. Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine. Am J Clin Nutr. 2003 Oct;78(4):728-33. 
• Kang SI, Ko HC, Shin HS, Kim HM, Hong YS, Lee NH, Kim SJ. Fucoxanthin exerts differing effects on 3T3-L1 cells according to differentiation stage and inhibits glucose uptake in mature adipocytes. Biochem Biophys Res Commun. 2011 Jun 17;409(4):769-74.
• Mubarak A, Hodgson JM, Considine MJ, Croft KD, Matthews VB. Supplementation of a high-fat diet with chlorogenic acid is associated with insulin resistance and hepatic lipid accumulation in mice. J Agric Food Chem. 2013 May 8;61(18):4371-8.  
• 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. 
• 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.
• Ong KW, Hsu A, Tan BK. Anti-diabetic and anti-lipidemic effects of chlorogenic acid are mediated by ampk activation. Biochem Pharmacol. 2013 May 1;85(9):1341-51.
• Soga S, Ota N, Shimotoyodome A. Stimulation of postprandial fat utilization in healthy humans by daily consumption of chlorogenic acids. Biosci Biotechnol Biochem. 2013 Aug 23;77(8):1633-6. 
• Peng J, Yuan JP, Wu CF, Wang JH. Fucoxanthin, a marine carotenoid present in brown seaweeds and diatoms: metabolism and bioactivities relevant to human health. Mar Drugs. 2011;9(10):1806-28.
• Vinson JA, Burnham BR, Nagendran MV. Randomized, double-blind, placebo-controlled, linear dose, crossover study to evaluate the efficacy and safety of a green coffee bean extract in overweight subjects. Diabetes Metab Syndr Obes. 2012;5:21-7.

Lemon Juice, Resistant Starch, Coffee, Blueberries, Chili, Ginseng, Ginger, Mate, Gymnema Sylvestre, Bitter Melon. Supplements to Improve & Restore Insulin Sensitivity #4

Lemon Juice, Resistant Starch, Coffee, Blueberries, Chili, Ginseng, Ginger, Mate, Gymnema Sylvestre, Bitter Melon - they are all in this fourth serving of the insulin sensitizing supplements series and they are all in this collage. Can you identify all of them?

First of all, let me thank you for flooding me with good suggestions for supplements that should be discussed in this last installment of the series. It's Friday now that I start writing this post and it is probably going to be Sunday, before I find the time to finish the last of your suggestions; and that despite the fact that I am going to try to cut the infos short when I can foresee that it is not worth going into more details, anyway.

Not worth going into details? Yep, one of the supps, where this is clearly the case was suggested by Colby who wants me to address sodium-R-lipoic acid, which is nothing else but R-ALA and in my mind a scientifically unsupported spin-off of ALA that may in fact be inferior to the regular racemic form of lipoic acid which contains both the R- as well as the purportedly pro-inflammatory S-form of ALA (more about the benefits of inflammation in the context of hormesis).

Before we start, just a brief reminder: Do not consider spending your money on any of these supplements before you've not made / begun to make the lifestyle changes described in episode one of this series. Otherwise all of these supplements are nothing but a crutch supporting you on your journey along the Royal Road to Diabesity.

Ok, enough of the finger wagging for today; let's get to "your" supplement wishes. Let's see, what have we got?

• Lemon juice (citric acid) - This is another of Colby's suggestions (also asked for by "anonymous" who just missed his chance of becoming semi-famous). Colby says, he read about lemon juice in Tim Ferriss' Four Hour Body (a fascinating book, by the way; the only problem is that people forget that it's an N=1 experiment and few things that worked for Tim will work for you or anyone else, as effectively).
  
  

  

  Not citric acid specific enough, but worth mentioning: In a study where citric acid (the purported active ingr. in lemon juice) was admin. w/ thiamine, arginine and caffeine it lead to FAT GAIN in normal weight individuals (Muroyama. 2003) - this should remind you of the smart rules of supplementation, right?

  Ferris claims that in his experiments only lemon juice, but not vinegar, which happens to work by the same mechanism, i.e. slowing down the absorption of carbs, did actually lower his postprandial blood glucose levels. Unfortunately there is no research to support this claim and thus lemon juice is at best of as limited use as vinegar (see previous post).
  
  Using lemon juice for cooking purposes, on the other hand, has been shown to reduce the formation of pro-diabetic glycation end products during cooking.
  
  Using a marinade with lemon juice for example will reduce the production of AGEs in beef by 10%  (Uribarri. 2010)
  
  Overall, lemon juice is thus another "C" as in "you C-an try it if you are looking for yet another C-rutch", but certainly nothing that is going to solve any of your problems.
• Resistant Starches - Starches that cannot be broken down in the small intestine and will thus not release any glucose are a no-brainer, as far as improvements in insulin sensitivity are concerned. Think of them as fat, because that is what the "really resistant" starches, i.e. those that make it almost unharmed to the long intesine (RS-3 for the natural ones and RS-4 for the artificial ones). Once they have arrived there they are metabolized to short chain fatty by the bacteria in your gut.
  
  

  

  WMHDP pancakes are not good for you, but maybe better than regular ones.

  Now, the one thing that renders this starches still interesting is the fact that the fatty acids the gut bacteria produce are "short chain fatty acids" (SCFA) . These are, as the name implies "short" and thus easier digested than their nasty long-chain brethren that make up the lion's share of regular keto diets. Moroever, the SCFA have direct (receptor mediated) effects on the production of the "satiety hormone" GLP-1 that has positive effects on both glucose and lipid metabolism (Yadav. 2013).
  
  It is thus the conversion to SCFA and not the resistant starches which come in the varieties RS1 (=physically inaccessible or digestible resistant starch, such as that found in seeds or legumes and unprocessed whole grains),  RS2 (=resistant starch that occurs in its natural granular form, such as uncooked potato, green banana flour and high amylose corn), RS3 (=resistant starch that is formed when starch-containing foods are cooked and cooled such as in legumes, bread, cornflakes and cooked-and-chilled potatoes, pasta salad or sushi rice) and  RS4 (= starches that have been chemically modified to resist digestion, e.g. WMHDP), due to which RS1-4 get a "B" as in "B-etter than regular starches or sugars, B-ut no quick fix for sure". They are useful only in conjunction with the previously mentioned life-style changes from episode I (no, I will never tire of repeating this ;-).

• 

  From an anti-diabetes perspecitve more coffee appears to help more; in view of its effects on the central nervous system you still better limit your intake to max. 3-4 cups per day (Matusheski. 2012)

  Coffee (caffeine & other stuff) - Is certainly too extensive to be treated in detail, so I will refer you to the numerous previous posts on coffee at the SuppVersity, as well as "Warding Off Holiday Weight Gain 2.0: The Anti-Diabesity Effect of Coffee Goes Beyond its Caffeine Content" | read more.
  
  In addition, I would like to invite you to take a look at the image to the right that shows quite clearly that the anti-diabesity effect, of which you have learned that it could mediated by the benefits of caffeine on the liver (cf. "Diabetes & the Liver - Chicken vs. Egg" | read more) are reversed when you are already obese, diabetic & hyperlipidemic.
  
  While I refuse to officially rank coffee, I can tell you that most of the negative side effects are dose-dependently brought about by its caffeine content, and that I personally have a "never consume more than 500mg caffeine or 2-3 cups per day" rule in place and regret it deeply whenever I defy my rule for more than 2-3 days in a row - not on the diabetic side of things (I am rather a low blood glucose guy), but as far as overall well-being and energy levels are concerned. 

• 

  SuppVersity suggested read: "Want to Relieve Insulin Resistance? Eat your Blueberries!" | read more

  Blueberries (real food) - Let me first tell you that I do not intend to give you an overview of the myriad of proven and purported health benefits of blueberries. If that's what you are looking for, I suggest you take a peak at the latest review by Noerberto et al. 2013 (see references).
  
  What I want to give you instead is a real world example: A 2010 study by Stull et al. who found that the provision of isocaloric smoothies with and without 22.5 g blueberry bioactives to 32 obese, nondiabetic, and insulin-resistant subjects for 6 weeks led to a significant improvement of insulin sensitivity in the absence of changes in adiposity.
  
  According to the scientists the same effects could be achieved with 2 cups of fresh blueberries (or 45g of the powder they used to prepare the study) that makes blueberries an "A" as in "A must, but A bit expensive to have them every day". That does not change that consuming blueberries on a regular basis is going to help you improve or maintain you insulin sensitivity.
  
  Thanks for reminding me of including such a reasonable whole food in the series, Erik - ah and Ian, if you want pterostilbene, just eat your blueberries.

• 

  MCT + Chili a fat loss duo that will reduce your insulin sensitivity. That does not matter while you are dieting or low-to-no-carbing, but is a no go when you are doing neither of that.

  Chili (capsaicin) - Capsaicin is another suggestion from Erik, of which I am not quite sure, where he picked it up. Being mislabeled as "fat burner" capsaicin is just like caffeine a substance that increases the efflux of fat from the fat cells and will thus increase the serum level of free fatty acids. This will promote, not inhibit, insulin resistance. Against that background it is not surprising that Islam et al. report that capsaicin had no hypoglycemic, but insulinotropic (more insulin, but same amount of glucose in the blood = decreases insulin sensitivity) effects in a rodent model of type II diabetes (Islam. 2008).
  Note: If you are wondering why I am so bold to state that MCTs reduce your insulin sensitivity (see caption of the image), here is the study (Marcal. 2013) and this is the explanation: Fast fats = increase in FFA in the blood = insulin resistance. At least in an "average" = non-low carb + non-calorically restricted scenario it's as easy as that. When you replace the "Atkins fats" (= long chain fatty acids) with MCTs, on the other hand, you will obviously see benefits from medium chain triglycerides (cf. De Vogel-van den Bosch. 2011).
  In other words, if it's not used to cut body fat (in conjunction with diet and exercise) it's unlikely that capsaicin will help with insulin sensitivity, which is why it gets a "D" as in "D-on't use". And that would be the case even if capsaicin did not have some dubious effects on the Langerhans cells in the pancreas Gram. 2007). It's weight loss effects are totally overblown (see today's Facebook news) and it has been shown to blunt the beneficial effects of the "satiety hormone" cholecystokinin two decades ago (Ritter. 1985). If you want a "hot" alternative, you should thus go for plain onions (Babu. 1997).
• Ginseng (purported active ingredient ginsenoside Rh2): While there are plenty of rodent studies available, Cho et al. were the first to investigate the effect of Korean red ginseng in human beings and the results of their study which has been published in March this year are not exactly impressive.
  
  

  

  It's easy to see: Ginseng doesn't help healthy people. While the reduction in insulin sensitivity in response to 6g ginseng was not significant, it's obvious that healthy individuals won't benefit (Cho. 2013)

  The Korean researchers administered 6 g of  Korean red ginseng rootlets (n=34) or a placebo to a group of 68 participants (average BMI 26kg/m², average body fat 30.7%) for 12 week period and observed that
  

  "Korean red ginseng had no significant effect on improving the insulin sensitivity over time." (Cho. 2013)

  This is significant, because you can safely assume that its effects on individuals with lower body fat percentages (like you?) are probably bordering zero.
  
  Other studies report a physiologically irrelevant improvement in postprandial glycemia, when ginseng (in this case American) was administered exactly 40min before an oral glucose challenge (Vuskan. 2001). And the (non-significant) reduction in insulin sensitivity in the healthy but chubby subjects of the Cho study (see figure on the top right of this paragraph) is a perfect example of the previously cited imperative of applying the selectivity and specificity principles, when you select and buy your dietary supplements (learn more).
  
  In view of the fact that there is some allegedly inconclusive and "not convincing" (Kim. 2011) scientific support for the usefulness of ginseng in sick people, it still qualify for a "C-" as in "C-ould be useful for those who are already suffering from what we call the "metabolic syndrome". Of these, especially those who suffer from high blood lipids (e.g. Mucalo. 2012) could benefit and in these individuals you will probably also observe downstream improvements in glucose metabolism. These are however secondary to the reduction in blood lipis and will not occur in people like yourself, people who work out regular and lead the lives of someone who has found his / her way to physical culture.

• 

  Suggested read: "Beyond Warding Off Holiday Weight Gain: 250-1000mg of Freeze-Dried Ginger Reduce Visceral Fat In Rodents on High Fat Diet" | read more
  

  Ginger - SuppVersity readers will remember ginger from the list of "20+ Anti-Obesity Agents That Have the Potential to Inhibit Fat Gain Right at the Cellular Level" (read full article). If you do remember this article, you may also remember that the anti-obesity effect is brought about by ginger's ability to inhibit the pro-adipogenic peroxisome proliferator-activated gamma receptors (PPAR-gamma).
  
  Ginger has also been shown to exhibit appetite suppressant effects (Mansou. 2012), to improve the thermic effect of food (ibid.), to hold potential as an anti-NAFLD (non-fatty liver disease) "drug" (Sahebkar. 2011), to ameliorate the negative side effects of diabetes (Li. 2012), and to improve glucose level, HbA1c and insulin sensitivity in type 2 diabetic patients (Mahluji. 2013)
  
  For whole ginger (i.e. not ginger extracts) the dosages are usually in the 2-4g range. And while this is probably not going to hurt anyone, there is simply too little evidence that the beneficial effects of ginger are not "solely" mediated by its potent anti-inflammatory action to award an "A"-level recommendation with respect to its insulin sensitizing effects.
  
  So, assuming that its usefulness is more or less limited to individuals with underlying inflammatory problems ginger gets a "B" as in "there are few B-etter general health foods out there, B-ut its benefits in lean individuals are probably not glucose specific". If you are looking for general anti-obesity effects, on the other hand, I'd suggest you go and grab a couple of ginger roots right now ;-)
• Mate tea (Ilex paraguariensis): The evidence from human studies for or against the usefulness of the last supplement on Erik's wishlist is not exactly what I would call extensive. A study by Klein et al. from 2011 is probably as good as it gets and, as it was to be expected, the results suggest that we are once more dealing with an anti-inflammatory agent that will have the greatest impact on people who already suffer from diabetes / the metabolic syndrome.
  
  

  

  SuppVersity suggested Read: "The Leptin-Ilex!? Does Yerba Mate (Ilex Paraguariensis) Restore Leptin Sensitivity or Does it Just Help You Lose Body Fat by Curbing Your Appetite?" | read more, but don't forget that fat loss and glucose sensitivity are not one and the same. While The former usually entails the latter, it does not always work the other way around.

  Contrary to the diabetic patients in the Klein study, the pre-diabetic mate-tea consumers (3x330ml of tea made from roasted mate tea) in his study, did not register any benefits in glucose metabolism and the improvements in lipid parameters may well be a mere consequence of the concomitant dietary changes Klein et al. observed (Klein. 2011).
  
  Just like many other purported "insulin sensitizers", Mate is thus another food / supplement that has only secondary effects on blood glucose. It's another "C" supplement with "C as in C-an be used by the obese diabetic". Drinking liters of mate, even if you don't like it, just to increase your glucose sensitivity does however seem to be pretty useless for anyone who ain't suffering from abnormal lipid levels and increased whole body inflammation.
• Gymnema Sylvestre - While there are a couple of human studies on gymnema their significance suffers from heavy sponsoring and / or the co-administration of other supplements. If you plod through the research that's out there you will however find some evidence for its usefulness in full-blown type II diabetics (500mg/day; Kumar. 2010) and some interesting effects on the sweet taste receptors (Sigoillot. 2012). The latter are blocked by gymnemic acid and could, at least when we are talking about the glucose receptors in the gut, modify both the absorption kinetics and hormonal response of / to glucose.
  
  In the end, the said effects on the sweet taste receptors may also be involved in the effects Shanmugasundaram et al. describe in a 1990 paper. In their study, the administration of 400mg of an GS extract lead to significant improvements in glucose management in 27 patients with insulin-dependent (=severe) diabetes. Since we do not really know that, and in view of the occasional reports of adverse reactions to gymnema supplements (e.g. a case-report by Shiyovich et al. (2010) that links the consumption of gymnema supplements to toxic hepatitis), I will still rank it as "D" as in "D-o wait until there is more and better research available".
  
  I personally consider the risk of consuming corresponding supplements very low, but the same goes for any potential benefits ... and one thing is certain, it's not "a potential panacea for the management of diabetes" which is what MJ Leach writes to attract attention to his 2007 review of the literature in the Journal of Alternative Complementary Medicine (Leach. 2007)

• 

  Suggested Read: "Purported Health Supplement Bitter Melon Induces Oxidative Damage in Rat Testes and Reduces Testosterone Levels by >50%" | read more

  Bitter melon (Momordica charantia): While the hype has already abated, the marketing guys did a pretty damn good job in pimping bitter melon as the goto panaceum for whatever health problem may have befallen you. With respect to it's insulin sensitizing effects Basch et al. wrote about a decade ago:
  

  "Bitter melon may have hypoglycemic effects, but data are not sufficient to recommend its use in the absence of careful supervision and monitoring." (Basch. 2003)

  Did that change over the course of the past 10 years? Of course not.
  
  So unless Google and sensationalist advertisements that are supposed to look like real journal articles are your main sources of "information" about dietary supplements you will probably have to concede that
  

  "[...] clinical trial data with human subjects are limited and flawed by poor study design and low statistical power [and] the clinical data regarding the anti-diabetic potentials of M. charantia and calls for better-designed clinical trials to further elucidate its possible therapeutic effects" (Leung. 2009)

  and conclude that
  

  "[t]here is insufficient evidence on the effects of momordica charantia for type 2 diabetes mellitus. Further studies are therefore required to address the issues of standardization and the quality control of preparations. For medical nutritional therapy, further observational trials evaluating the effects of momordica charantia are needed before RCTs are established to guide any recommendations in clinical practice." (Ooi. 2013)

  That does not necessarily mean that it does not work, at all, but as a direct comparison with metformin shows, it's not a real alternative for type II diabetics (Fuangchan. 2011), whose HbA1c levels declined by meager 0.24% after being treated with a bitter melon supplement three times a day for three months (undisclosed amount of active ingredients in the caps; cf. Dans. 2007). I hope I do not have to point out that it is unrealistic to expect that you would see better effects in non-diabetics.
  
  I guess, it's probably not necessary to say that, but bitter melon is a bitter pill that gets a "D" as in "D-on't fall for the hype".
  

No block buster supps in this serving: Ok, I have to admit this last installment of the series had a couple of supplemental non-starters in it. Honestly, Ginger is the only one of the items listed above that stands a chance to make it into the insulin sensitizing protocol that's about to conclude this series next Sunday.

Until then, I hope all of you enjoy the rest of this weekend and come back for your daily dose of SuppVersity news tomorrow (all muscle heads listen up, you will like tomorrows news ;-)!

References:

• Babu PS, Srinivasan K. Influence of dietary capsaicin and onion on the metabolic abnormalities associated with streptozotocin induced diabetes mellitus. Mol Cell Biochem. 1997 Oct;175(1-2):49-57. 
• Fuangchan A, Sonthisombat P, Seubnukarn T, Chanouan R, Chotchaisuwat P, Sirigulsatien V, Ingkaninan K, Plianbangchang P, Haines ST. Hypoglycemic effect of bitter melon compared with metformin in newly diagnosed type 2 diabetes patients. J Ethnopharmacol. 2011 Mar 24;134(2):422-8.
• Islam MS, Choi H. Dietary red chilli (Capsicum frutescens L.) is insulinotropic rather than hypoglycemic in type 2 diabetes model of rats. Phytother Res. 2008 Aug;22(8):1025-9.
• Kim S, Shin BC, Lee MS, Lee H, Ernst E. Red ginseng for type 2 diabetes mellitus: a systematic review of randomized controlled trials. Chin J Integr Med. 2011 Dec;17(12):937-44. 
• Kumar SN, Mani UV, Mani I. An open label study on the supplementation of Gymnema sylvestre in type 2 diabetics. J Diet Suppl. 2010 Sep;7(3):273-82.
• Leach MJ. Gymnema sylvestre for diabetes mellitus: a systematic review. J Altern Complement Med. 2007 Nov;13(9):977-83. Review.
• 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. doi: 10.1017/S0007114509992054. Epub . Review.
• Li Y, Tran VH, Duke CC, Roufogalis BD. Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review. Evid Based Complement Alternat Med. 2012;2012:516870.
• Mansour MS, Ni YM, Roberts AL, Kelleman M, Roychoudhury A, St-Onge MP. Ginger consumption enhances the thermic effect of food and promotes feelings of satiety without affecting metabolic and hormonal parameters in overweight men: a pilot study. Metabolism. 2012 Oct;61(10):1347-52.
• Marçal AC, Camporez JP, Lima-Salgado TM, Cintra DE, Akamine EH, Ribeiro LM, Almeida FN, Zanuto RP, Curi R, Boldrini SC, Liberti EA, Fiamoncini J, Hirabara SM, Deschamps FC, Carpinelli AR, Carvalho CR. Changes in food intake, metabolic parameters and insulin resistance are induced by an isoenergetic, medium-chain fatty acid diet and are associated with modifications in insulin signalling in isolated rat pancreatic islets. Br J Nutr. 2013 Jun 28;109(12):2154-65. doi: 10.1017/S0007114512004576.
• Matusheski et al. Coffee and Type 2 Diabetes Risk. In "Coffee: Emerging Health Effects and Disease Prevention" edited by Yi-Fang Chu.John Wiley & Sons, Mar 27, 2012.
• 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. Review.
• Muroyama K, Murosaki S, Yamamoto Y, Ishijima A, Toh Y. Effects of intake of a mixture of thiamin, arginine, caffeine, and citric acid on adiposity in healthy subjects with high percent body fat. Biosci Biotechnol Biochem. 2003 Nov;67(11):2325-3.
• Norberto S, Silva S, Meireles M, Faria A, Pintado M, Calhau C. Blueberry anthocyanins in health promotion: A metabolic overview. Journal of Functional. Foods, Available online 21 September 2013.
• Ritter RC, Ladenheim EE. Capsaicin pretreatment attenuates suppression of food intake by cholecystokinin. Am J Physiol. 1985 Apr;248(4 Pt 2):R501-4. 
• Sahebkar A. Potential efficacy of ginger as a natural supplement for nonalcoholic fatty liver disease. World J Gastroenterol. 2011 Jan 14;17(2):271-2. doi: 10.3748/wjg.v17.i2.271. 
• Shanmugasundaram ER, Rajeswari G, Baskaran K, Rajesh Kumar BR, Radha Shanmugasundaram K, Kizar Ahmath B. 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.
• Shiyovich A, Sztarkier I, Nesher L. Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus. Am J Med Sci. 2010 Dec;340(6):514-7.
• Stull AJ, Cash KC, Johnson WD, Champagne CM, Cefalu WT. Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. J Nutr. 2010 Oct;140(10):1764-8. doi: 10.3945/jn.110.125336.
• Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, Yong A, Striker GE, Vlassara H. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc. 2010 Jun;110(6):911-16.e12.
• Yadav H, Lee JH, Lloyd J, Walter P, Rane SG. Beneficial Metabolic Effects of a Probiotic via Butyrate-induced GLP-1 Hormone Secretion. J Biol Chem. 2013 Aug 30;288(35):25088-97.

Cinnamon, Curcumin (Turmeric), Licorice (Glycyrrhizin), Melatonin, Milk Thistle (Silymarin). Supplements to Improve and Restore Insulin Sensitivity - Serving #3

Sleep hygiene was part of the lifestyle tips in the first episode of this series, with this episode you get a tool that can help you get back into the groove: melatonin.

This is Sunday number three with supplements that may help you improve / maintain your glucose sensitivity and I can already tell you it's going to be the last one. In other words, if there are any compounds that have not yet been covered in this series - just a reminder

• Alpha Lipoic Acid, GABA, Taurine, Green Tea, Gooseberry & Fenugreek were addressed in detail as part of supplement list #1
• Berberine, Banaba (Corosolic Acid), Rauwolfia Serpentina, (Apple Cider) Vinegar, Chromium were addressed in detail on supplement list #2 

- this is your last chance to make a wish! So, if you have something special in mind, use the comment section at the end of this article and tell me which agents you want to see in issue #4 on next Sunday.

Ah, ... it should be obvious that none of the following agents qualifies: Cinnamon, Curcumin (Turmeric), Licorice (Glycyrrhizin), Melatonin, Silymarin - why? Well those are the ones you can read about in the paragraphs below :-)

• Dosages for cinnamon supplements range from 1-6g+ of pure real cinnamon (cinnamomum vera) to 150-500mg of extracts (depending on their quality). You should be aware though that "fake" cinnamon (cinnamomum cassia, which is sold in the US simply as "cinnamon") contains (highly variable amounts) of coumarin a liver toxic and carcinogenic substance w/ an upper intake limit of 0.07mg/kg body weight that may easily be exceeded by eating common foodstuffs like oatmeal with cinnamon in small children (Fotland. 2012).
  

  According to Fotland et al. this can lead to toxicity reactions within weeks. So don't be cheap and better make sure not to buy "fake cinnamon" (=cassia) for you or your kids and loved ones.
  Cinnamon (Cimmomium verum!) [B]: Cinnamon is unquestionably one of the best known supplements for diabetics. "High blood sugar? Have some cinnamon in your sugar-laden Starbucks coffee!"... and this is exactly where the problem is. Everyone knows that cinnamon works - acutely(!), because he or she can measure his blood glucose after the ingestion of the said Starbucks coffee with and without cinnammon, but...
  1. according to the latest meta-analysis the long-term benefits of using cinnamon to manage blood glucose levels in type II diabetics are zero - the most important measure of their overall glycemic status, i.e. HbA1c, does not change significantly; or I should say: it reacts formidable in studies lik Lu et al. (2012; 120 or 360mg/day treated alongside standard diabetes drug) and deteriorates in others (Mang. 2006; Wainstein. 2011; etc.)
  2. studies in healthy individuals suggest that the blood glucose lowering effects are a mere results of an inhibition of the digestion and absorption of high GI carbs (6g regular cinammon w/ rice or pudding; Hlebowicz. 2007)
  There is however recent evidence that some of the secondary plant material, i.e. the proanthocyanidins you will find in cinnamon water extracts exert a direct protective effect on stressed pancreatic beta cells.
  Just a note for those who feel I am a "supplement hater": I am not the only one displaying a healthy degree of skepticism towards the hoopla that surrounds the use of cinnamon as an anti-diabetic. The "gold standard" review from the Cochraine Foundation says: "There is insufficient evidence to support the use of cinnamon for type 1 or type 2 diabetes mellitus. Further trials, which address the issues of allocation concealment and blinding, are now required. The inclusion of other important endpoints, such as health-related quality of life, diabetes complications and costs, is also needed" (Leach. 2013)
  Overall, cinnamon is thus a "B" as in "one of the B-est agents to protect yourself from developing insulin resistance and diabetes": It can also be interesting for type II diabetic looking to improve his blood lipids, but this is a different topic (cf. Khan. 2003). So, if you can't keep away from the sweet stuff of which you know ever since episode 1 of this series that you are not supposed to eat it, some cinnamon won't hurt - if you hate the taste, though, don't force it down. It's not really worth gagging.

• 

  In healthy human beings the administration of 6g of curcuma longa before a 75g glucose tolerance test does just one thing: It spikes insulin without improving the glucose uptake. Technically this is a decrease - not an increase in insulin sensitivity, which would have to be observed if curcumin was an insulin-sensitizer.

  Curcumin (Turmeric; curcuma longa) [C] - Curcumin is probably among the hottest supplements out there. Everybody appears to know exactly what it does and obviously everything is ueber-potent and super-healthy. It does therefore appear almost unquestionable that curcumin is going to help with insulin resistance, as well... right? Well, unquestionable as it may apper, the mere assumption that it would do so is not just unwarranted, but downright misleading.
  
  While there is evidence that its anti-inflammatory effects can help restore normal insulin sensitivity in diabetic individuals and animals, such as the streptocitozin-induced diabetic rodents in a 2011 study by Na et al., the important evidence from human studies is not there. In fact, in a 2010 study from the Skåne University Hospital in Sweden, Wickenberg, Ingemasson and Hlebowicz were able to show that curcumin worsens the insulin sensitivity of fourteen healthy subjects.
  
  Being first and foremost and anti-inflammatory agent, it is at imho not surprising that curcumin is not the ideal insulin sensitizer. In view of the fact that the obese and inflamed may need a little help to get their baseline inflammation back in check, before any "anti-diabesity" agent may even start working curcumin does however still qualify as a "C" as in "take in C-ombination" with other agents, but only if you're actually dealing with inflammatory problems (e.g. high CRP-1 value in serum; type 1 diabetes and problems with heme oxygenation, cf. Aziz. 2013). After all, the emerging role of reactive oxygen specimen in muscule- and thus tissue- and anti-obesity-specific glucose uptake clearly suggest that the suffocation of all inflammatory signals is not going to help, but hinder glucose uptake (Merry. 2012).
• Licorice (glycyrrhizin) [D] - While it has a bad rep as a "cortisol increasing" agent that puts you at risk of developing high blood pressure glycyrrhizin does actually have the ability to reverse diet-induced insulin resistance and get the GLUT-4 glucose transporters back out on the cell surfaces. Sil et al., for example report that they observed corresponding improvements of insulin sensitivity in a rodent model of high frutcose feeding (which is actually not much different from the average victim of the American diet; dosage was 50mg/kg or 600-750mg/day for a human being; Sil. 2013)

  

  Table 1: Analysis and comparison of active ingredients in Radix Glycyrrhizae (licorice) from Europe and China by capillary-zone electrophoresis (Rauchensteiner. 2005)

  As you can see in the table above the glycyrrhizin content of different forms of licorice is somewhere between 2-3mg/100mg (Rauchensteiner. 2005). In other words, to hit the 600-750mg you will necessarily need an extract - unless you want to consume kilograms of licorice.
  
  

  

  What about testosterone? A larger scale 4-week trial with 100g/day of licorice containing 0.15% glycyrrhizic acid could not find any significant changes in sex steroid hormones (Sigurjonsdottir. 2005)

  Whether that's a smart thing to do is however questionable, as licorice does not just have the potential to increase blood pressure, but is also a relatively unpredictable agent. Most of the glycyrrhizin will never even make it through the gut and into your blood, but rather be converted to other metabolites by your gut microbiome. Injections on the other hand appear to be possible, but the example of a 72-year old subject of a case report from the year 2000 goes to show you that in some cases the anti-diabetic effects may be a tad bit to potent. The subject did after all end up being profoundly hypoglycemic after the injection of 80mg of glycyrrhizin (Motoo. 2000).
  
  Despite potential anti-diabetic effects (read more) and the potent anti-obesity effects (3g of licorice per day = 2% body fat reduction in normal weight volunteers w/out dietin → learn more) you have read about here at the SuppVersity licorice does therefore get a "D" as in "D-on't take", because it seems as if the margin between 'enough to elicit beneficial effects' and 'so much that you are risking side effects' is pretty narrow.

• 

  Melatonin has also been shown to have beneficial effects on glucose uptake and glycogen synthesis after exercise and scientists speculate that it could play a major (facilitative) role in skeletal muscle adaptation to exercise (learn more)

  Melatonin [C]- I know, I know, it's a "dangerous hormone" ... well, nobody will propose that, when we talk about prescribing verifiably more dangerous oral contraception to women. I wonder how that is!? After all, this "dangerous hormone" could, mitigate the negative side effects many of the oral contraceptive appear to exert on the glucose metabolism of young, previously healthy women (for an in-depth discussion see Lopez. 2012). Ah, I am digressing, once again. So let's get back to melatonin.
  
  Assuming you follow all the recommendations from installment 1 of this series you should not be in dire need of melatonin supplementation. Sometimes, however, life comes in the way - for me that happened in the course of the last weeks. Oftentimes it's not even necessarily the "bad things" in life that keep you from getting enough sleep and producing a truckload of endogenous melatonin. It is in these situation, where some supplemental help in pill- or capsule-form may in fact come extraordinarily handy as an acute treatment that will work by its beneficial effects on skeletal muscle glucose uptake (Ha. 2006), leptin expression in response to insulin (Alonso-Vale. 2005) and 24h glucose homeostasis (la Fleur. 2001)
  
  In view of its many-fold effects on the mammalian metabolism and the age-related decline in melatonin production, it is actually not surprising that the provision of melatonin to aging rodents (0.4μg/ml in drinking water) was able to restore plasma insulin and leptin levels to youthful levels and continued treatment until old age maintained suppression of visceral (retroperitoneal + epididymal) fat levels without any effects on plasma corticosterone and total thyroxine (T4),  testosterone, insulin-like growth factor I (IGF-I) and total triiodothyrone (T3) compared to placeo (Rasmussen. 2002)
  
  That being said, for young(er) individuals, it may be sufficient to restore a normal circadian rhythm by strategically supplementing at the right times. In conjunction with a consequent "lights out strategy" (learn more), this should get you back on track and your insulin resistance up. Melatonin is thus a classic "C" as in "C-an be used by everyone"; a "C" that does however need some basic information about when you want to take the 1-10mg of melatonin to derive the greatest benefits (learn more about phase shifting your circadian rhythm) .
• Silymarin (Milk thistle) - Not exactly one of the agents you would expect on a list like this, but contrary to many better known anti-diabetic agents milk thistle can - just like cinnnamon, by the way - inhibit the accumulation of human islet amyloid polypeptide in the pancreas and the subsequent development of the end stages of diabetes (=the inability to produce insulin). In a 2006 study from Iran the provision of milk thistle to type II diabetics (200mg silimarin, 3x daily) lead to significant reduction in acute (blood glucose) and long-term measures of (HbA1c) of glucose management, as well as improvements in insulin levels (see figure below).

  

  Changes in fasting blood sugar (FBS), long-term marker of FBS (HbA1c) and insulin levels in randomized controlled trial w/ 51 type II diabetics; data expressed relative to median values across all groups (Huseini. 2006)

  In view of the results from the randomized controlled human study depicted in the figure above and based on the fact that silybin / silymarin / milk thistle helps controlling NAFLD, of which you learned earlier this week that it may as well be the cause not the consequence of insulin resistance (learn more). Milk thistle deserves a "B" as in "B-etter than many more specific agents". Dosages range from 500-1,500mg per day and you should make sure you get a standardized product and not an extract with non-disclosed amounts of active ingredients in it.

I know there are more agents, but I do also know that I cannot address each and every herb that may have the potential to reduce your blood glucose levels by 1pt. So unless you want me to make the last five picks, take your chance and let me know which agents you are still missing in the comments.

References:

• 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.
• Alonso-Vale MI, Andreotti S, Peres SB, Anhê GF, das Neves Borges-Silva C, Neto JC, Lima FB. Melatonin enhances leptin expression by rat adipocytes in the presence of insulin. Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E805-12.
• Aziz MT, El Ibrashy IN, Mikhailidis DP, Rezq AM, Wassef MA, Fouad HH, Ahmed HH, Sabry DA, Shawky HM, Hussein RE. Signaling mechanisms of a water soluble curcumin derivative in experimental type 1 diabetes with cardiomyopathy. Diabetol Metab Syndr. 2013 Mar 12;5(1):13.
• Fotland TØ, Paulsen JE, Sanner T, Alexander J, Husøy T. Risk assessment of coumarin using the bench mark dose (BMD) approach: children in Norway which regularly eat oatmeal porridge with cinnamon may exceed the TDI for coumarin with several folds. Food Chem Toxicol. 2012 Mar;50(3-4):903-12. 
• Ha E, Yim SV, Chung JH, Yoon KS, Kang I, Cho YH, Baik HH. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res. 2006 Aug;41(1):67-72.
• Hlebowicz J, Darwiche G, Björgell O, Almér 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. 
• Huseini HF, Larijani B, Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M. The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Phytother Res. 2006 Dec;20(12):1036-9.
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