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.
• Metformin - 3x 300-500mg (not lipoic acid, this is why)
• 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.