Vitamin A Educates T-Cells, Joins Forces With Vitamin D Against Liver Cancer. Milk Better Than Sugary Electrolyte Solutions for Rehydration? Helicobactor Pylori: Probiotics from Breast Milk & Feces Better Than Amoxicillin!

Lactobacilli are hip, vitamin A is not - at the SuppVersity you still get news on both

1kg! That's the amount of weight you could probably lose if you rid yourself of all the microbes in your gut - from the weight of the bacteria alone, of course. Whether this would be a good idea or not, is however very questionable. On the one hand, we do have the still not fully understood studies on obesity-resistant germ free mice and an accumulating amount of evidence that having the "wrong" bacteria in the gut is at least associated with an increased obesity risk (Blaut. 2012). On the other hand, however, we are seeing new studies on the various benefits of having the "right" gut microbiome being published on an almost daily basis. So what?

Before we take a closer look at a definite benefit of having the "right" gut bacteria, though, let's start out with another likewise gut-related news item on the role of retinoic acid in T-cell education. In a way it's funny, it starts right where the bacteria reside, could have immune-modulatory effects that are way more pronounced and far reaching than probiotics and is still hardly discussed.

Vitamin A is of critical importance to (intestinal) T-cell education

If you have ever asked yourself how the immune cells in your body know what they are supposed to do, Catharine Ross' latest paper that was published in the American Journal of Clinical Nutrition and is based on a short talk the researcher from the Department of Nutritional Sciences at the Pennsylvania State University held at a conference earlier this year may provide at least some additional insides into the role a still way underrated molecule plays in this "T cell education" (Ross. 2012): Vitamin A!

Figure 1: Model of T cell differentiation, from uncommitted naive T cells into different T cell subsets that produce different cytokines and thus promote different functional activities (adapted from Ross. 2012)

As you can see in figure 1, retinoic acid does not simply promote the differentiation of regulatory T cells, which help to suppress inflammatory reactions, it also plays a significant role in normal mucosal immunity (in the gut, the airways and elsewhere) by modulating T cell activation and regulating cell trafficking. Moreover, vitamin A promotes antibody responses to T cell–dependent antigens. Needless to say that

"[...] in a state of vitamin A deficiency, inflammatory T cell reactions may be inadequately opposed and therefore become dominant [...] Although data from human studies are still needed, the framework now developed from studies in mice and rat models suggests that adequate vitamin A status, [...] is  important for maintaining a proper balance of well-regulated T cell functions and for preventing excessive or prolonged inflammatory reactions." (Ross. 2012).

Discovery a beta carotene derived vitamin A receptor blocker is only one of a couple of intriguing findings wrt to vitamin A.

One thing that sticks out from the complex interactions (see figure 1), really is the way by which the interaction of vitamin A with the T-cells in the gut crucially determine the efficiency of the 'fist line defenses' and their downstream effects on the whole organism. It is by no means co-incidental that diarrhea is rampant in areas of the "third world", where a large amount of the population is vitamin A deficient (Beaton. 1994). And in fact studies have shown consitently that

"RA is essential for 'imprinting' gut-homing specificity on T cells activated by intestinal DCs [dendritic cells] and suggested that MLN DCs are a source of RA that drives T cell differentiation toward the gut-homing phenotype" (Ross. 2012)

Moreover, oral tolerance to foreign antigens and thus an allergy free live requires a form of immune suppression, which can be proffered or hampered by sufficient and insufficient vitamin A intakes. In that, the exact effects of vitamin A will depend on the cytokine milieu the T-cells are exposed to. Examples are...

• an exaggerated IL-17 response with vitamin A deficiency, on the one hand, and
  
• an increase of the inflammatory response due to high vitamin A in an IL-15 environment 

Based on these observations, Ross rightly points out that "when RA is used for therapeutic purposes, it should be used cautiously in subjects with various inflammatory bowel conditions and sensitivities to dietary antigens." (Ross. 2012) People with gluten intolerance, celiac and other allergic reactions, for example would probably be better off avoiding the consumption of any form of supplemental vitamin A (on top of what's in their regular diet). Someone with high IL-17 and IL-6 levels as they have been observed in non-celiac inflammatory bowel disease, type 1 diabetes, multiple sclerosis and rheumatoid arthritis, on the other hand, could actually benefit from vitamin A's (especially ATRA) presence during activation of CD4⁺ T cells, because it will - even in the presence of IL-6 - "favor the development of the a Treg lineage at the expense of T cells secreting IL-17" and could thus help reduce chronic inflammation and keep autoimmune reactions at bay (Schambach. 2007; also Ramgolam. 2010).

More news

• 

  Figure 2: Who cares about cell viability, the survival time (in days) matters

  Combination therapy with vitamin A and a vitamin D (not D3, but calcitriol) analog EB1089 kills liver cancer cells. And it does so more effectively than any of the two molecules alone. That's the actually unsurprising result of a study that has been conducted at the Beijing Army General Hospital in China. The researchers injected nude mice with molecules that made them develop hepatocellular cancer. Afterwards, the rodents received either 10 μmol/L retinoic acid (vitamin A), 10 nmol/L EB1089 or both as a combination treatment.
  
  Compared to vitamin A or the calcitriol analog alone, the combination treatmend resulted in a significanlty higher reduction of the viability of hepatocellular cancer cells. Based on TUNEL analysis, Zhang et al. did also establish that individual cancer cells had a higher apoptotic ratio in the combined drug group than in the groups for which the drugs were used separately. Most importantly, however, the tumor weight was decreased and the mice on the combination treatment lived significantly longer (see figure 2; Zhang. 2012)

• 

  In the same publication, Pritchett and Pritchett recommend 1.0-1.5ml / kg body weight per hour of chocolate milk as the optimal post-workout drink to be consumed in the 2 h after a workout.

  Skimmed milk, the ideal post-workout rehydration formula? According to L James' paper in Lamprecht's compendium Acute Topics in Sport Nutrition, milk is a way better choice then the standard sugar + electrolyte rehydration formulas. Interestingly this is not due to the minerals in the milk, or the sugar, but, as James argues, a direct consequence of the milk proteins, which help restore "fluid balance after exercise-induced dehydration to a greater extent than a carbohydrate-electrolyte sports drink." As James points out it will yet have to be elucidated, whether the simple addition of whey protein to a standard sugar + electrolyte formula would exert similar effects (James. 2013).
• Probiotics to kill Helicobacter Pylori? While not every bacteria stands a chance against the nasty gut bug H. Pylori, certain Lactobacillus spp. strains obviously do. At least, if the results of a recent in-vitro + in vivo rodent study by Pei-Shan Hsieh can be replicated in human studies.

  

  Figure 3: Urease activity in H. pylpori after co-incubation with the specific probiotic and resulting bacteriostatic ratio (100% = bacteria free; data adapted from Hsieh. 2012)

  Lactobacillus acidophilus TYCA08, L. acidophilus TYCA15, L. johnsonii MH-68, and L. salivarius subsp. salicinius AP-32 were the most effective strains the researchers from National Chung Hsing University in Taichung, Taiwan, analyzed. And believe it or not, the latter of these, i.e. L. johnsonii MH-68, and L. salivarius subsp. salicinius AP-32, both of which are  by the way found in feces, were even minimally more potent effective than Amoxicillin, a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections. L. acidophilus TYCA15, however, steals the show. This probiotic that occurs naturally in breast milk reduced the urease activity of H. Pylori by -97.1% (see figure 3).
  
  In the consecutive rodent study, Hseieh et al. did yet still use 10⁹ CFU/mL of either AP-32 alone, MH-68 alone, or an equal mix of cultures of the two strains and both, "either alone or as a mixture in powder form were effective in reducing H. pylori load in gastric mucosa and help in reducing gastric inflammation and in regulation of gastric acid production." (Hsieh. 2012)

Thats it for today and for this weekend. As mentioned yesterday, there was simply not enough time to do the necessary research for the follow up to the Athlete Triad Series, so that this will have to wait. So don't dig an even deeper whole in the mean time. Maybe you want to do some of the psychomotor tests mentioned in yesterday's news, and check whether you are already overtrained!? How steady are your hands, for example? And whatever the result may be, don't forget to enjoy the rest of the weekend!

References:

• Beaton GH, Martorell R, Aronson KA, Edmonston B. McCabe, G, Ross, AC, Harvey, B. Vitamin A supplementation and child morbidity and mortality in developing countries. Food Nutr Bull 1994;15(4): 282–9.
• Blaut M, Klaus S. Intestinal microbiota and obesity. Handb Exp Pharmacol. 2012;(209):251-73.
• Hsieh PS, Tsai YC, Chen YC, Teh SF, Ou CM, King VA. Eradication of Helicobacter pylori Infection by the Probiotic Strains Lactobacillus johnsonii MH-68 and L. salivarius ssp. salicinius AP-32. Helicobacter. 2012 Dec;17(6):466-77.
• James L. Milk Protein and the Restoration of Fluid Balance after Exercise. In Lamprecht M (ed): Acute Topics in Sport Nutrition. Med Sport Sci. Basel, Karger, 2013, vol 59, pp 120–126. 
• Pritchett K, Pritchett R. Chocolate Milk: A Post-Exercise Recovery Beverage for Endurance Sports. In Lamprecht M (ed): Acute Topics in Sport Nutrition. Med Sport Sci. Basel, Karger, 2013, vol 59, pp 127–134.
• Ramgolam VS, Markovic-Plese S. Interferon-beta inhibits Th17 cell differentiation in patients with multiple sclerosis. Endocr Metab Immune Disord Drug Targets. 2010 Jun;10(2):161-7.
• Ross AC. Vitamin A and retinoic acid in T cell-related immunity. Am J Clin Nutr. 2012 Oct 10.  
• Schambach F, Schupp M, Lazar MA, Reiner SL. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol. 2007 Sep;37(9):2396-9. 
• Zhang J, Zhang H, Zhang X, Yu Z. Synergistic effect of retinoic acid and vitamin D analog EB1089-induced apoptosis of hepatocellular cancer cells. Cytotechnology. 2012 Oct 16.

Anti-Vitamin A Effects of Beta Carotene, Leptin Resistance and Potential Implications for the Diabesity Epidemic

Image 1: Ever thought why your granny had to take her cod-liver oil, whenever there she suffered from an ailment as a child? Probably not due to the rancid omega-3 oils which were partly responsible for its awful taste. That its high vitamin A content may not just have helped her to ward off the colds and infections, but also to stay lean, is yet a potential "side-effect" of dietary retinol for clear-cut which evidence is emerging only recently.

Facebook followers of mine have probably seen my post on the beta carotene metabolites called β1-apocarotenoids - recently discovered naturally occurring vitamin A receptor antagonist (block the activity or "real" vitamin A = retinol) about two to three days ago (Eroglu. 2012). As a SuppVersity regular, you will also be aware that vitamin A in its active form is not simply a dangerous substance that is to be avoided at all costs. And though beta carotene has long lost its image as (yet another) super-vitamin, with  both direct supplementation and food-enrichment being scrutinized, the aforementioned results yield a couple of interesting hypothesis that may be worth investigating - if we also take into account the results of another recently published study that was conducted by researchers from the Department of Biophysical Chemistry at Kyoto Pharmaceutical University in Kyoto, Japan (Tsuchiya. 2012), you could even make an argument that the combined overconsumption of beta carotene (mostly from supplements and enriched convenience foods) and the conditioned avoidance of the high fat foods that contain 'real' vitamin A may in fact be another maybe non-negligible contributer to the current obesity epidemic.

2.5x more all-trans-retinoic acid in chow reverse diet induced weight gain

In their manuscript that has been published online in advance, Tsuchiya et al. followed up on the results of a previous trial, in which genetically modified mice with almost no functioning vitamin A receptors showed a profound decrease in hepatic insulin-like growth factor-1 production and profound hepatic steatosis (fatty liver) - a pathology the scientists ascribed to profound insulin resistance as a direct consequence of the lack of vitamin A signaling. In their latest study, that was financed with a national research grant, and is soon to be published in the international journal Hepatology (Tsuchiya. 2012), Tsuchiya et al. fed C57BL/6J mice, which had been pre-fattened on the same high-fat, high-fructose diet many of our fellow human beings are indulging these days, diets containing either standard amount of vitamin A or 50mg of all-trans-retinoic acid per kg of chow.

Figure 1: Body weight (left) and glucose and insulin management (right) in normal and diabetes and obesity prone mice receiving control diet, standard high fat high fructose diet (HFHFr) or HFHFr + 50mg all-trans-retinoic acid (ATRA); data in the right is expressed relative to non-supplemented control (data calculated based on Tsuchiya. 2012)

Not much to the researchers surprise, the administration of the high fructose high fat diet that contained 50mg/kg (normal chow has 20mg/kg), i.e. 2.5x more all-trans-retinoic acid, than the standard HFHFr chow, did not only stop the almost linear weight gain the animals had experienced in the course of the 16-week pre-fattening phase in normal mice (cf. figure 1, left), it did also have statistically significant beneficial effects on the blood glucose (diabetes prone) and insulin (obesity prone) levels of mice that are genetically predisposed to develop diabetes (KK-Aγ) and obesity (ob/ob), in a second experiment.

The all-trans-retinoic acid (ATRA) <> leptin connection

And although the aforementioned results are certainly impressive, this is not an essentially novel finding - what was yet observed for the fist time in this study, is the reversal of the diet-induced reduction of hepatic leptin receptor expression in the HFHFr group receiving additional all-trans-retinoic acid in their diets (cf. figure 2, left).

Figure 2: Effects of additional ATRA in diet on leptin receptor expression (left) and relative diet- and diet + supplementation induced changes in selected makers of non-alcoholic fatty liver disease (right; data adapted / calculated based on Tsuchiya. 2012)

The latter went hand in hand with a restoration of IGF-1 BP2 and ameliorative effects on the measured markers of non-alcoholic fatty-liver disease markers (liver weight, lipid content; cf. figure 2, right).

Vitamin(s) A - obesity and beyond

These still "incompletely understood" (Bonet. 2011) metabolic effects of 'real' vitamin A and its metabolites are yet only the tip of an iceberg of the largely ignored health effects of the first micronutrient in the vitamin alphabet. Other only partly related effects are

Table 1: Vitamin A functions, major roles in the immune system and effects of vitamin A deficiency in undernutrition and obesity (Th1, T-helper type 1 response; Th2, T-helper type 2 response; UCP, uncoupling protein; BAT, brown adipose tissue; directly adapted from Garcia. 2012)

• a coordinating / controlling effect of the enzyme that converts dietary vitamin A into the active form (ATRA) on lipid metabolism (Kiefer. 2012)
• a genetic blockade of adipocyte growth and thusly a direct inhibitory effect on die-induced obesity (Berry. 2012)
• a facilitative role in the maturation and replenishment of muscle progenitor cells  (Ryan. 2011)
• an ability to prime pluripotent stem cells to become myocytes (muscle cells; Le May. 2011)
• anti-cancer effects (Streb. 2011; Siddikuzzaman. 2011)
• the repair of damaged heart muscle (Kikuchi. 2011; Freire. 2011)
• protective effects on cardio-myocytes against damage due to hyperglycemia (Guleria. 2011)
• systemic anti-inflammatory and immune regulatory effects via inhibition of interferon-gamma, TNF-alpha, NF-kappa-beta, IL-12, and  promoting  "an anti-inflammatory environment and adequate Th1:Th2 ratios" (Garcia. 2012)
• more general metabolic functions and immune-specific+ obesity-specific deficiency effects are summarized in table 1 (Garcia. 2012)

If we use the study at hand as a guide and the respective human equivalent dose of the ATRA contained in the 5g of chow/day the rodents consumed, the anti-NAFLD + anti-obesity effects would require a daily vitamin A intake of ~833IU for a mouse and 1,930IU /kg body weight  for a human being, which is - I guess I don't have to tell you that - hilariously much and potentially hazardous.  

How much vitamin A and where do you get it from?

If we let ourselves be guided by the 2.5x amount of the standard dose (which was what the mice were actually fed), take the RDA as a reference for the latter and assume that the conversion of dietary vitamin A to all-trans-retinoic acid works properly, the corresponding human doses do actually seem pretty reasonable, with 11,250IU for men and 8,750IU for non-pregnant women and can in fact be achieved relatively easily by eating, e.g.

• 25g chicken or pig liver or 30g of beef liver
• 100g butter + 300g cream + 300g cheddar cheese
• 200g of bluefin tuna + 3 eggs + tbsp of cod liver oil

In many cases it should thus suffice to simply forget your fat- and organ-meat phobia, to satisfy your retinol requirements - after all, the foods listed above may have the highest vitamin A content, but are by no means the only valuable sources of vitamin A and reasonable amounts of its natural, plant-derived precursor beta carotene in a whole-foods diet.

Image 2: I don't know if you realize this, but all the good sources of vitamin D in this illustration also contain significant (measured in IU mostly way more) vitamin A.

Unresolved issues with vitamin D: There was a time, when people used vitamin A to counteract vitamin D toxicity. Hard to imagine in the days of D-phoria, where everybody is advised to supplement, when a recent paper on the common measurement methods for vitamin D concluded that "several studies demonstrated that current 25(OH)D measurement methods do not meet" the prerequisite of being "sufficiently accurate over time, location and laboratory procedures" (Tienpont. 2012). Recent research on the underlying physiological relation / antagonism of vitamin A and D is almost non-existent. The handful of rodent trials I am aware of that actually compared the effects of co-supplementation were conducted in the mid 20th century and yield no conclusive results as far as an 'optimal' A to D ratio would be concerned - mostly because they only elucidated how much vitamin A it would take to keep the rodents on vitamin D enriched diets alive for a few more days. A recently published study does yet suggest that the often heard recommendation to take 1,000IU of supplemental vitamin D3 per day does not effect vitamin A or leptin levels. Whether the -14% and -19% reductions in serum alpha- and gamma-tocopherol (vitamin E) levels that were observed in this trial (800IU D3 + 2g calcium) are physiologically significant would yet warrant further investigation (Chai. 2012). The same is true for higher doses of vitamin D3, specifically, when those are - as it is often suggested taken in conjunction with those few fatty meals that actually contain 'real' vitamin A.

Assuming that you avoid supplementing high doses of beta carotene (don't care about the various forms of carotenes in real food), as well as highly fortified convenience food (yeah, cereals belong to this category, as well, and may in fact be among the worst offenders) and do not fall for the idea that you need at least 10,000-20,000IU of supplemental vitamin D3 per day, simply because your skin is supposed to be capable of producing 10,000IU within less than 1h of sun exposure, you should get more then enough "raw material" for your body to produce ATRA from your diet.

Vitamin A (Retinol) & Glucose Management | Part VIII of the "There is More To Glucose Control Than Low Carb"- Series. Plus: Retinol's Effects on Pancreas, Liver, Muscle and Fat

Vitamin A is not exactly known for being an anti-diabetes vitamin. If anything people will associate it with skin health... and SuppVersity Readers probably with anti-cellulite treatments | learn more

In the previous installments of this series I have addressed many of the "usual suspects" everyone associates with non-carbohydrate dependent improvements in blood glucose management. In today's installment of this series I will now take a look at an important vitamin of which only few would expect that it is in any way involved in glucose management: Vitamin A - real, pre-formed retinoic acid, not beta-carotene.

In view of the misleading news about the "involvement" of retinol binding proteins in the etiology of the diabesity epidemic and the bullocks about the negative effects of vitamin A on vitamin D, the vast majority of health junkies all over the web will probably associate high vitamin A intakes with insulin resistance, not -sensitivity.

You can learn more about this topic at the SuppVersity

Proteins, Peptides & Blood Glucose

SFA, MUFA, PUFA & Blood Glucose

Vitamin D & Diabetes

Glucose Manager Calcium?

Flush & No-Flush Niacin & Diabesity

Vitamin C & Glucose Control

Against that background it's funny that both human type II diabetics, as well as one of the most commonly used rodent models of type II diabetes, the streptozotocin-induced diabetic rat, show an impaired metabolic availability of vitamin A (Basu. 1989; Tuitoek. 1996).

As the scientists from the University of Alberta point out, the increased hepatic and the decreased plasma and retina vitamin A levels clearly "suggest a defect in the transport of the vitamin from the liver" - a defect of which it's not unlikely that it is the cause of the previously mentioned increases in retinol binding protein 4 (RBP4) that are so characteristic of the average overweight type II diabetic (Cho. 2006). Whether this problem can be resolved by the provision of supplemental vitamin A is albeit highly controversial.

Vitamin A is involved in body fat control (Bonet. 2003)

Low vitamin A status favors increases in fat deposition: The important effects of vitamin A on the proliferation of pre-adipocytes and adipose tissue morphology in general are often overlooked. In 2003, Bonet et al. were yet able to show that low levels of vitamin A are not just associated with insulin resistance and type II diabetes, they will also favor the deposition of body fat, which would otherwise be blunted by the negative effects of retinol on the activity of the body fat storage initiator C/EBPb (Bonet. 2003).

Basu & Basualdo, for example, argue that "subnormal vitamin A status in poorly controlled diabetic subjects may not respond to vitamin A supplementation". Even worse, if the vitamin A is not released into circulation and transported to the target tissue, where it appears to be dearly needed, it may "increase [the] load in the liver", eventually "leading to hepatoxicity" (Basu. 1997); and the increased levels of CRP and blood lipids Farhangi et al. observed in obese women in response to the ingestion of albeit exorbitant amounts of vitamin A (25.000IU/day; Farhangi. 2013).

Table 1: Overview of correlation coefficients of vitamin A and weight, BMI, tricep skinfold thickness (TSF), subscapular skinfold thickness (SST), total, HDL and LDL cholesterol, as well as triglycerides (Viroonudomphol. 2003)

In view of the fact that Viroonudomphol et al. have observed a negative correlation between weight, BMI, skinfold thickness, LDL & total cholesterol, triglycerides and hip circumference, on the one hand, and the serum retinol levels of overweight and obese subjects it is in fact a pity that a simple 10,000IU vitamin A supplement could do more harm than good to overweight and obese individuals with a messed up vitamin A metabolism (Viroonudomphol. 2003).

There are other things vitamin A can day for the diabetic patient -- It can promote wound healing, for example (Seifter. 1981). It can (at least in rodent trials) reduce the expression of resistin (Felipe. 2004), which is associated with increased levels of "bad" oxidized LDL cholesterol and is in itself a biomarker for the risk of heart failure (Salam. 2013; Takeishi. 2013). When it's administered with zinc at a daily dose of 25,000IU retinol can the improve serum apoprotein A-I, apoprotein B and the apoprotein B/apoprotein A-I ratio in patients with type I diabetes (Shidfar. 2013) and may thus directly reduce their heart disease risk.

Whether the potential side effects will yet occur in subjects, in whom the elevated glucose levels are adequately controlled is yet questionable. The results a group of researchers from the Ankara University presented in 2002 article in the peer-reviewed scientific journal Cell Biochemistry and Function, for example, would suggest that the addition of supplemental vitamin A to the standard insulin therapy in type II diabetes will not just help to keep the exuberant glucose levels in check, it may also blunt the oxidative reactions in diabetic heart and may thus "provide more benefits than use of either agent alone in the treatment of the "general characteristics of diabetes and the maintenance of antioxidant defense of diabetic heart and thus in the reduction of peroxidative stress-induced cardiac injury" (Zobalı. 2002).

Figure 1: Vitamin A affects several key steps in glucose metabolism (highlighted by dark arrows Berdainer. 2001)

In the pancreas, vitamin A deficiency leads to defects in both glucagon and glucose-stimulated insulin secretion (Chertow. 1987 & 1994), of which the latter can be restored with retinol palmitate supplements.

As Berdainer et al. point out, "glucose-stimulated insulin secretion is a complex process that requires the metabolism of glucose and the mitochondrial production of ATP" (Berdanier. 2001) - a process, in which the rate limiting enzymes that are regulated by retinoic acid (see Figure 1).

The vitamin A metabolite all-trans-retinoic acid is a real "anti-metabolic syndrome"-agent (Bonet. 2012)

An increase in skeletal muscle fatty acid oxidation is another not "glucose"-related benefit of vitamin A supplementation. As of now this effect has only been confirmed in rodent studies, where the administration of the potent vitamin A metabolite all-trans-retinoic acid (ATRA) lead to a 3.5x increase in PPAR-delta expression and corresponding increases in skeletal muscle fatty acid oxidation (Amengual. 2008) and increases in fatty acid oxidation in the liver (Amengual. 2010).

In conjunction with its ability to "brown" white fat cells and thus turn fat stores into fat furnaces (Mercader. 2006), the increases in skeletal muscle fatty oxidation will obviously also have secondary anti-diabetic effects (warning: ATRA is significantly more toxic than vitamin A and liposomal delivery reduces, but does not abolish these effects; cf. Ozpolat. 2003).

Glucokinase, which is thought to act as a glucose sensor, regulating insulin secretion and liver glucose uptake, is one of the enzymes regulated by retinoic acid in both the beta cell and the liver. Against that background it's no wonder that the systemic vitamin A deficiency that's so characteristic of insulin resistant and diabetic individuals worsens the already impaired glucose control.

Figure 2: In the absence of adequate vitamin A levels mature (myocyte) and immature (myoblast) muscle cells won't react to insulin by an increase in GLUT-4 expression and corresponding glucose uptake (Sleeman. 1995)

In conjunction with a reduction of the retinoic acid induced up-regulation of insulin-stimulated glucose transport via GLUT 4 in muscle cells (see Figure 2), the loss (?) of vitamin A that occurs at the onset of type II diabetes (Lu. 2000) is thus part of the often-cited vicious cycle of diabesity.

In that, the negative association between vitamin A and non-alcoholic fatty liver disease José Botella-Carretero et al. observed in morbidly obese subjects just another component of the under-appreciated involvement of vitamin A in the etiology of diabetes (Botella-Carretero. 2010) - an involvement of which we yet don't know whether it's causally, corellative or both.

Just as an aside: Vitamin A will also increase the expression of the master anti-oxidant glutathione in muscle tissue and promote the survival skeletal muscle precursor cells (El Haddad. 2012). It is necessary to preserve protein (Esteban-Pretel. 2010). And protects the muscle from the catabolic effects of corticosteroid overload (Aubry. 2009). Not glucose related, but not bad either, right?

Bottom line: There is little doubt that low vitamin A levels will contribute to the development of insulin resistance - both directly, by its negative effect on the pancreatic insulin production, and its insulin-induced glucose uptake in skeletal muscle tissues, as well as indirectly by its pro-obesogenic effects, and reductions in fatty acid oxidation and brown adipose tissue activity.

What is questionable, though, is whether the provision of supplemental vitamin A will have any direct or indirect beneficial effects on glucose metabolism in the average lean vitamin A sufficient individual and/or vitamin A deficient (pre-)diabetics. Against that background I would recommend to keep an eye on an adequate dietary vitamin A intake from eggs, dairy, butter, meat, fish and the occasional serving of liver and / or supplemental retinyl palmitate (e.g. 10,000 IU; 2-3x per week).

References:

• Amengual, Jaume, et al. "Retinoic acid treatment enhances lipid oxidation and inhibits lipid biosynthesis capacities in the liver of mice." Cellular Physiology and Biochemistry 25.6 (2010): 657-666. 
• Aubry, Evelyne M., and Alex Odermatt. "Retinoic acid reduces glucocorticoid sensitivity in C2C12 myotubes by decreasing 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor activities." Endocrinology 150.6 (2009): 2700-2708.
• Basu, T. K., W. J. Tze, and J. Leichter. "Serum vitamin A and retinol-binding protein in patients with insulin-dependent diabetes mellitus." The American journal of clinical nutrition 50.2 (1989): 329-331.
• Basu, Tapan K., and Carlotta Basualdo. "Vitamin A homeostasis and diabetes mellitus." Nutrition 13.9 (1997): 804-806.
• Berdanier, Carolyn D., et al. "Role of vitamin A in mitochondrial gene expression." Diabetes research and clinical practice 54 (2001): S11-S27.
• Bonet, M. L., et al. "Vitamin A and the regulation of fat reserves." Cellular and Molecular Life Sciences CMLS 60.7 (2003): 1311-1321. 
• Bonet, M. Luisa, Joan Ribot, and Andreu Palou. "Lipid metabolism in mammalian tissues and its control by retinoic acid." Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1821.1 (2012): 177-189.
• Botella-Carretero, José I., et al. "Retinol and α-tocopherol in morbid obesity and nonalcoholic fatty liver disease." Obesity surgery 20.1 (2010): 69-76.
• Chertow, B. S., et al. "Effects of vitamin A deficiency and repletion on rat insulin secretion in vivo and in vitro from isolated islets." Journal of clinical Investigation 79.1 (1987): 163.
• Chertow, B. S., et al. "Effects of vitamin A deficiency and repletion on rat glucagon secretion." Pancreas 9.4 (1994): 475-484.
• Cho, Young Min, et al. "Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes." Diabetes care 29.11 (2006): 2457-2461. 
• El Haddad, Marina, et al. "Glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival." Journal of cell science 125.24 (2012): 6147-6156.
• Esteban-Pretel, Guillermo, et al. "Vitamin A deficiency increases protein catabolism and induces urea cycle enzymes in rats." The Journal of nutrition 140.4 (2010): 792-798.
• Farhangi, Mahdieh Abbasalizad, et al. "Vitamin A supplementation, serum lipids, liver enzymes and C-reactive protein concentrations in obese women of reproductive age." Annals of clinical biochemistry 50.1 (2013): 25-30.
• Felipe, Francisco, et al. "Modulation of resistin expression by retinoic acid and vitamin A status." Diabetes 53.4 (2004): 882-889. 
• Lu, Jing, et al. "The metabolic availability of vitamin A is decreased at the onset of diabetes in BB rats." The Journal of nutrition 130.8 (2000): 1958-1962.
• Mercader, Josep, et al. "Remodeling of white adipose tissue after retinoic acid administration in mice." Endocrinology 147.11 (2006): 5325-5332.
• Ozpolat, Bulent, et al. "Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers." J Pharm Pharm Sci 6.2 (2003): 292-301.
• Salam, Gazbar, et al. "Relationship between Oxidized-LDL and Resistin Levels in Obese Diabetic Subjects." (2013).
• Seifter, E., et al. "Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin A." Annals of surgery 194.1 (1981): 42. 
• Shidfar, Farzad, et al. "Effects of combination of zinc and vitamin A supplementation on serum fasting blood sugar, insulin, apoprotein B and apoprotein AI in patients with type I diabetes." International journal of food sciences and nutrition 61.2 (2010): 182-191.
• Sleeman, Mark W., et al. "Retinoic acid stimulates glucose transporter expression in L6 muscle cells." Molecular and cellular endocrinology 108.1 (1995): 161-167.
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