Sunday, March 9, 2014

There is More To Glucose Control Than Carbohydrates (3/?): Non-Carbohydrate Nutrients And Their Effects On Blood Glucose Management ➲ Vitamin D - The Sunshine Vitamin

Is the vitamin D you produce at the beach you're visiting only rarely the secret to perfect glucose control?
In the past two weeks you've learned much about the unquestionably beneficial effects of protein on glucose metabolism and the ambigous, since "context depend" effects of various fatty acids. Today, in the third installment of this series, we are leaving the "macros" behind and turning our heads towards the micronutrients.

I have long thought about the micros I would include in today's installment, started out with vitamin D and realized: "Damn! 50% of my Sunday gone already." In other words, you will have to live with the fact that today's installment of this series is an homage to the hype.
You can learn more about this topic at the SuppVersity

Proteins, Peptides & Blood Glucose

SFA, MUFA, PUFA & Blood Glucose

Vitamin D & Diabetes

Read these ➲ while waiting

16 Weeks High Fat Diet

Fat to Blunt Insulin?
Vitamin D unquestionably is a top candidate for the "micronutrient with the most bullshit science published", and contrary to what the mainstream media articles would suggest, it's by no means the panacea as which it is depicted even in "scientific" reviews, of which I am pretty sure that 90% of them are solely written to get published - I mean, every editor wants a vitamin D article in his journal, right?

Before this whole article turns into a rant, I'd suggest we take a look at the facts: It's beyond doubt that there are clear-cut (epidemiological determined) correlations between low vitamin D levels, insulin resistance and type II diabetes (Need. 2005). As a SuppVersity Reader you do yet know better than some of the previously mentioned scientists who will - without the blink of an eye - make the transition from "There is a correlation between low vitamin D levels and insulin resistance in our data" to statement like these:
  • Vitamin D is an acute phase reactant - but what are the impli- cations? Firstly, this would imply that serum 25-hydroxy- vitamin D is an unreliable biomarker of vitamin D status after an acute inflammatory insult (for the obese, even a meal is an acute inflammatory result; Blackburn. 2006). Secondly, hypovitaminosis D may be the consequence rather than the widely purported cause of a myriad of chronic diseases (Gama. 2012).
    "Low vitamin D causes / triggers insulin resistance." -- An excellent example of someone confusing correlation and causation. What is often accepted as a scientific fact, is possible. In view of the fact that vitamin D has recently been shown to act as an acute phase reactant in inflammatory conditions, it is yet rather unlikely. In fact, it appears more likely that what we are seeing here is a correllative reduction of vitamin D, whenever someone - like a type II diabetic, for example - is chronically inflamed (Waldron. 2013)
  • "Vitamin D supplements can be used to ameliorate insulin sensitivity." -- In an assertion like this, the authors go even one step further. After making the unwarranted conclusions that vitamin D triggers the onset of insulin resistance, they assume that supplemental vitamin D (usually D3), of which the current evidence shows that it does not elevate the levels of 1,25-hydroxy vitamin D, i.e. calcitriol, the only form of vitamin D, of which we actually have some rodent data that it's exogenous administration produces the anti-diabetic + weight loss effects everyone appears to expect from "regular" D3. An immediate effect of calcitriol on glucose uptake does yet not appear to exist - at least not in healthy individuals (Fliser. 1997).
When you're looking at the previously cited study by Filser, you could rightly argue that it is unrealistic too expect an already "optimal" insulin sensitivity to improve... and you are right! Studies like the one by Fliser et al. can thus hardly serve as a yardstick to gauge the usefulness of vitamin D
Figure 1: If we compare the fat "loss effects" of vitamin D supplementation in the studies by Zitterman (2009) and Salehpour (2012) in Figure 1 (left), and invoke the results of the latest meta-analysis by Pathak, et al. (2014) in Figure 1 (right), it is hard to argue Pathak's conclusion that the divergent results from previous trials would suggest that "Vitamin D supplementation did not decrease measures of adiposity in the absence of caloric restriction" (Pathak. 2014).
The studies we have to look for are studies with subjects who have a compromised glucose metabolism or full-blown type II diabetes (note: we cannot look at studies in type I diabetes, because any benefits vitamin D would provide here are most likely related effects on the immune system). Studies like these, for example:
  • Inomata (1986) - 1-alpha (OH)D3 (active vitamin D) administration improves glucose tolerance in diabetic subjects
  • Nilas (1983) - No effect of vitamin D or its analogues on body weight or glucose management in post-menopausal women
  • Orwoll (1994) - No effect of calcitriol (active vitamin D) on glucose homeostasis in non-insulin-dependent diabetes mellitus
Figure 2: The latest meta-analysis says: No long-term improvement in blood glucose management w/ vitamin D supplements (George. 2012).
I could add one study after the other, but I know what you are thinking right now: Who cares about studies on vitamin D sufficient individuals?

You're right. If we don't make the totally irrational, yet not uncommon assumption that the initially mentioned correlation between low vitamin D and low insulin sensitivity would apply beyond deficiency levels. There is thus no reason to assume that supplementation would help anyone with normal vitamin D levels so that we have to focus on those individuals with an impaired insulin resistance who are actually vitamin D deficient.
"Our results suggest that hyperinsulinemia and/or insulin resistance are directly responsible for decrease of 25(OH)D levels in obesity." (Pergola. 2013) That's the logical conclusion from a closer analysis of the correlation between low vitamin D and insulin resistance that revealed that 25(OH)D levels are negatively associated with inflammatory parameters such as CRP and C3 and C4 levels, but not independently of BMI, body fat distribution, insulin levels, or insulin resistance.
Unfortunately (for the average vitamin D enthusiast), the situation is not entirely unambiguous in this population either. Even in studies on vitamin D deficient subjects, you will find quite impressive null results (impressive, because the D-levels increase significantly, but nothing happened), though. Tai et al., for example, found no improvements in insulin sensitivity in spite of the fact that the vitamin D supplement they had administered to their 33 vitamin D insufficient subjects (serum 25-hydroxyvitamin D concentration ≤50 nmol/L; 12 with impaired glucose tolerance) increased their 25OHD levels from 39.9 ± 1.5 (SEM) to 90.3 ± 4.3 nmol/L (Tai. 2008).

Rule of thumb: If anyone is actually likely to benefit, though, it's the overweight, inflamed (pre-)diabetic, for whom George et al. calculated a small effect on fasting glucose (−0.32 mmol/l) and a small improvement in insulin resistance (standard mean difference −0.25), but no improvements in long-term glucose management (HbA1c, see Figure 2) in response to vitamin D supplementation (George. 2012).

Figure 3: No improvement in insulin sensitivity in people w/ normal, min. effects in those with compromised insulin sensitivity w/ vitamin D supplements, says meta-analysis (George. 2012).
As with every "rule" there are exceptions to this one, as well. Nagpal et al. for example observed that the provision of three doses of vitamin D3 (120 000 IU each; supplemented group) improved the postprandial glucose excursions of the abdominally obese, but allegedly "apparently healthy" subjects (Nagpal. 2009). The results of a paper by Belenchia from 2013, on the other hand, violate the "no improvements in long-term glucose management rule". The scientists from the University of Missouri School of Medicine did after all find that adding 4,000IU/day of vitamin D to a standard life-style intervention lead to significant improvements in blood glucose management in their adolescent subjects with low baseline vitamin D levels (Belenchia. 2013).

For someone with an established (=tested) vitamin D deficiency, supplementation does therefore appear to be clearly indicated. As long as you stick to reasonable amounts (see Recommendation I, below) there is little to no risk of doing any harm (although I know from anecdotes that some people react with fatigue to relatively slow quantities of vitamin D).

Recommendation #1: Unless you are a sun-worshipper living in a country near the equator, you want to make sure to get ~1,000IU, if you are normal-weight and light-skinned, or 2,000IU, if you are overweight and/or dark-skinned (Gallagher. 2013; Ng. 2014), vitamin D per day from food or supplements.

Figure 4: Increase in vitamin D levels in response to supplementation w/ different amounts of vitamin D3 in caucasian (!) women according to BMI categories (Gallagher. 2013)
In that, it does not matter, if you get to those 7,000-10,000 IU per week by taking a single cap of a high dose vitamin D supplement once a week, or adding enough cod liver (oil), fatty fish, fortified dairy, oysters, or eggs (remember there is active vitamin D in eggs | learn more) to your diet. What is important, though is recommendation #2, which is:

Recommendation #2: Get a 25OHD test done today and start supplementing with 20,000IU per week for 3 months, if the test comes back low - that's the dosage that has brought the low D3 levels of 30 club-level athletes in Close et al. (2013) back to the official and certainly not unreasonable target of >50 nmol/L.

Needless to say that recommendation #3 would be to retest either after 3 months, in case you had low baseline levels and want to make sure your supplementation regimen brought them back up, or after 6 months, as part of a bi-annual checkup of all relevant health parameters, including the standard blood panel and HPTA function.
Why shall I make sure my level is normal, if low vitamin D does not cause insulin resistance? That's a warranted question and I have an comprehensive answer. If vitamin D acts as an acute phase reactant this may mean that it protects your body from further pro-inflam- matory assaults - it's making a martyr of itself, so to say. If you have almost no "vitamin D martys" to sacrifice, this will accelerate your progress from insulin resistance to diabetes (cf. Forouhi. 2008)
Bottom line: Things are, I am sorry to say that yet again, complicated. My personal assessment of the contemporarily available evidence is that the reduced vitamin D levels are correlatively and not causally linked to insulin resistance. We've known forever that chronic inflammation is a if not the most common cause of insulin resistance (Johnson. 2013) and vitamin D, whether it is an acute phase reactant or the panaceum everyone is trying to tell you it was, is reduced under inflammatory conditions.

In view of the fact that the provision of additional vitamin D and restoration of "normal" (whatever that may be) levels of 25OHD3 in serum does not necessarily entail an improvement in insulin sensitivity, we must therefore assume that both, low vitamin D and insulin resistance have the same underlying cause and are thus complementary. Dies this mean, you should ignore low vitamin D levels? Probably not, but it certainly means that you better take a look at the way you eat, sleep and train if you are insulin resistant - irrespective of your vitamin D levels, by the way.
  • Belenchia, Anthony M., et al. "Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial." The American journal of clinical nutrition 97.4 (2013): 774-781.
  • Blackburn, Patricia, et al. "Postprandial variations of plasma inflammatory markers in abdominally obese men." Obesity 14.10 (2006): 1747-1754. 
  • Close, Graeme L., et al. "The effects of vitamin D3 supplementation on serum total 25 [OH] D concentration and physical performance: a randomised dose–response study." British journal of sports medicine 47.11 (2013): 692-696.
  • Fliser, D., et al. "No effect of calcitriol on insulin‐mediated glucose uptake in healthy subjects." European journal of clinical investigation 27.7 (1997): 629-633.  
  • Forouhi, Nita G., et al. "Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance the medical research council ely prospective study 1990–2000." Diabetes 57.10 (2008): 2619-2625.
  • Gama, Rousseau, et al. "Hypovitaminosis D and disease: consequence rather than cause." BMJ 345 (2012): e5706-e5706.
  • Gallagher, J. Christopher, Vinod Yalamanchili, and Lynette M. Smith. "The effect of vitamin D supplementation on serum 25OHD in thin and obese women." The Journal of steroid biochemistry and molecular biology 136 (2013): 195-200. 
  • George, P. S., E. R. Pearson, and M. D. Witham. "Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta‐analysis." Diabetic Medicine 29.8 (2012): e142-e150. 
  • Johnson, Andrew MF, and Jerrold M. Olefsky. "The origins and drivers of insulin resistance." Cell 152.4 (2013): 673-684.
  • Inomata, S., et al. "Effect of 1 alpha (OH)-vitamin D3 on insulin secretion in diabetes mellitus." Bone and mineral 1.3 (1986): 187-192. 
  • Nagpal, J., J. N. Pande, and A. Bhartia. "A double‐blind, randomized, placebo‐controlled trial of the short‐term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle‐aged, centrally obese men." Diabetic Medicine 26.1 (2009): 19-27.
  • Need, Allan G., et al. "Relationship between fasting serum glucose, age, body mass index and serum 25 hydroxyvitamin D in postmenopausal women." Clinical endocrinology 62.6 (2005): 738-741.
  • Ng, Kimmie, et al. "Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial." The American journal of clinical nutrition (2014): ajcn-067777.
  • Nilas, L., and C. Christiansen. "Treatment with vitamin D or its analogues does not change body weight or blood glucose level in postmenopausal women." International journal of obesity 8.5 (1983): 407-411.
  • Orwoll, Eric, Matthew Riddle, and Melvin Prince. "Effects of vitamin D on insulin and glucagon secretion in non-insulin-dependent diabetes mellitus." The American journal of clinical nutrition 59.5 (1994): 1083-1087.
  • Pathak, K., et al. "Vitamin D supplementation and body weight status: a systematic review and meta‐analysis of randomized controlled trials." Obesity Reviews (2014).
  • Salehpour, Amin, et al. "A 12-week double-blind randomized clinical trial of vitamin D3 supplementation on body fat mass in healthy overweight and obese women." Nutr J 11.1 (2012): 78.
  • Tai, Kamilia, et al. "Glucose tolerance and vitamin D: effects of treating vitamin D deficiency." Nutrition 24.10 (2008): 950-956.
  • Waldron, Jenna Louise, et al. "Vitamin D: a negative acute phase reactant." Journal of clinical pathology 66.7 (2013): 620-622.
  • Zittermann, Armin, et al. "Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers." The American journal of clinical nutrition 89.5 (2009): 1321-1327.