What's the Optimal Dose of Vitamin D3 for Lean, Normal-, Overweight & Obese Women With Established Vitamin D Deficiency to Get 25OHD Back into the Normal Range?

Both ladies are D-ficient, but will probably need profoundly different amounts of D3 to get their 25OHD back in range.

Actually, I guess, I don't really have to tell you that there is not going to be guest post by Adelfo Cerame, today. Adelfo is busy with the last weeks of school, but will be back as soon as he has passed all the tests. And while I am not sure, whether or not you would call the latest on vitamin D supplementation an adequate replacement for a contest prep update from "your's truly", I suppose that it's better than nothing to bridge the time that still remains until the SuppVersity  Science Round-Up on the Super Human Radio Network is going to air (the show starts at 12PM, EST; the Science-Round-Up airs in the 2nd hour and will thus begin at 1PM, EST; click here to listen live or wait for the podcast // update: now available).

I am honestly not yet sure what exactly we will cover today, but among the things I am still thinking about how we can squeeze them into a 1h show are...

• methylxanthines caffeine, theobromine and theophylline can bind to human DNA - what does that tell us about the purported health benefits of caffeine & co?
• caffeine prevents memory impairment - in this case in a model of sporadic Alzheimer's disease
• anti-Alzheimer's effect of CLA - plus a list of supplements that have been implicated in the prevention of Alzheimer's and other amyloid diseases such as Parkinson's, Cerebellar Ataxis, Amyotrophic lateral sclerosis and (hardly recognized as an amyloid disease) diabetes type II
• the effect of body weight on the benefits of circuit training in older women - turns out that those who need it the most, namely the obese, also see the greatest benefits
• Gum arabicum to ward off holiday weight gain - that this could actually work is at least what a recent human study would suggest
• more on vitamin E, resveratrol, soldiers don't get hurt in battle, but by geranium (DMAA), ...

I think there should be something for everyone of you. Plus: If everything works out, this is going to be the first show to air live via Skype, so no nagging land line echoes and noise any more.

Let's get to the D-news, now

The general consensus among the vitamin D advocates currently is that 2,000 IU of vitamin D3/day is the minimum you need to bring low levels of 25OHD back into the normal range. A soon-to-be-published study by Gallagher, Yalamanchili and Smith that's available ahead of print on the website of the Journal of Steroid Biochemistry and Molecular Biology does yet contradict this notion - at least for women with a body mass <25kg/m² even the meager RDA of 400IU would be enough (Gallagher. 2013). That said the concise paper actually describes the results of two, not just one experiment, with

• study 1 (ViDOS) being a one-year randomized, double-blind placebo controlled study (ViDOS – Vitamin D supplementation in Older Subjects) of increasing doses of vitamin D3 (400,  800, 1600, 2400, 3200, 4000 or 4800 IU/day vitamin D3 vs. placebo + calcium supplements to maintain calcium intake between 1,200-1,400mg/day) in 163 Caucasians, age 57–90 years; all vitamin D insufficienty, i.e. serum 25OHD ≤ 20 ng/ml (50 nmol/l), and 
• study 2 (STOP IT) being a 3-year intervention study of calcitriol 0.25 mcg (the active form of vitamin D) twice daily, conjugated estrogens 0.625 mg  daily, a combination of both and placebo in 488 elderly women, age 65–77 years

Body composition indices for the studies at hand (i.e. percentages of total and regional fat and fat-free mass) were measured by dual energy X-ray absorptiometry (DEXA Hologic Delphi) at baseline and after 12 months.

Figure 1: Mean total body weight, total body lean mass, total body fat mass and serum 25OHD in different BMI subgroups of study 2 (STOPIT); right, corresponding calculated ratios (based on Gallagher. 2013).

Even the baseline data in figure 1 does actually yield some insights into the relation of BMI, adiposity and 25OHD levels. While the data on the left already shows that the fat mass increases almost linearly across the BMI levels, while the lean mass remains relatively stable (with the highest value in the overweight group, though), the ratios I calculated and plotted on the right-hand side of figure 1 make it even more obvious clear: The lean / fat mass ratio scales with the BMI. With identical levels in the normal- and overweight individuals and significant increases and declines in the lightest and heaviest study participants. Moreover, the 25OHD vitamin D to fat mass ratio drops most significantly between the low BMI and the upper normal zone, where I suppose even most of the "healthy" individuals will be hovering around these days.

Being lean is a positive predictor of increases in 25OHD with supplementation

That this latent "chubbiness" of the average Westerner may be of particular significance in view of the negative / non-significant outcomes in many of the vitamin D supplementation trials, becomes self-evident, when you take a closer look at the data in figure 2, however you will have to realize that my plot which comprises above all the highly relevant relative changes (middle, marked in red) tells a different story than the original plot from the study showing only the absolute changes (left, but in form of a line graph).

Absolute, relative (compared to baseline) changes and total 25OHD levels (ng/ml) after supplementation with low, medium and high amounts of vitamin D3 in lean, normal, overweight and obese women (based on Gallagher. 2013)

Accordingly, the conclusion of the abstract, which says that "the response to vitamin D is dependent on body weight" and that "women with BMI <25 kg/m² develop much higher levels of serum 25OHD after vitamin D supplementation compared to those with BMI of >25 kg/m²" (Gallagher. 2013) may be correct, but is somewhat misleading as it is open to be interpreted as 'lean women respond most favorably to vitamin D supplementation' - an interpretation that is not really sustainable in view of the relative changes I calculated for figure 2  (middle), yet by no means as incredible as the abstract of another vitamin D study, I dessicated back in September (see "Stronger & Leaner or Fatter & Less Muscular W/ 4,000IU Vitamin D3 - What if Abstract and Data Tell Different Stories?")

Bottom line: The data from this most recent investigation into the differential response of lean, normal, overweight and obese women to vitamin D3 supplementation shows that the absolute increases appear on BMI and that...

• 

  Always take vitamin D with fatty foods! (see "A Fat D-Ficiency")

  low dose supplementation (400 or 800IU/day) is probably only sufficient to rise and maintain adequate vitamin D levels in lean women,
• medium dose supplementation (1,400 or 2,400IU/day) yields the most favorable outcomes in total 25OHD levels and 
• high dose supplementation (3,200, 4,000 or 4,800IU/day) does not yield additional benefits in either the the normal-, overweight and obese subgroup and only marginally higher levels in the lean women.

Overall the study at hand would thus support the notion that a daily vitamin D supplement containing ~2,000IU is the best way to get deficient levels back up, esp. for lean women it should be no problem to cut back to 2x the RDA, i.e. 800IU after normal vitamin D levels are achieved. For the rest, future studies will have to show if low dose supplementation is enough.

These longissimus dorsi slices of mice on a normal and a vitamin D3 supplemented diet show that supplemental vitamin D3 can be used as a fat synthesizer and meat tenderizer in "meat-producing animals". (learn more)

The often-heard hypothesis that the decreased response to vitamin D supplementation in the obese would be a result of the preferential storage of vitamin D in the adipose tissue was not supported by data of the Ghallagher study "there is no evidence from the dose response curves that in obesity serum 25OHD is being deposited in fat" (Gallagher. 2013). In view of the fact that contrary to total vitamin D, which is in fact preferentially stored in adipose tissue (78%) over lean muscle (14%), 25OHD stores are distributed much more evenly with 33% being stored in body fat and 20% in muscle tissue in omnivores like humans and swine (the data is in fact based on a study in pigs; cf. Jakobsen. 2007).

Lastly, a beneficial effect of increase / normalized vitamin D levels on lean or fat mass was (once again) not observed in any of the studies; and that despite the fact that "body fat was an independent predictor of serum PTH", which decreased in response to calcitriol supplementation in study 2 (which is actually more of an adjunct for correlative analysis and as a data source to compare the results of study 1 to). In other words, normalizing your vitamin D levels without taking appropriate measures to counter what's probably behind both, the nasty body fat and the low vitamin D level is not going to make you lean or musclar - at least as of now, it rather appears as if this was yet another instance, where we are - if anything - treating isolated symptoms instead of the root causes of the obesity epidemic.

References

• Gallagher JC, Yalamanchili V, Smith LM. The Effect Of Vitamin D Supplementation On Serum 25OHD In Thin And Obese Women. J Steroid Biochem Mol Biol. 2013 Dec 11.
• Jakobsen H, Maribo A, Bysted HM, Sommer OH. 25-Hydroxyvitamin D3 affects vitamin D status similar to vitamin D3 in pigs – but the meat produced has a lower content of vitamin D. British Journal of Nutrition. 2007; 98 908–913.
• Shephard RJ. Limits to the measurement of habitual physical activity by questionnaires. Br J Sports Med. 2003 Jun;37(3):197-206; discussion 206.

Serious Lifting Increases SHBG, Muscle & Total Mass, While Decreasing Total and Trunk Fat in Overweight Young Men. Plus: Why an Increase in SHBG is Nothing to Be Afraid Of

Warning: Used correctly, this dumbbell will increase your BMI, your glucose sensitivity and - at least if you still got some fat to shed - your SHBG! And what's the result? Metabolic health, strength and a significantly improved body composition!

If you read the headline of today's news closely and did not freak out due to bro-scientific indoctrination and the firmly held believe that "SHGB is bad for you, bro. I'll bind your testosterone, bro!" you will probably have noticed that the 12-week resistance training regimen 36 of the 49 participants (BMI 31.4 kg/m² age 22 years) of a recently published study by Roberts et al. underwent would have to be considered an epic fail, if we went for the mainstream assessment of workout / dietary success - the infamous body mass index. If the add the broscientific notion that you best reduce your SHBG to zero (or into the negative range, if you find a way to do so), squats, deadlifts, lunges, rows, side raises, overhead presses, triceps extensions and biceps curls appear to be the worst thing you can do for your health and physique!

Yep, there is no debating: The overweight guys gained even more weight...

... and this change in BMI was statistically significant (p = 0.03). In kilograms that means the average 21.5 year old member of the resistance training group gained 1.8kg body weight, but at the same time he lost 1kg of body fat, reduced his waist circumference by 0.55cm and gained a whopping 2.7kg of lean body mass (p < 0.0001; see figure 1, right).

Figure 1: Changes in body composition and strength in the course of the 12-week study period (Roberts. 2013)

As the data in figure 1 (left) goes to show, the resistance training protocol, which comprised three pases with a 2-week introductory period of 12-15 reps to failure, a second hypertrophy phase from week 3-7, in the course of which they lifted in the 8-12 rep range and a subsequent heavier lifting phase with 6-8 reps during phase 3 (weeks 8-12).

"As participants adapted to the training overload, the weight was increased to maintain the prescribed training intensity. All participants trained on 3 non-consecutive days/week, rotating between two daily workout regimens. Workout I consisted of dumbbell (DB) squat, cable row, DB front lunge, DB row, barbell (BB) deadlift, DB triceps extension, and DB curl.Workout II was DB step-up, BB chest press, machine squat, DB overhead press, DB incline chest press, DB side raise, DB reverse fly, and abdominal crunches. A certified personal trainer led all training sessions with a maximum 3:1 participant to trainer ratio." (Roberts. 2013)

You see, real training yields real results. And while diets (in the study at hand "participants were instructed tomaintain their normal ad-libitum diet") are necessary to cut weight and lose fat in those who are already lean, healthy (not metabolically deranged) overweight individuals can achieve a whole lot by just lifting their behind off the couch and into the gym thrice a week.

Aesthetics are not all that counts

That said, in addition to the aesthetic improvements due to the changes in body composition, it should not be forgotten that despite the weight gain that would have discouraged many uneducated dieters, the resistance training only program yielded similar beneficial effects as far as the glucose management and insulin sensitivity of the participants is concerned.

Figure 2: Relative (% baseline) changes in response to oral glucose tolerance test (OGGT) and hormone levels after 12 weeks of resistance training (Roberts. 2013)

How and if this has any direct relation to the hormonal changes (figure 2, right) in general and the increase in SHBG, in particular, is as of now, not 100% certain.

"The function of SHBG has classically been ascribed to the binding of steroid hormones in circulation to regulate their bioavailability. Because SHBG is decreased with obesity, it was thought that SHBG may be a marker for obesity in relation to T2D risk. However, evidence suggests that SHBG independently affects glycemic control and predicts both  T2D and metabolic syndrome. In addition, it is known that insulin and glucose also have reciprocal action on SHBG to regulate SHBG production in the liver." (Roberts. 2013)

Despite the fact that the perception of SHBG as an inactive binding protein is changing as of late, the study at hand does not provide clear cut evidence that the improvements in insulin tolerance occur in response to the changes in SHBG. This result matches perfectly with human data by Daka et al. and a study Simó et al. In those two 2013 paper, the researchers state that type I diabetics (=low to no insulin) have very high, type II diabetics, on the other hand, very low SHBG levels (Daka. 2013), and that the inflammatory cytokine TNF-alpha and a hallmark feature of diabesity directly represses SHBG production, as well (Simó. 2013; check out the blue infobox below to get a "feeling" for further things that are related by one way or another to SHBG).

Increasing SHBG levels in the lower third of the normal range are nothing to worry about

SHBG does also figure (unsorted list; (+) = positive association meaning high SHBG high whatever, (-) = neg. association, meaning low SHBG high whatever) in ... Bone density (+) in male prostate cancer patients (Varsavsky. 2013) as well as US men in general (Trabert. 2013) || BMI, BP and HOMAR-IR (+) in postmenopausal women (Davis. 2013), in premenopausal women from the Japanese Saku cohort, the exact opposite was the case, i.e. high SHBG = low risk of type II diabetes (Gota. 2013) || breast cancer risk (-) based on data from the Nurses Health Study (Zhang. 2013) || prostate cancer (+ when abnormally high and testosterone low; García-Cruz. 2013) || weight loss after gastric bypass (+), obese women (Ernst. 2013) || peripheral artery disease (-) in older men and women (Maggio. 2013) || vascular dementia (-) in men (Xing . 2013)

In view of the results of previous studies which had a resistance training component, involved healthy, normalweight young (McCall. 1999), middle-aged (Cadore. 2008) or old individuals (Hakkinen. 2002) and had no effect on SHBG levels, it appears way more likely that increased insulin sensitivity in response to the resistance training lead to increases in SHBG and not vice-versa. This hypothesis would be supported by a rodentt study Roberts and his co-workers refer to in the conclusion of their paper:

"Selva et al. [Selva. 2007] elegantly demonstrated that elevated glucose (and fructose), rather than insulin might be the primary stimulus to lower SHBG. In this study, transgenic mice expressing different SHBG transgenes exposed to diets with elevated monosaccharides led to large decreases in SHBG." (Roberts. 2013)

This alone still does not suffice to shed more light on the SHBG <> diabesity connection, it should yet be enough to finally draw the curtain over the initially mentioned broscientific myth that SHBG was your enemy. As long as it's within the lower third of the normal range (which was the case in the study at hand) any further decrease is almost certainly going to have more negative than positive effects on your overall health - and if it impairs insulin sensitivity, your physique, as well (important note: both age and sex appear to modify the role of SHBG, for examples see in the infobox to the right)

Bottom line: Whether SHBG is an active modulator or passive indicator of efficient / inefficient glucose management has not been fully understood. It does yet appear to be more likely that changes in SHBG occur in response to changes in blood glucose. In any way, you certainly don't have to worry about the potential increase in SHBG in response to resistance training. Ah,... and in case you are wondering at least in obese postmenopausal women the same increases in SHBG occur in response to aerobic exercise, as well (Kim. 2013)

References:

• Cadore EL, Lhullier FL, Brentano MA, da Silva EM, Ambrosini MB, Spinelli R, Silva RF, Kruel LF. Hormonal responses to resistance exercise in long-term trained and untrained middle-aged men. J Strength Cond Res. 2008 Sep;22(5):1617-24.
• Daka B, Rosen T, Jansson PA, Råstam L, Larsson CA, U Lindblad. Inverse association between serum insulin and sex hormone-binding globulin in a population survey in Sweden Endocr Connect. 2013;1:129-133.
• Davis SR, Robinson PJ, Moufarege A, Bell RJ. The contribution of SHBG to the variation in HOMA-IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women. Clin Endocrinol (Oxf). 2013 Oct;77(4):541-7. 
• Ernst B, Wilms B, Thurnheer M, Schultes B. Reduced Circulating Androgen Levels After Gastric Bypass Surgery in Severely Obese Women. Obes Surg. 2013 Nov 29.
• García-Cruz E, Carrión Puig A, García-Larrosa A, Sallent A, Castañeda-Argáiz R, Piqueras M, Ribal MJ, Leibar-Tamayo A, Romero-Otero J, Alcaraz A. Higher sex hormone-binding globulin and lower bioavailable testosterone are related to prostate cancer detection on prostate biopsy. Scand J Urol. 2013 Nov 27.
• Goto A, Morita A, Goto M, Sasaki S, Miyachi M, Aiba N, Terauchi Y, Noda M, Watanabe S; the Saku Cohort Study Group. Associations of sex hormone-binding globulin and testosterone with diabetes among men and women (the Saku Diabetes study): a case control study. Cardiovasc Diabetol. 2013 Oct 16;11(1):130.
• Hakkinen K, Kraemer WJ, Pakarinen A, et al. Effects of heavy resistance/power training on maximal strength, muscle morphology, and hormonal response patterns in 60–75-year-old men and women. Can J Appl Physiol 2002;27:213–31.
• Kim JW, Kim DY. Effects of aerobic exercise training on serum sex hormone binding globulin, body fat index, and metabolic syndrome factors in obese postmenopausal women. Metab Syndr Relat Disord. 2013 Dec;10(6):452-7.
• Maggio M, Cattabiani C, Lauretani F, Artoni A, Bandinelli S, Schiavi G, Vignali A, Volpi R, Ceresini G, Lippi G, Aloe R, De Vita F, Giallauria F, McDermott MM, Ferrucci L, Ceda GP. The relationship between sex hormones, sex hormone binding globulin and peripheral artery disease in older persons. Atherosclerosis. 2013 Dec;225(2):469-74.
• McCall GE, Byrnes WC, Fleck SJ, Dickinson A, Kraemer WJ. Acute and chronic hormonal responses to resistance training designed to promote muscle hypertrophy. Can J Appl Physiol. 1999 Feb;24(1):96-107.
• Roberts CK, Croymans DM, Aziz N, Butch AW, Lee CC. Resistance training increases SHBG in overweight/obese, young men. Metabolism. 2013 Jan 11.
• Selva DM, Hogeveen KN, Innis SM, Hammond GL. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest 2007;117:3979–87. 
• Simó R, Barbosa-Desongles A, Sáez-Lopez C, Lecube A, Hernandez C, Selva DM. Molecular Mechanism of TNFα-Induced Down-Regulation of SHBG Expression. Mol Endocrinol. 2013 Mar;26(3):438-46. 
• Trabert B, Graubard BI, Nyante SJ, Rifai N, Bradwin G, Platz EA, McQuillan GM, McGlynn KA. Relationship of sex steroid hormones with body size and with body composition measured by dual-energy X-ray absorptiometry in US men. Cancer Causes Control. 2013 Dec;23(12):1881-91.
• Varsavsky M, Reyes-García R, García-Martín A, Ramírez RG, Avilés-Perez MD, Muñoz-Torres M. SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer. Osteoporos Int. 2013 May 16.
• Xing Y, Qin W, Li F, Jia XF, Jia J. Associations between sex hormones and cognitive and neuropsychiatric manifestations in vascular dementia (VaD). Arch Gerontol Geriatr. 2013 Jan-Feb;56(1):85-90.
• Zhang X, Tworoger SS, Eliassen AH, Hankinson SE. Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Res Treat. 2013 Jan 3