Vanadium for Type II Diabetes!? Beneficial Effect of Trace Element on Blood Glucose Management in Rat Model.

Some of you may remember that vanadium has once been hailed as nutrient repartitioner (it has been shown to increase glucose uptake into muscle tissue via GLUT4-receptors) in the fitness & bodybuilding community. After reports on possible toxicity issues, which were - at least in parts - based on reports of people who dosed according to the common "more helps more" mentality of our society, vanadium supplements, stand-alone or larger doses as part of micronutrient blends, have disappeared from the market. Science, on the other hand has not given up on this promising, yet non-benign "medication".

A recent study (Kurt. 2011) published in the journal Biometals underlines that the effects of vanadium, which was named after the Scandinavian goddess of beauty and fertility, Vanadis, do in fact border on those of a pharmaceutical drug. After treating rats with streptozotocin and thus inducing a metabolic profile that is generally considered an appropriate model for human type II diabetes, the researchers from the Department of Chemistry, at the University of Istanbul, supplemented the chow of their animals (control & STZ-induced type II diabetic rats) with 100mg vanadyl sulfate per kg of body weight. For an 80kg male human this would amount to a massive dose of 1.200mg vanadium sulfate per day, the consumption of which is not advisable until definitive human data on short- and especially long-term consequences are available.

Figure 1: Blood glucose levels (mg/dl) of rats at different time-points
(data adapted from Kurt. 2011)

Regardless of the results of future studies on the effects & safety of vanadium on humans, the study results (as shown in figure 1) clearly indicate that vanadium is able to counter, maybe even reverse, the negative effects streptozotocin has on blood glucose and insulin management in rats.

Its also noteworthy that, according to the scientists, the administration of vanadium also reversed the pro-oxidative effects of streptozotocin-induced diabetes. I am yet not sure if this conclusion Kurt et al. base on a reduction of anti-oxidant activity in the tissue of the diabetic rats is valid. After all, the latter could also be a direct consequence of potential toxic effects of the trace mineral. Until further human data will be available, I would thus strongly advice against taking high dose vanadium supplements, even if you have type II diabetes.

DHEA the Slimming Hormone? Study Finds: Dehydroepiandrosterone Directly Inhibits Cortisol Synthesis in Rodent Adipocytes

After initially being hailed as the fountain of youth, the pharma-financed medical sciences dropped DHEA, when investors realized that a naturally occurring hormone would not be patentable. This and some discouraging and/or inconclusive results from long-term studies had DHEA literally disappear from the research scene for quite some time. Therefore, I am positively surprised that on the forthcoming European Congress of Endocrinology 2011 researchers from the Kobe University in Japan are going to present a paper (Tagawa. 2011) that shows that there may in fact be more to the initial findings of DHEA induced weight loss than follow-up studies would have it.

Tagawa et al. investigated the possible mechanism behind the weight loss effects of DHEA and found that there is a direct inhibitory effect of DHEA on glucocorticoid (re-)synthesis in adipose tissue:

Using differentiated 3T3-L1 adipocytes, we demonstrated that DHEA inhibited 11β-HSD1 activity at a concentration of 1 μM within 10 min. Inhibition was also observed in a cell-free system comprised of microsomes prepared from rat adipose tissue and NADPH, a coenzyme of 11β-HSD1. A kinetic study revealed that DHEA acted as a non-competitive inhibitor of 11β-HSD1. Further, DHEA did not inhibit 11β-HSD type 2, which inactivates cortisol or corticosterone in tissues involved in water and electrolyte metabolism, in rat kidney microsomes at a concentration <25 μM. Moreover, no conversion from DHEA to other sex steroid hormones or their precursors was observed under the present experimental conditions.

These are three significant observations. Firstly, the presence of DHEA inhibits the synthesis of cortisol via 11Beta-HSD1. Secondly, it does not prevent exogenous cortisol to be converted to the "inactive" cortisone via 11Beta-HSD2 and thirdly, the dreaded conversion into estrogen, testosterone or DHT does not take place. All this would make the naturally occurring hormone DHEA a perfect selective 11β-HSD1 inhibitor, of which Stewart et al. from the University of Birmingham write (Stewart. 2011):

Selective 11β-HSD1 inhibitors lower blood glucose, improve insulin sensitivity and cause weight loss in animal models. Biomarkers have been validated to confirm target inhibition in primate and human studies. Recent clinical trials show reduction in HbA1c and blood pressure in obese patients with diabetes mellitus who have failed on metformin therapy. Potentially the therapy offers a ‘magic bullet’ for patients with Metabolic syndrome with reduced blood glucose accompanying improved insulin sensitivity, lower lipids and blood pressure and reversal of hepatic steatosis secondary to reduced autocrine generation of cortisol in liver, adipose tissue, pancreas and muscle. Liabilities include activation of the HPA axis secondary to increased cortisol clearance with hyperandrogenism, though the extent and significance of this is debated.

One thing, though, before you now go about eradicating cortisol to zero. Your body needs a healthy level of cortisol to function. It goes hand in hand with thyroid hormone, helps you manage stress, perform in the gym and is even necessary to "burn" body fat. Again, moderation is key and you certainly want to know where you stand before you start tweaking your cortisol levels into the wrong direction.

An Old Dog Learns New Tricks: "Fatloss Fat" Tetradecylthioacetic Acid (TTA) Cardioprotective in Diabetic Rats

Do you remember the acronym TTA? Tetradecylthioacetic Acid? No. Well, I guess then you were not into fat burners in the early 2000s. TTA, a thia-fatty acid, was all the rage back in the day: Supplement producers claimed it would literally melt fat away and it actually turned out that some users had outstanding results megadosing respective supplements. Others, however, got bloated and/or started cramping. In view of these nasty side effects, most companies decided to reformulate their products and - with the exception of a few so-called "non-thermogenic" fat burners - TTA has almost disappeared from the market.

An international team of scientists from Norway and Canada (Khalid. 2011) has now discovered that the artificial fatty acid tetradecylthioacetic acid, which was originally intended as a drug for the treatment of the metabolic syndrome, might have the potential to protect type II diabetics from heart attacks.
In a previous study (Hafstad. 2009) the scientists had already shown that TTA does increase myocardial fatty acid oxidation in normal mice, a finding that would generally suggest impaired cardiac efficiency and thus be considered detrimental. In the current study on hyperlipidemic [high blood lipid levels] type 2 diabetic mice, however, TTA-treatment (0.5%, 8 days) had almost opposite effects on on cardiac metabolism and function

We found that TTA treatment increased myocardial FA oxidation, not only in non-diabetic (db/+) mice, but also in diabetic (db/db) mice, despite a clear lipid-lowering effect. While TTA had deleterious effects in hearts from non-diabetic mice (decreased efficiency and impaired mitochondrial respiratory capacity), these effects were not observed in db/db hearts. In db/db hearts TTA improved ischemic tolerance, an effect that is most likely related to TTA's antioxidant property.

Being a specifically designed (Pan-)PPAR-ligand [TTA seems to activate all PPAR-receptors] the lipid lowering effect of TTA was to be expected. The differential effect on heart function in healthy and diabetic rats, however, comes as a surprise and reminds us, again, that not all that has been shown to help sick people is beneficial - and sometimes its not even safe! - for the healthy part of the population.

Figure 1: Myocardial fatty acid and glucose oxidation in hearts of db/+ (white  545
bars) and db/db (gray bars) mice. Results are mean of 8-9 hearts in each group. (Khalid. 2011)

So, regardless how promising the shift in substrate metabolism from carbohydrates to fats, as it is visualized in figure 1 may appear, if you just want to shed a few pounds of unaesthetic, but healthy subcutaneous body fat, stay away from tetradecylthioacetic acid - for your heart's sake!

Fat or Fire, What Comes First? Scientists Answer: Obesity Alone Triggers Inflammatory Signaling in Mice

The metabolic syndrome, i.e. the combination of obesity, inflammation and insulin resistance, is at the center of contemporary medical research. In my appearance on Carl Lenore's Super Human Radio, I already mentioned that from a logical perspective the mainstream belief, inflammation was the root of all evil, must be flawed. How should the reaction to a problem be the cause of the very problem itself? A recent study coming from a group of Korean scientists strengthens my conviction that out of the triad that not inflammation, but rather obesity or - one step further up in the genesis of the pathology - the combination of an unhealthy diet and a sedentary lifestyle is at the heart of the triad we now call the "metabolic syndrome".

Kim et al. investigated the pro-inflammatory signaling cascade in either diet-induced (DIO) or leptin gene deficient (ob/ob) obese mice and found that obesity alone ...

[...] up-regulated the expression of TLR1–9 and TLR11–13 in murine adipose tissues, a phenomenon linked with downstream nuclear factor κB [inflammatory protein linked to linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development], interferon regulatory factors, and STAT-1 activation, and up-regulated the expression of cytokines and chemokines via MyD88-dependent and MyD88-independent cascades [activate NF-κB].

Thus, obesity sets the scene for inflammation and inflammation in turn triggers a cascade of unfavorable metabolic and hormonal changes which in and out of themselves result in further weight gain...

Here, we have a self-enhancing pathologic circle, which - and this is probably an even more important result of the study - was especially "effective" in the group of diet-induced obese mice:

The magnitudes of the obesity-induced up-regulation of the TLR1, TLR4, TLR5, TLR8, TLR9 and TLR12 genes in the visceral adipose tissue were greater in the DIO mice than in the ob/ob mice. Similarly, the expression of the IFNα and IFNβ genes significantly increased in the adipose tissues of the DIO mice but did not change in the adipose tissues of the ob/ob mice.

So, its not in your genes, but in your hands, feet and mouth to ward off the plague of the 21st century: Exercise and eat healthy to get lean and/or stay lean and stave off inflammation and diabetes.

Licorice for Diabetes!? Licorice Extract Reverses (!) Diabetic Nephropathy in Rats

Diabetes is the big "D" in the metabolic synDrome and probably the most destructive of the various faces of the plague of the century. Now researchers from the United Arabian Emirates have found that licorice may ameliorate the destructive effects of high blood glucose levels on your kidneys.

In a rat experiment, Kataya et al. (Kataya. 2011) found that...

... oral ingestion (1 g/kg body weight) of licorice extract for 60 days after the onset of diabetes reversed the adverse effect of diabetes on rats. Licorice extract alleviated blood glucose levels, restored renal function, and attenuated body-weight loss. In addition, licorice extract modulated the adverse effect of diabetes on renal malondialdehyde, glutathione, superoxide dismutase, and catalase activity. Further, licorice extract restored the total antioxidant capacity of diabetic rat kidneys.

What I find most intriguing is that licorice ingestion at a dosage that would amount to roughly 12g for an average male human being could reverse, i.e. not only ameliorate, diabetic nephropathy. Yet, the sheer amount of extract you would have to consume raises the question if there would not be other complications / unwanted side effects of this protocol. According to Isbrucker & Burdock (Isbrucker. 2006), the "acceptable daily intake" of licorice is "0.015-0.229 mg glycyrrhizin/kg body weight/day" - depending on the concentration of the extract the scientists used, 12g may well exceed this critical limit (high cortisol, high BP, water retention could be the consequences).

L-Arginine Biscuits Exhibit Ameliorated Insulin Response. A Viable Alternative for People with Metabolic Syndrome!?

"L-Arginine ameliorates insulin resistance and has beneficial effects on blood pressure", "Fat people love cookies and tend to develop insulin resistance!" - if these two thoughts get together in the head of an Italian scientists, a new product is born: the L-Arginine Biscuit!

In a recent study Emanuela Setola (Setola. 2011) investigated the effect of a biscuit with 6.6g arginine on selected metabolic parameters of 7 healthy subjects. The results are encouraging:

A significant increase of nitric oxide (NOx) and cGMP levels were significantly increased with Biscuit +L-ARG 6.6 g and Powdered L-ARG as compared to Biscuit. AUC NOx and cGMP were significantly increased (p<0.04vs Biscuit). Percentage incremental increase of post-ischemic blood flow significantly increased with Biscuit +L-ARG 6.6 g and Powdered L-ARG, suggesting a functional effect of L-ARG added to the food preparation. Further, at 240 minute mean arterial blood pressure and peripheral vascular resistances slightly declined with Biscuit +L-ARG 6.6 g without reaching a statistical significance. At metabolic levels, the addition of L-ARG to a biscuit decreased insulin levels in the presence of similar glycemic levels, in particular a significant decrease of AUCinsulin during the test with Biscuit +L-ARG 6.6 g in comparison to Biscuit alone was found (p<0.05).

The last result, i.e. the decreased insulin release is probably the most interesting finding of this study and was further investigated by the researcher:

From the results of glucose and insulin, two indices were derived: a Modified Matsuda, (index of whole-body insulin sensitivity) and the Disposition Index (index of the product of insulin sensitivity and first phase insulin secretion). We were able to define that both indices were significantly increased with 6 Biscuits having 6.6 g of L-Arginine while intermediate values were found when 3 Biscuits (3.3 g) were eaten as compared to Biscuits without L-Arginine addition.

After all, I think it would be better to avoid cookies and biscuits completely, but if you just cannot resist, you may well add some arginine to the dough for this years Christmas baking.

Even Low "Normal" Plasma Testosterone Levels Associated with 2.5x Higher Risk of Insulin Resistance

"Your levels are in range!" Did you ever have your doctor say that to you? It appears as if next time you hear that sentence, you better ask him "Where 'in range' are my levels, exactly?" At least, the results of a recently published study by Menendez et al. (Menendez. 2011) suggests that it might be worth digging somewhat deeper into this issue. Studying a cohort of 282 men (aged 36 to 85 years) who had "normal concentrations of total testosterone", the scientists found:

Serum concentrations of testosterone and bioavailable testosterone were negatively correlated with age, body mass index, waist circumference, blood glucose, glycated hemoglobin levels and insulin. Serum concentrations of total testosterone, bioavailable testosterone and SHBG were lower in men with glucose intolerance or diabetes than in those with normal glucose tolerance. After multivariate analysis, age and total testosterone levels were independent predictors of the presence of diabetes or glucose intolerance. The risk of glucose intolerance or diabetes mellitus was over 2.5 times higher in men with total testosterone levels in the lowest quartile than in those with total testosterone in the top quartile.

While the results of this study are certainly interesting and significant, it is unfortunately impossible to tell, whether glucose intolerance and diabetes reduce the natural production of testosterone, OR low testosterone levels reduce glucose intolerance and lead to diabetes. In other words: What comes first, low testosterone or glucose intolerance? Further research will be needed to answer this question, but if you want my opinion, I suspect that they just go hand in hand, i.e. a bad diet lowers glucose tolerance, high sugar reduces testosterone production, low androgen levels impair glucose tolerance etc. - a viscous circle.

Pot Belly and High Triglycerides Indicative of Low LDL & HDL Particle Size

A recent study by scientists from the Mayo Clinic in Minnesota (Irving. 2011) found that the most reliable indicators of LDL & HDL particle size in 84 healthy non-diabetic men and women were a huge amount of trunk fat and high triglyceride levels.

[...] the accumulation of atherogenic lipoprotein particles (e.g. small, dense, low-density lipoprotein particles and small, high-density lipoprotein particles) was associated with low levels of insulin sensitivity, cardiorespiratory fitness, and higher levels of adiposity. However, multivariate forward-stepwise regression revealed that triglycerides, followed by truncal fat mass, were the strongest predictors of the lipoprotein particle size and concentration data.

These results are of particular interest to those who cannot afford having a comprehensive lipid panel done. Since the standard tests often do not provide any information about the size of the cholesterol particles, looking and triglycerides and truncal fat may be a useful indicator of whether or not it will be necessary to check cholesterol particle sizes, as well.

On a side note: Other than it has long been thought, current research suggests that neither the amount of total cholesterol, nor the amount of LDL cholesterol, but rather the size of the cholesterol lipo-proteins is the main determinant of how likely one is to develop arteriosclerosis: Large particle size = benign; small particle size = dangerous.

Beta-Hydroxy-Beta Methylbutyrate Strikes Back: HMB Increases GH and IGF-1 at the Expense of Insulin Resistance

"HMB" - do you remember these three letters? If you have been around the supplement world in the early 2000s, you probably will. Beta-hydroxy-beta methylbutyrate (HMβ) is a metabolite of leucine which has been advertised to enhance exercise performance, reduce fatigue and promote muscle gains. Nothing of that has been substantiated within larger human studies, though; and thus HMB a former star among the amino acid supplements has almost been forgotten.

Now, a recent study from Brazil (Gerlinger-Romero. 2011) provides data suggesting that HMB may in effect raise the content of pituitary GH mRNA and growth hormone [GH], as well as hepatic IGF-I mRNA and serum IGF-I concentrations.

It was observed that the HMβ treatment induced an increase in GH mRNA by 65% (P < 0.001) and in GH content by 20% (P < 0.05) compared to control group. The IGF-I mRNA expression in liver, as well as the serum IGF-I concentration was also significantly increased in the HMβ-treated animals.

There are some downsides to these results, however. Firstly, this is another rodent study, so we do not know how the results of this 4 week intervention would translate to human beings. At least, other than in previous investigations, the amount of HMB, 320mg/kg body weight, which is equivalent to roughly 52mg/kg body weight in a human being, would be affordable, but ...

Figure 1: Effect of the HMβ-treatment on Insulin concentrations.
Data are expressed as mean ± SEM. *P < 0.05; n = 9–16 animals per group
(Gerlinger-Romero. 2011)

... and here comes secondly, the rats became hyperinsulinemic (cf. figure 1), or in other words HMB supplementation induced insulin resistance. With the latter being at the heart of the metabolic syndrome I would think twice before attempting to boost my growth hormone level with an amino acid metabolite that will compromise my body's insulin management.

Dietary Oxidized Frying Oil Impairs Pancreatic Insulin Release. Vitamin E Helps!

It certainly is no coincidence that a recent study on the detrimental effects of oxidized frying oil (OFA) was published in the British Journal of Nutrition. Afterall, it suggests that the British are at risk of dying out, if they just listened to their appetite and kept over-consuming "Fish and Chips".

After feeding rats with either soy (HF) or oxidized frying oil (HO) over a period of 8 weeks the researchers found:

[...] mice in the HO group showed glucose intolerance and hypoinsulinaemia, and their islets showed impaired glucose-stimulated insulin secretion (P,0·05; HO group v. LF and HF groups). Significantly higher oxidative stress and a lower mitochondrial membrane potential were observed in the islets in the HO group compared with the LF and HF groups. Immunoblots showed that the reduction in insulin levels in HO islets was associated with activation of the c-Jun NH2-terminal kinase and a reduction in levels of pancreatic and duodenal homeobox

Furthermore, they found that, "when dietary OFO-induced tissue vitamin E depletion was prevented by high-dose vitamin E supplementation (500 IU(1·06 mmol all-rac-a-tocopherol acetate)/kg diet; [...] the OFO-mediated reduction in islet size and impairment of glucose tolerance and insulin secretion were significantly attenuated."

So, obviously it is the interplay of oxidation and lack of antioxidants (in this case vitamin E) which collectively initiate these metabolic changes, which consequently are at the bottom of what is often called "the metabolic syndrome". Bottom line: Beware of oxidized fats and support your antioxidant capacity by healthy food choices and supplements.

Anti-obesity & Anti-diabetic effect of Trehalose in Rats on a High Fat Diet

I know, I know, rats on a high fat diet are a topic on their own: "Are they a valid model for metabolic disease in man?" etc. - Be that as it may, the findings of scientists from the Biomedical Institute, Research Center, Hayashibara Biochemical Laboratories in Okayama (Arai. 2010) suggest that, of all things, a sugar(!) molecule may help prevent the negative effects of a high fat diet on fat mass and insulin resistance, which are commonly observed in the rat-model of the typical western-world high-fat diet.

Other than rats on a glucose [Glc], a maltose [Mal], a high-fructose corn syrup, or a fructose [Fru] rich high-fat-diet [HFD], the rats which were fed the natural alpha-linked disaccharide trehalose did not exhibit the typical signs and symptoms subsumed under the keyword "metabolic syndrome":

After 7 weeks of HFD and saccharide intake, fasting serum insulin levels in the Tre/HFD group were significantly lower than in the Mal/HFD and Glc/HFD groups (P < .05). Furthermore, the Tre/HFD group showed a significantly suppressed elevation of homeostasis model assessment–insulin resistance compared with the Mal/HFD group (P < .05) and showed a trend toward lower homeostasis model assessment–insulin resistance than the Glc/HFD group. After 8 weeks of feeding, mesenteric adipocyte size in the Tre/HFD group showed significantly less [fat] hypertrophy than the Glc/HFD, Mal/HFD, high-fructose corn syrup/HFD, or Fru/HFD group. Analysis of gene expression in mesenteric adipocytes showed that no statistically significant difference in the expression of monocyte chemoattractant protein–1 (MCP-1) messenger RNA (mRNA) was observed between the Tre/HFD group and the distilled water/standard diet group, whereas a significant increase in the MCP-1 mRNA expression was observed in the Glc/HFD, Mal/HFD, Fru/HFD, and distilled water/HFD groups.

While these results certainly appear promising, I better add that the laboratory that did the study is financed by the Hayashibara company, the same company which recently developed a new technique to produce or rather to extract trehalose commercially. So treat these results with a grain of skepticism, if you understand what I mean ;-)

Melatonin for Patients With Metabolic Syndrome!?

When was the last time your mother asked you, whether you would get enough sleep? Can't remember? Well, a recent study by scientists (Kozirog. 2010) from the Department of Internal Diseases and Clinical Pharmacology at the Medical University of Lodz suggests you better listen to your mothers words and get a decent amount of sleep, just to make sure you reap the benefits of melatonin.

In the study 30 patients with metabolic syndrome (MS) were treated with 5mg/day of melatonin 2hr before bedtime for 2 month. The results were quite remarkable:

Melatonin administered for 2 months significantly improved antioxidative defense (increase in CAT activity, decrease in TBARS level) and lipid profile (decrease in LDL-C), and lowered blood pressure.

It is not news that lack of sleep contributes to metabolic disorders. What is interesting, however, is that direct supplementation with melatonin, which is secreted at dawn and in the course of the night reverses existing symptoms of the metabolic syndrome. In view of the complex endocrine interactions and the various hormonal responses which depend on sufficient and regular sleep, my suggestion is however not (only) to supplement tons of melatonin, but just to get a good nights sleep everyday, or, in other words, to practice "sleep hygiene", instead.

Eat Rice, Stay Healthy!?

A recently published study (Fulgoni. 2010) analyzing data from 25 374 eligible participants identified as rice consumers study on the correlation of rice-eating to several markers of metabolic health showed that people who ate at least one serving of rice (white or brown) a day tend to have

better health and diet parameters including less total fat, saturated fat, and added sugars; higher amounts of more than 12 essential vitamins and minerals, including iron, folate, and other B vitamins; more fruit and legumes; nearly 4 tsp (16 g) less added sugar; and 7 g less solid fats. For the 19- to 50-year-old subgroup, main results (P < .05) also showed rice consumption associated with reduced likelihood of being overweight or obese, 34% reduced risk of high blood pressure, 27% reduced likelihood of having an increased waist circumference, and 21% reduced risk of metabolic syndrome.

This, however, should not encourage you to just add one serving of rice to your bad diet habits, because the most important information coming from the study is the first one: Rice eaters tend to have better diet parameters. In other words their general dietary regimen is more healthy, no wonder they have a reduced likelihood of obesity and health issues. Overall, rice is still a very dense source of energy and overeating on it would not be advisable, both from a caloric, as well as (this is more important) from a nutritious point of view - with its high amount of carbohydrate one serving of rice may well amount to all the carbs you may eat, if you follow a heart healthy low carbohydrate diet. Bottom line: Moderation is the key!