There Are Two Sides to Each Coin: Vitamin D Increases Insulin Sensitivity in Obese, Yet Decreases it in Lean Mice

I am probably repeating myself, but I cannot emphasize enough that a common fallacy of medical research is the focus on pathologies. A recent example with respect to the "omnipotency" (that's what the Internet news could make you believe) of vitamin D comes from researchers at George Town University (GU. Press Release).

The scientists were able to replicate the results of previous studies, where high dose vitamin D supplementation had "significantly reduced development of estrogen receptor-positive (ER+) breast cancer", but for estrogen receptor-negative (ER-) breast cancer they found either no effect (lean mice) or even an increased rate of cancerous growth in the group of obese mice.

What's yet even more interesting that a similar contradiction was evident with respect to vitamin D's widely perpetuated beneficial effects on insulin resistance. In the pathologic model of the obese mice, vitamin D @ 15-25k IU per day was in fact able to ameliorate insulin resistance, in the lean, naturally insulin sensitive mice, however, insulin sensitivity was reduced by supplemental vitamin D.

As I've discussed it in the context of the most recent fish oil study (and will probably repeat for other "super nutrients"), in 99.9% of the cases the effect of - especially high dose - supplementation with ostensibly harmless "vitamins" or "nutrients" vary enormously depending on the subjects current nutritional and health status. To derive one-size-fits-it-all recommendations from individual studies and to transfer results obtained from a pathological model without further scientific investigations to a healthy one is careless and may turn out to be very dangerous.

Ironclad Liver Hampers Insulin Sensitivity: Association Between Hepatic Iron Load and Insulin Resistance Discovered

"Insulin resistance", "insulin sensitivity", etc. Type in these key words and find 4.000.000 +1 results on Google. I want to focus on the +1 here and briefly report the results of a study (Haap. 2011) coming from the University of Thübingen, Germany.

Via magnetic resonance gradient echo imaging technique Michael Haap and his colleges assessed the iron load in the livers of of 113 healthy nondiabetic subjects [69 females, 44 males; age 47 ± 1 yr; body mass index (BMI) = 28.9 ± 0.5 kg/m2], who were "at increased risk for type 2 diabetes". Various statistical analysis of their data revealed that:

[Hepatic iron levels] adjusted for age negatively associated with serum ferritin levels (P < 0.0001) and positively associated with IS [insulin resistance] (P = 0.009). In addition, T2* values [indicator of hepatic iron load] associated with LF [liver fat] (P = 0.008) but not with BMI (P = 0.6). In a multivariate model, IS adjusted for gender, age, and BMI was associated with T2* values (P = 0.015). IS adjusted for gender and age was independently associated with LF (P = 0.033) and T2* values (P = 0.004). In a stepwise regression analysis, LF explained 13.5% (P < 0.01) of the variation in IS, and HIL [hepatic iron load] explained an additional 4.1% (P = 0.03).

With 4.1% the contribution of iron to the development of type II diabetes is certainly only one out of a multitude of factors. I would yet still be interested in further information on the interplay of iron, insulin and blood glucose, also because low ferritin levels, which, according to the study, go hand in hand with high hepatic iron loads, have also been implicated in other metabolic disorders such as hypothyroidism, which in and out of itself would further aggravate existing blood sugar and weight issues within the pre-diabetic study population.

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.

Acquittal: Anti-Oxidants do not Blunt the Beneficial Effect of Endurance Training on Insulin Sensitivity!

Regular visitors of the SuppVersity will remember that there has been and still is a controversy about whether or not athletes and average gymrats benefit from antioxidants or whether this may even blunt training induced adaptation effects. Other than a 2009 study by Ristow et al. (Ristow. 2009), a more recent investigation into the effects of antioxidant supplementation (Yfanti. 2011), coming from my northern neighbors from Denmark, did not find any negative effects of antioxidants on the exercise induced rise in insulin sensitivity.

In the study 21 young, healthy men, who received 500 mg vitamin C and 400 IU vitamin E (α-tocopherol) daily, completed a 5-days-a-week supervised intense endurance-training (interval training on Tuesday & Thursday; steady-state cardio on Wednesday & Friday). Insulin response, maximal oxygen consumption (VO_2max), maximal power output (P_max) and body composition (fat mass, fat-free mass) were measured and "muscle biopsies were obtained for determination of the concentration and activity of proteins regulating glucose metabolism". The scientists summarize their results as follows:

Although plasma levels of vitamin C (P < 0.05) and α-tocopherol (P < 0.05) increased markedly in the AO group, insulin-stimulated glucose uptake increased similarly in both the AO (17.2%, P < 0.05) and the PL (18.9%, P < 0.05) group in response to training. VO_2max and P_max also increased similarly in both groups (time effect: P < 0.0001 for both) as well as protein content of GLUT4, hexokinase 2 and total Akt (time effect: P ≤ 0.05 for all).

I don't know if you consider this "good" or "bad" news, but in any case, I suspect you will want to know what happened to the participants body composition (at least I would want). Well, the scientists say, there were no significant pre-post changes and from a statistic point of view, this is unquestionably right. I find it interesting, nevertheless that the average decline in fat mass was somewhat larger in the placebo (-21%)  vs. the anti-oxidant group (-8%); the intra-group differences are however so large that, with the given count of subjects, this is hardly meaningful.

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.

A Natural Cure for Obesity and Insulin Resistance!? Promising Results from Animal Experiments with Bitter Melon Bioactives

In a very recent investigation, researchers from the Pennington Biomedical Research Center (Wang. 2011) found that high-fat diet fed mice gained less weight and had less compromised insulin response, if they received an (unfortunately) unspecified amount of an aquaeus extract from bitter melon:

Body weight, plasma glucose, insulin, leptin levels and HOMA-IR values were significantly lower in the BM-fed HFD group when compared to the HFD group. BM supplementation significantly increased IRS-2, IR β, PI 3K and GLUT4 protein abundance in skeletal muscle, as well as phosphorylation of IRS-1, Akt1 and Akt2 when compared with HFD (P<.05 and P<.01). BM also significantly reduced muscle lipid content in the HFD mice. BM extract greatly increased glucose uptake and enhanced insulin signaling in L6 myotubes. 

There is however two major caveat to these findings. Firstly, mice ain't a particularly good model for predictions concerning the effect of supplements that are added to a high fat diet. And secondly, even if we would see similar results in human beings, the most obvious conclusion one MUST (but obviously nobody does) draw from the results of this study is that without supplementation the low fat diet, i.e. the group of mice that consumed a diet that is appropriate to their genetic make-up, gained the least amount of weight, had the lowest leptin levels and the best insulin sensitivity.

Figure 1: Insulin levels of the mice on a low fat diet (LFD), a high fat diet (HFD) and a high fat diet supplemented with bitter melon extract (BM)

Does this tell you that you should revert to a low fat diet? No, at least not if you ain't a mouse. What it should tell you, however, is that revamping your diet, making correct food choices and eating according to what our bodies are made for is the key to health and long jeopardy - the "natural cure for obesity and insulin resistance", it's already out there. Don't even think about dietary supplements before you've got that in check...

Scientific Evidence Links High Carbohydrate Intake to the Development of Alzheimer's and Other Neurological Diseases

"Fats are bad, carbs are healthy!" I hope nobody out there still believes this late 20th Century slogan. If you do, chances are you will soon forget about it due to the neuronal damage you are inflicting to your brain by eating a high carb diet.

In a very recent review, a group of international scientists (Seneff. 2011) summarize the current state of research as follows:

[...] an excess of dietary carbohydrates, particularly fructose, alongside a relative deficiency in dietary fats and cholesterol, may lead to the development of Alzheimer's disease. A first step in the pathophysiology of the disease is represented by advanced glycation end-products in crucial plasma proteins concerned with fat, cholesterol, and oxygen transport. This leads to cholesterol deficiency in neurons, which significantly impairs their ability to function. Over time, a cascade response leads to impaired glutamate signaling, increased oxidative damage, mitochondrial and lysosomal dysfunction, increased risk to microbial infection, and, ultimately, apoptosis. 

They also compiled a comprehensive list of take-home-massages, some of which may have far reaching consequences:

• Researchers have identified mitochondrial dysfunction and brain insulin resistance as early indicators of Alzheimer's disease.

• ApoE-4 is a risk factor for Alzheimer's disease, and ApoE is involved in the transport of cholesterol and fats, which are essential for signal transduction and protection from oxidative damage.

• The cerebrospinal fluid of Alzheimer's brains is deficient in fats and cholesterol.

• Advanced glycation end-products (AGEs) are present in significant amounts in Alzheimer's brains.

• Fructose, an increasingly pervasive sweetening agent, is ten times as reactive as glucose in inducing AGEs.

• Astrocytes play an important role in providing fat and cholesterol to neurons. [...]

• Glycation damage interferes with the LDL-mediated delivery of fats and cholesterol to astrocytes, and therefore, indirectly, to neurons. [...]

• Synthesis of the neurotransmitter, glutamate, is increased when cholesterol is deficient, and glutamate is a potent oxidizing agent.

• Over time, neurons become severely damaged due to chronic exposure to glucose and oxidizing agents, and are programmed for apoptosis due to highly impaired function. [...]

• Simple dietary modification, towards fewer highly-processed carbohydrates and relatively more fats and cholesterol, is likely a protective measure against Alzheimer's disease.

So, if you have not already forgotten what you just read, make sure to cut back your carbohydrate consumption, limit fructose intake and stop being afraid of fats and cholesterol before you cannot remember anymore.

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.

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 ;-)

Viscous Circle: Low Testosterone > Increased Visceral Fat > Insulin Resistance > Even Lower Testosterone

E.J. Hamilton and colleges (Hamilton. 2010) investigated the effect of androgen deprivation therapy (ADT) in prostate cancer patients on subcutaneous and visceral fat. There results are far from being surprising:

Twelve months ADT increased visceral abdominal fat area by 22% (from 160.8 ± 61.7 to 195.9 ± 69.7 cm²; p<0.01) and subcutaneous abdominal fat area by 13% (from 240.7 ± 107.5 to 271.3 ± 92.8 cm²; p<0.01). Fat mass increased by 14% (+3.4 kg; p<0.001) and lean tissue mass decreased by 3.6% (-1.9 kg; p<0.001). Insulin resistance (HOMA-IR) increased by 12% (2.50 ± 1.12 to 2.79 ± 1.31, p<0.05).

All that by itself is bad enough, but in the end, by the medical suppression of androgens doctors put their poor patients in a viscous circle, from which it will be very difficult to escape, as obesity and insulin resistance will further reduce testosterone production and overall metabolic health regardless of whether they are secondary to low testosterone, come from bad eating habits or whatever.

Vitamin D & Insulin: A Question of Race?

Could it be that vitamin D intake is more important for people with an African American (AA) background than for their European American (EA) neighbors? This is exactly, what a study that was recently published in Nutrition&Metabolism (Alvarez. 2010) seems to suggest.

In 115 African American (AA) and 137 European American (EA) healthy, premenopausal women the scientists  determined with 4-day food records and assessed the individual insulin sensitivity indexes (SI), as well as the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) values. The results are quite unequivocal:

Vitamin D intake was positively associated with SI (standardized β = 0.18, P = 0.05) and inversely associated with HOMA-IR (standardized β = -0.26, P = 0.007) in AA, and the relationships were independent of age, total body fat, energy intake, and % kcal from fat. Vitamin D intake was not significantly associated with indices of insulin sensitivity/resistance in EA (standardized β = 0.03, P = 0.74 and standardized β = 0.02, P = 0.85 for SI
and HOMA-IR, respectively). Similar to vitamin D, dietary calcium was associated with SI
and HOMA-IR among AA but not EA.

While the scientists refrain from premature speculation about the underlying reasons of the observed discrepancy, they highlight the importance of both, adequate vitamin D, as well as dietary calcium consumption for premenopausal women of African American descent. What I consider noteworthy is the fact that the mean vitamin D intake of both groups was way beyond even the currently suggested 400IU (most experts already suggest 1.000-2.000 IU per day). With a mean vitamin D intake of 111.5IU and 133.7IU per day. All subjects carry the risk of being "vitamin D deficient" and this is where increased intake may produce significant positive effects on various health marker (cf. More on Vitamin D).

Mitochondrial Density in Muscle is Key Determinant of Metabolic Flexibility

If you happened to have listened to Carl Lenore's interview with Mike T Nelson's on SuperHumanRadio, last week, you will be familiar with the concept of metabolic flexibility and how important it is for your body to be able to adapt quickly to varying energy demands and sources. A recent study by scientists from the Pittsburgh School of Medicine (Chomentowski. 2010) had a similar background. Along with several markers of metabolic flexibility the group measured intermyofibrillar and subsarcolemmal (SS) mitochondrial content in a sample of forty sedentary adults with a wide spectrum of insulin sensitivity (insulin-sensitive lean subjects, insulin-resistant nondiabetic subjects, and subjects with type 2 diabetes mellitus).

Intermyofibrillar mitochondrial content was lower in the insulin-resistant nondiabetic subjects and type 2 diabetes mellitus groups, significantly correlating with glucose disposal in both men (R = 0.72, P < 0.01) and women (R = 0.53, P < 0.01). In contrast, SS mitochondrial content was similar among groups. Lower intermyofibrillar mitochondrial content was not explained by mitochondrial size, altered fiber-type distribution, or differences in maximum aerobic capacity. Intermyofibrillar mitochondrial content was significantly correlated with fasting respiratory quotient (R = -0.46, P = 0.003) and metabolic flexibility (R = 0.38, P = 0.02).

The correlation between low intermyofibriallar mitochondrial content and insulin-resistance the researchers found seems to substantiate the longstanding recommendation to exercise and build muscle or make existing muscle work more effectively to prevent and treat diabetes and the metabolic syndrome. However, dietary factors and genetics may as well be important factors influencing mitochondrial density.