Healthy Fish Swims in the Sea, not the Pan | 7% Increased Type II Diabetes Risk per Add. Serving/Wk of Fried Fish

Within the fried fish category the study did unfortunately not distinguish between regularly fried (left) and breaded or otherwise crumbed fried fish. While this may be simply because they simply didn't have the data, it clearly reduces the practical value of the study.

Sometimes, eating healthy can be more difficult than you'd think. Let's take your two weekly servings of fish as an example. With fish, there are the issues with nasty heavy metals and plastics in wild-caught and the increased omega-6 fatty acids in farmed fish that I've addressed at length in my 2013 and 2014 articles "Making the Right Fish Choices: Fatty Acid Contents of 33 Different Fish Species" (read it) and "Farmed vs. Wild-Caught: Pollutants and A Low Omega-3/6 Ratio" (read it).

Unfortunately, it doesn't stop there. Whether or not you will see the full, if any health benefit you certainly will have heard of, will not just depend on making the right fish, but also on making the cooking choices. Choices I will briefly address in today's SuppVersity article.

You can learn more about fish & co. at the SuppVersity

Fish Oil Makes You Rancid?

POPs in Fish Oils are Toxic!

All Top-Selling US Fish Oils Rancid

Fish Hydrolysate for Fat Loss

Steam Fish in the Microwave

Rancid Fish Bad for Your Health

The reason why this topic, which is closely related to the "Quest for the Optimal Cooking Oil", (re-)appeared on my radar is the publication of the latest study from the Unit of Nutritional Epidemiology and the Medical Research Council Epidemiology Unit at the venerable Karolinska Institute in Sweden and the University of Cambridge School of Clinical Medicine (Wallin 2017). In the corresponding paper, Alice Wallin and colleagues highlight that consistent evidence in favor of beneficial effects of fish consumption exist only for one's heart- but not for one's metabolic disease risk. In fact, ...

[...r]esults from epidemiological studies on fish consumption in relation to risk of developing diabetes have [...] been largely inconsistent and inconclusive[; with s]everal meta-analyses hav[ing] highlighted the heterogeneity of results and brought attention to potential geographical differences, with inverse associations observed in studies conducted in Asia, overall null associations in European populations and higher risks in US populations." (Wallin 2017).

Next to the type of fish that is consumed and the corresponding level of contaminants (see links above), scientists have long suspected that the way the fish is prepared "could possibly help explain the discrepancy between the findings" (Wallin 2017).

Figure 1: Frying could explain the heterogeneity (from 22% increase to 10% decreased T2DM risk) with high(er) fish intakes in previous studies (forest plot from Zhang 2013).

As the authors outline, "previous studies on fish consumption in relation to type 2 diabetes risk have not fully accounted for such factors" (Wallin 2017) - and that despite the fact that the frying process could trigger the formation of...

• 

  Figure 2: Among other things, frying will reduce the amount and ratio of healthy polar lipids (PL) while increasing the amount of total (TL) and neutral (NL) lipids as you will find them in processed meats (Perkins 1983), too (Nomikos 2006).

  advanced glycation end products (AGEs), of which studies show that their avoidance will immediately improve the insulin sensitivity of overweight, but healthy individuals (Mark 2014)., 
• mutagenic compounds, which have long been known to increase one's risk of several cancers (Felton 1997), diabetes and heart disease (Birlouez-Aragon 2010), 
• changes in fatty acid composition, lipids and the vitamin content of fish, meat and other foods that usually end up in the frying pan before they finally make it to your plate , I've discussed at length in previous articles (learn more).

In view of the fact that studies which focussed on the CVD-protective effects of fish have already pointed towards a potential difference between fried and non-fried fish dishes, a re-analysis of the data as it has now been conducted by Wallin et al. was overdue.

If you hate boiled or steamed fish, I suggest you bake your fish. According to a 2006 study by Mozaffarian, baked fish shares the same beneficial health effects as boiled fish... ok, that's not a T2DM study, but considering the fact that the scientists observed associations between fried fish consumption and left ventricular (LV) wall motion abnormalities, reduced ejection fraction, reduced cardiac output, and, possibly, larger LV diastolic dimension, it doesn't seem to be unreasonable to assume that baking your fish is much better than frying it.

For their re-analysis, the international team of researchers used the population-based "Cohort of Swedish Men", which includes 35,583 men aged 45–79 years, who were followed from 1998 to 2012.

Figure 3: Odds ratio (1.00 = no increased risk; 1.27 = 27% increased risk) for developing type II diabetes according to frequency of fried fish intake per month; the graph shows the results adjusted either for age, only (blue), and for age, BMI, activity, education, smoking, and several dietary factors (orange | plotted based on data from Wallin 2017).

In this cohort, the authors observed 3624 incident cases of type II diabetes over the course of the 15 years of follow-up and calculated the hazard ratios w/ 95 % confidence intervals using Cox proportional hazards models.for total and fried, as well as shellfish consumption. Their data shows that...

• total fish consumption (≥4 servings/week vs. <1 serving/week) was not associated with type 2 diabetes in multivariable-adjusted analysis (HR 1.00; 95 % CI 0.85–1.18),  
• fried fish consumption  (≥6 servings/month vs. ≤1 servings/month) was associated with a 14% increase in T2DM risk (HR 1.14 | 95 % CI 1.03–1.31), and
• shellfish consumption (≥1 serving/week vs. never/seldom) 21% increase in T2DM risk (1.21 | 95 % CI 1.07–1.36), respectively.

In this context, it is clearly worth mentioning that the risk due to a high fried fish consumption was not modified when Wallin et al. further adjusted their already age-, BMI-, activity-, education-, smoking-, and diet-adjusted data for the dietary exposure to polychlorinated biphenyls (ng/day, quintiles) and methyl mercury (µg/day, quintiles) from fish. The scientists were likewise able to exclude any influence of the type of fish that was consumed: the diabetes risk for herring and mackerel, salmon, whitefish, and char, as well as cod and saithe were quasi-identical.

I know, I know steaming can be a real hassle (compared to frying). Thus you will probably be delighted to hear that - unlike olive oil, which deteriorates in the microwave oven - fish can be steamed in the microwave without ill effects on its nutritional value | more.

So what's the verdict? Never fry your fish? With adjustments for almost all relevant confounders and evidence that the increased diabetes risk is not a function of the intake/exposure to environmental pollutant, the study at hand does indeed suggest that you should avoid the regular consumption of fried fish.

And what I find most astonishing is that (a) "regular", in this case, is not daily or every other day, but only 1-2 times per week. It is thus only logical that the scientists' restricted cubic spline model estimates the T2DM risk increase per weekly serving of fried fish by a statistically significant 7% (HR 1.07 | 95 % CI 1.02–1.11).

This number is clearly high enough to warrant that we reconsider out fried fish consumption, ... well, at least, if it were not for one important methodological shortcoming the lack of adjustment for (a) the type of cooking oil and (b) a distinction between breaded/crumbed and plain fried fish. Until corresponding data is not available, I wouldn't start to panic, after all evidence that would support the importance of "packaging" comes from both the previously cited (see red box) and an older study by Mozaffarian et al. (2003) who were able to show that fish sandwiches intakes had none of the heart relevant benefits of boiled or baked fish | Comment on Facebook!

References:

• Birlouez-Aragon, Inès, et al. "A diet based on high-heat-treated foods promotes risk factors for diabetes mellitus and cardiovascular diseases." The American journal of clinical nutrition 91.5 (2010): 1220-1226.
• Felton, James S., et al. "Health risks of heterocyclic amines." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 376.1 (1997): 37-41.
• Mark, Alicja Budek, et al. "Consumption of a diet low in advanced glycation end products for 4 weeks improves insulin sensitivity in overweight women." Diabetes Care 37.1 (2014): 88-95.
• Mozaffarian, Dariush, et al. "Cardiac benefits of fish consumption may depend on the type of fish meal consumed." Circulation 107.10 (2003): 1372-1377.
• Mozaffarian, Dariush, John S. Gottdiener, and David S. Siscovick. "Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics." The American journal of cardiology 97.2 (2006): 216-222.
• Perkins, Edward George, and W. J. Visek, eds. Dietary fats and health. No. 10. The American Oil Chemists Society, 1983.
• Wallin, A., Di Giuseppe, D., Orsini, N. et al. "Fish consumption and frying of fish in relation to type 2 diabetes incidence: a prospective cohort study of Swedish men." Eur J Nutr (2017) 56: 843. doi:10.1007/s00394-015-1132-6
• Zhang, Ming, Eliane Picard-Deland, and André Marette. "Fish and marine omega-3 polyunsatured fatty acid consumption and incidence of type 2 diabetes: a systematic review and meta-analysis." International journal of endocrinology 2013 (2013).

HIIT Sheds 25% Intra-Bellyfat in 32 Workouts - Despite T2DM & W/Out Dieting! Plus: Always 'Add Weights' When Dieting

High-intensity interval training (HIIT) sheds significantly more belly fat over (-10% vs. 0%) and under (-25% vs. +10%) female abs than isocaloric medium intensity steady state exercise aka MICT.

Losing 25% of visceral fat without dieting and with only two workouts per week (16 weeks x 2 workouts = 32 workouts total)? That sounds like straight from a 'spam ad' on Facebook, right? Well, it is based on scientific evidence, though... evidence from a study in Diabetes & Metabolism that tested the effects of a very manageable high-intensity interval training regimen (2 x 20 min per week) on abdominal fat mass in postmenopausal women with type 2 diabetes (Maillard. 2016).c

Ok, I have to admit that's different from both, (a) the athletes in the second study that made it into today's SuppVersity short news (the one about maximal fat oxidation) and (b) the average SuppVersity readers, but knowing the exact protocol, which is different from much (if not everything) you may have seen so far, alone, should be reason enough to read the rest of today's SuppVersity Short News (all short news | make sure to scroll down and click on "older news" at the bottom).

Read more about exercise-related studies at the SuppVersity

Tri- or Multi-Set Training for Body Recomp.?

Aug '15 Ex.Res. Upd.: Nitrate, Glycogen, and ...

Pre-Exhaustion Exhausts Your Growth Potential

Full ROM ➯ Full Gains - Form Counts!

Body Pump, Cardio & Exercise Expenditure

Study Indicates Cut the Volume Make the Gains!

The former is particularly true since the scientists tested another, albeit non-HIIT training regimen, too, one that resembles what the seventeen women (69 ± 1 years; BMI: 31 ± 1 kg/m²) who participated in the study would probably have done if they had not been randomly assigned to the classic, but useless ...

• medium intensity cycling training (MICT) - 40 min at 55–60% of their individual HRR as calculated by (estimated HRmax − HRrest) × 0.55 (or 60%, respectively) + HRrest - instead of the previously hinted at
• high-intensity interval training (likewise cycling) HIIT program - 60 × 8 s at 77–85% HRmax, 12 s of active recovery (at 20–30 rpm) - that yielded impressive results

for only for 16 weeks with two isocaloric (= EEs per session did not differ between the two modalities (262 ± 58 kcal with HIIT and 240 ± 58 kcal with MICT; this is a difference to many previous studies, where, oftentimes, the steady state group burned more energy during their workouts) workouts per week. As promised in the headline, it did thus take as little as 32 workouts for the results to become measurable (via dual-energy X-ray absorptiometry) and visible - and that in spite of the lack of reductions in energy intake in both groups:

"Women were asked to maintain their normal eating habits during the 16-week study period. At baseline and at week 16 of training, each participant provided a 7-day food-intake diary, which was evaluated by a dietitian using nutrition analysis software (Nutrilog®, Marans, France)" (Maillard. 2016).

In addition, the subjects were "asked to maintain their normal levels of physical activity during the study period" (Maillard. 2016).

Whatever you do: If you want to lose weight - exercise! It's not just the study at hand that underlines how powerful (especially) HIIT exercise is when it comes to fat, not weight loss. Another recently published study by Edward P. Weiss et al. adds to the already convincing evidence that exercise protects you from the decreases in lean mass and reductions of VO2max that occur with deficits as low as only 20% (Weiss. 2016). In their study, Weiss et al. had observed that the ~2% (p=0.003) whole body and ~4% (p<0.0001) lower body lean mass loss that occurred during 15-18 weeks of dieting at 80% of the maintenance intake was reduced to non-significant 1% (p=0.44) and only just significant <2% (p=0.05) lower body lean mass loss while the ~6% decrease in aerobic exercise capacity was totally blunted with only 4.4+/-0.5 hr/wk of walking, jogging, cycling or more intense functional physical activities, such as yard work - needless to say that replacing that by a fast-paced strength training regimen (explicitly precluded in Weiss et al.) or concomitant strength + cardio training may have reduced the lean mass losses to zero, as well. 

Now, I have to admit I haven't told about the importance of a small word in the headline yet. The word is "intra-" and points away from belly fat in general and towards the "intra-belly" visceral fat with it's unhealthy effect on blood lipids and glucose levels.

Figure 1: Body composition changes [based on dual-energy X-ray absorptiometry (DEXA) imaging] between baseline and end of the 16-week exercise program with MICT (n = 8) and HIIT (n = 8). Data are means ± SEM. MICT: moderate-
intensity continuous training; HIIT: high-intensity interval training; FFM: fat-free mass; FM: fat mass; delta
change (%) = [(16 weeks − baseline/baseline) × 100]. *P ≤ 0.05 (MICT vs. HIIT groups | Maillard. 2016).

With ~10%, though, even the total belly fat loss (visceral and subcutaneous) is remarkable. After all, there was (a) no dieting involved and (b) not even the slightest fat loss in the classic cardio group!

In January 2015 I wrote an article with the title "5 Reasons Why 50%+ of Your 'Cardio' Should Be HIIT". Now in 2016 the science is still valid | more

Beware of condemning MICT training! While you have read about the benefits (listed here) of doing HIIT before, there are also good sides of LISS and MICT. This is why I would like to remind you / prepare you for / a fact I highlight / will highlight in the bottom line, too: the study at hand shows nothing but the fact that in this subject group and (solely) for the purpose of losing visceral fat in the absence of dieting and, more importantly, in the absence of lifting weight, HIIT appears to be (albeit vastly) superior to an isocaloric bout (=you spend the same amount of energy training intensely and with intervals) ofsp steady state cardio (MICT).

If you lifted weight, for example, doing two types of exercise that tax the sympathetic nervous system may tax the CNS and produce results that are worse or not better than steady state cardio. Alternatively, if you lifted the calorie limit on the MICT, on the other hand, you may see (just as many previous studies did) that the extra calories burnt during MICT will help you lose more weight and often also more body fat. It's all about specificity and finding out what works for you!

A group of which the data in Figure 1 tells you that the subjects who have been randomly assigned to do "their cardio" (MICT) even got 10.5±9.7 % fatter (viscerally, as measured by CT scans) over the course the 16-week study.

Figure 2: Lipid, fasting glucose and HbA1c changes from baseline to week 16 with moderate-intensity continuous training (MICT; n = 8) and high-intensity interval training (HIIT; n = 8 | Maillard. 2016).

Against that background, the scientists' observation that the 'bad' plasma triglyceride levels were higher with HIIT (group effect, P ≤ 0.05), while "overall, HbA1c and TC-to-HDL ratio both decreased after the intervention (time effect, P ≤ 0.05)" without significant inter-group differences. That sounds odd. As odd as the increase in fasting glucose. So what? Well, what is important, is that

"[...] the total cholesterol (TC) reduction was positively correlated with total visceral FM loss (r = 0.39; P ≤ 0.05) and HbA1c change was positively associated with the decrease in abdominal FM (r = 0.29; P ≤ 0.05)" (Maillard. 2016).

which points to an overall long-term benefit of HIIT on both, lipid and glucose metabolism. All that after 16 weeks, over which the scientists' nutrition and activity data confirm that the subjects did not - as they were advised - change their levels of physical activity (IPAQ score) or total energy (kcal) intake and macronutrient consumption (distribution and total amount).

'Inspiratory Muscle Training, HIIT or RT for Your Kids? Cold Water Immersion & Altitude Training - Who Benefits, When?' Learn about the latest exercise science on HIIT and more

Shouldn't the extreme visceral fat loss... trigger more significant improvements in 'bad' blood lipids (LDL) and glucose metabolism and by no means elevate triglycerides?

The latter is a valid question, but one you wouldn't ask if you were familiar with the effects of intense glycolytic training (HIIT, sprints, weights, etc.) on triglyceride levels, which are increased, because (a) HIIT & co will increase the amount of fat that is released from the fat cells (esp. after the workouts), while they (b) burn less fat than "classic cardio" during the workouts. To consider that "health-damaging" would thus be unwarranted.

And while I cannot explain, though, is why we don't see more significant improvements in the blood lipid composition of the HIIT group, I do know that (a) this is likewise a result, scientists have previously observed in scientific studies and that (b), and more importantly, none of the inter-group differences (including the nasty increase in LDL) was statistically significant (in fact, the p - values were all p > 0.5 [no typo], when p < 0.05 would signify statistical significance).

Overall, the studies main and only message is thus exactly what you've read in the headline: You can lose highly significant and significantly more belly fat (not total body fat, where both groups lost the same 1-2% of their total fat mass | another potential explanation for the lack of sign. differences as far as health benefits are concerned) if you invest 2x20 minutes into HIIT training per week compared to "classic steady state cardio" aka MICT. That's the message of the study - a message I would like to complement with (a) the advice from the light blue box, i.e. "Whenever you're tryin' to lose weight, do resistance training, too. Your muscles will thank you!", and (b) the reminder that this is a single study with an important limiter that is not always valid in the real world, i.e. identical energy expenditure in both arms of the study, if that's not guaranteed (and usually people burn more during "cardio" than during HIIT (including its aftermath)) the HIIT advantage you see in this study may easily melt away | Comment!

References:

• Maillard, F., et al. "High-intensity interval training reduces abdominal fat mass in postmenopausal women with type 2 diabetes." Diabetes & Metabolism (2016).
• Weiss, P et al. "Effects of Weight Loss on Lean Mass, Strength, Bone, and Aerobic Capacity." Medicine & Science in Sports & Exercise: Post Acceptance: August 30, 2016 [ahead of print]. doi: 10.1249/MSS.0000000000001074.

High Dose Caffeine Restores Insulin Sensitivity and Limits Total as Well as Visceral Fat Gain Due to High Sugar Diets

Yes, the study at hand is on caffeine, but the results are relevant for coffee, too.

A decade ago, the medical community though coffee would dehydrate you, would make you insulin resistant and would increase your risk of heart disease. Recent studies show that coffee does not negatively affect your hydration status (Killer. 2014), that higher coffee consumption is associated with reduced diabetes risk and increasing your coffee consumption can reduce your risk of T2DM (Akash. 2014) and that a "daily intake of ∼2 to 3 cups of coffee appears to be safe and is associated with neutral to beneficial effects" on coronary heart disease, congestive heart failure, arrhythmias, and stroke (O'Keefe. 2013).

Against that background it may not be as surprising as it would have been 10 years ago that Joana C. Coelho, et al. (2016) found caffeine to be able to restores insulin sensitivity and glucose tolerance in high-sucrose diet rats. And yet, I personally believe that it is still worth pointing out the results of this study as the high sucrose diet the mice were fed is the same "high sugar diet" about which you will read all over the news that it is to blame for the obesity and diabetes epidemic.

You can learn more about coffee and caffeine at the SuppVersity

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Caffeine Resis- tance - Does It Even Exist?

Against that background, it is particularly interesting to take a closer look at the data from Coelho's study, because it is the first to actually provide a valid explanation for the observed improvements in glucose sensitivity in response to the ingestion of caffeine.

Figure 1: 16-wk food intake, weight gain, fat gain and visceral fat gain according to caffeine intake (Coelho. 2016).

Now, the bad news is that significant effects were only observed for the highest dose of caffeine, ie..e 1g/L drinking water. That appears to be ridiculously high, but is in fact only "very high". If you do take into consideration that a wistar rat consumes only 100 ml/kg body weight per day, that's a dosage equivalent of 100 mg/kg for a rodent and thus ~16 mg/kg for a human being or ~6-7 cups of coffee (over a 24h period).

University of Memphis: Caffeine can help control the increase in blood lipids and oxidation after inhaling (10 minutes) a high calorie + high fat milk shake, controlled trial involving twelve healthy men shows (Crone. 2016).

Yes, the dosage is high, but actually less may have more benefits, and...  the most relevant benefits (reduced fat gain) were seen at a dosage that would be equivalent to only 4-5 cups of coffee, which happens to be roughly what epidemiological studies show to be in the zone of maximal benefits. Don't mistake this as a recommendation to guzzle liters of coffee, though... and that even if another recent study shows that 400mg of caffeine will lower the fatty acid onslaught and oxidation 12 men experience after consuming a large high fat milk-shake (Crone. 2016)... and speaking of coffee: you may also want to make sure to get a dark roast, because the latter has just been found to improve glucose metabolism and redox balance even if it is low in caffeine (Di Girolamo. 2016). 

While I am not sure how healthy the chronic consumption of these amounts of caffeine actually is. I am aware of several people who get their 6-7 cups of regular coffee per day and are in perfect health. With that being said, the latter may be at least partly due to the the highly beneficial effects of caffeine on the expression of glucose transporter 4 (GLUT4) and insulin receptor expression and phosphorylation (not shown in Figure 2) in the visceral fat depots of coffee connaisseurs.

Figure 2: Effects of different doses of caffeine on GLUT4 and insulin receptor expression in rats (Coelho. 2016).

The above elevations were accompanied by profound increases in protein kinase B (Akt) expression and activity, as well - an observation the scientists regard as being evidence of the fact that "[c]hronic caffeine administration improved whole-body glucose homeostasis and insulin signaling pathways in adipose tissue" (Coelho. 2016).

This conclusion cannot be questioned. What can be questioned, though, is the scientists assumption that this would occur only with high doses of caffeine and in response to increases in GLUT4 and insulin receptor expression in the visceral fat. Why's that? Well take a look at the figure in the bottom line: it shows that significant improvements in glycemia were improved at all dosages. The latter wouldn't have been possible if the lower dosages wouldn't have had an effect on glucose uptake, as well. Whether that's an effect in muscle cells (which would be great), needs further investigation. The previously discussed effects of caffeine on muscle glycogen storage (learn more), on the other hand, would suggest just that: an effect on skeletal muscle, and or a reduction in gluconeogenesis which could, among other things, be triggered by coffee's / caffeine's ability to inhibit the reactivation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1" (Atanasov. 2006).

As you can see sign. improvements in glycemia occured even with the lowest amount of caffeine in the drinking water. And that in spite of the fact that the GLUT4 and insulin receptor levels in the visceral fat did not increase significantly... well, maybe those in the rodents' muscle did?

Bottom line: I am not suggesting that the rodent study at hand would provide enough evidence to suggest that everyone should drink at least 4 cups of high caffeine coffee per day. What I do suggest, however, is that the study at hand provides more evidence on potential mechanisms that explain why coffee drinkers are plagued less often by metabolic disease.

With that being said, I would like to remind you that the abuse of caffeine to combat a lack of sleep and/or overtraining may make you dig a deep black hole out of which you will be able to crawl only within weeks of abstinence... and I am talking about abstinence from caffeine and exercise, assuming that it was the combination of both that got your into trouble | Comment on Facebook!

References:

• Akash, Muhammad Sajid Hamid, Kanwal Rehman, and Shuqing Chen. "Effects of coffee on type 2 diabetes mellitus." Nutrition 30.7 (2014): 755-763.
• Atanasov, Atanas G., et al. "Coffee inhibits the reactivation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1: A glucocorticoid connection in the anti-diabetic action of coffee?." FEBS letters 580.17 (2006): 4081-4085.
• Coelho, Joana C., et al. "Caffeine Restores Insulin Sensitivity and Glucose tolerance in High-sucrose Diet Rats: Effects on Adipose Tissue."
• Crone, et al. "Impact of Meal Ingestion Rate and Caffeine Coingestion on Postprandial Lipemia and Oxidative Stress Following High-Fat Meal Consumption." Journal of Caffeine Research (2016): Ahead of print. DOI: 10.1089/jcr.2016.0004.
• Di Girolamo, Filippo Giorgio, et al. "Roasting intensity of naturally low-caffeine Laurina coffee modulates glucose metabolism and redox balance in humans." Nutrition (2016).
• Killer, Sophie C., Andrew K. Blannin, and Asker E. Jeukendrup. "No evidence of dehydration with moderate daily coffee intake: a counterbalanced cross-over study in a free-living population." PloS one 9.1 (2014): e84154.
• O'Keefe, James H., et al. "Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality." Journal of the American College of Cardiology 62.12 (2013): 1043-1051.

The Insulin / Glucagon Ratio and Why Diabetics and People W/ Severe Insulin Resistance Must be Careful With Protein

You're insulin resistant and trying to lose weight with high protein intakes? Then you got to read this article carefully...

High protein diets can help you lose weight while maintaining muscle mass. This should make them the ideal choice of diabetic patients, many of whom are suffering from weight issues that are often not corollary, but rather causatively involved in the development of type II diabetes.

Unfortunately, studies in type I diabetics and preliminary evidence from type II diabetics and other insulin resistant individuals suggests that - if the disease has progressed significantly - eating too much protein can be a problem, as well, one that may worsen the ill effects of diabetes.

Having high amounts of protein after fasting may ruin your glucose levels?!

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The reason for the potentially detrimental effects of high protein intakes on glycemia is well-known, but rarely acknowledge: gluconeogensis. As early as in the 1970s, researchers observed that the administration of a high-protein diets to rats, can significantly elevate plasma glucose and insulin concentrations and reduce the sensitivity of fat cells to insulin (Blazquez. 1970).

Figure 1: Post-prandial insulin and glucose levels in rats after several weeks of high protein feeding (Blazquez. 1970).

Over the decades after the publication of the Blazquez study, evidence for both the beneficial (Tremblay. 2007) and potential ill effects (Unger. 1971; Eisenstein. 1974) of high protein diets on diabetes and insulin resistance has been accumulating (Linn. 2000).

Sign. increases in urea prod. are another consequence of protein-based gluconeogenesis (Gannon. 2001).

As usual you will find conflicting evidence: In 2001, for example, Gannon et al. found only a modest increase in serum glucose levels in type II diabetics in response to the ingestion of 50g of protein - in spite of the fact that ~20-23g of it were converted to glucose in the liver.

What is important to note, however, is the fact that the protein source in the Gannon study was lean beef - one of the slowest sources of protein you can have and thus not exactly the #1 candidate for being subjects to immediate and thus glucose raising gluconeogenesis.

In that, it has been know for almost as long that the degree of offset of the ratio of glucagon to insulin in type I and II diabetics may decide, whether the ingestion of high(er) protein diets will help or hinder glucose management. In the pertinent, seminal review, Unger observes that "the insulin:glucagon ratio (I/G) varies inversely with need for endogenous glucose production, being lowest in total starvation and highest during loading with exogenous carbohydrate" (Unger. 1971). It is thus not surprising that studies have observed that

• the infusion of the glucose precursor, alanine, in the fasting state causes a fall in I/G, a “catabolic response,” but increases I/G during a glucose infusion, an ”anabolic response, which spares alanine from the fate of being abused for gluconeogenesis, 
• similar effects have been observed after a protein load; normally after an overnight fast I/G rises in response to a beef meal, an anabolic response, while in the carbohydrate-deprived subject, the I/G does not rise, remaining at a catabolic level (cf. Chevalier. 2006)

Now, back in the day these observations were mainly used to support the concept of a "protein sparing action" of glucose. Today, the effect on gluconeogenesis, i.e. the production of glucose from proteins / amino acids in the liver, has moved to the center of attention of a number of scientists. Calbet and MacLean, for example, investigated how the plasma glucagon and insulin responses of humans would depend on the rate of appearance of amino acids after ingestion of very fast vs. fast protein sources.

Figure 2: Glucose and glucagon levels in the blood of healthy volunteers after ingesting either 25g glucose or protein solutions containing whey protein hydrolysate (WPH), pea peptide hydrolysate (PPH) or milk protein (MS | Calbet. 2002).

Their results (see Figure 2) indicate the obvious: Even in healthy individuals and even upon co-administering protein sparing and 25 g of anti-gluconeogenic glucose, the fastest protein sources (whey protein, WPI; pea peptide hydrolysate; PPH) produce the highest increase in glucagon, gluconeogenesis and thus serum glucose levels in the first 20 minutes after the ingestion of the 25 g of glucose plus ~30g of the different proteins.

Let's just be clear here: I am not saying that high protein diets cannot help with diabetes. I am just saying that bolus intakes of protein can be problematic for type I diabetics and people with severe insulin resistance and progressive type II diabetes.

What may not be a major problem for healthy individuals, though, can be a deal-breaker for diabetics, in whom studies into the inter-organ flux of substrates after a protein-rich meal (slow digesting beef 3g/kg body weight) show that the normally non-significant effect on glycemia (<5% in healthy subjects) was exuberant in the diabetic subjects in whom you will see a greater rise in blood glucose, and a three-to-fourfold increment in splanchnic glucose output at 30-90 min that was triggered by a doubling of arterial glucagon, which was not compensated for by an concomitant increase in insulin as it occurred in the healthy test subjects (Wahren. 1976).

Figure 3: Rel. changes in blood glucose after ingestion of 3g/kg lean meat in healthy and diabetic subjects (Wahren. 1976).

Whether an increase in protein intake will have beneficial or ill effects on your ability to control your glucose levels will thus clearly depend on the degree of hepatic insulin resistance / pancreatic dysfunction you expose.

• If you are severely diabetic and/or insulin resistance, i.e. you either don't produce enough or no insulin in response to the ingestion of protein or your body does not react to the insulin, as it would be the case in type I diabetes and progressive type II diabetes, your glycemia may be impaired by high protein meals.
• If you are only slightly insulin resistant, you will probably benefit from the insulinogenic effects of protein and the ability to replace carbohydrates in your meals with protein. You may nevertheless want to test your individual glucose response to fast-digesting proteins like whey or amino acid supplements, which may still result in an uncontrolled gluconeogenic response.
• If you are healthy and insulin sensitive, you won't have to worry about the gluconeogenic effects of high protein intakes - regardless of whether we are talking about fast or slow protein sources, because the former will spike insulin enough to blunt any pro-gluconeogenic effects of the concomitant increase in glucagon to keep the rates of gluconeogenesis and thus your glucose levels in check.

So, just as you've read it here at the SuppVersity before, what's good and what's bad for your cannot be generalized - even when it comes to something as popular as increasing your protein intake.

What do you have to remember? High protein intakes, especially in form of large bolus intakes of 30g or more protein per session can trigger unwanted glucose excursions. These problems with glucose management occur almost exclusively in diabetics, in whom the protein-induced increase in insulin and / or the effects of this increase in insulin is / are blunted.

Figure 1: GIP and GLP-1 response to whey and white bread (left, top & bottom); insulin release (%) per islet relative to glucose after incubation with different amino acids, amino acid mixtures and mixture + GIP (Salehi. 2012) | more

Due to the unavoidable protein induced increase in glucagon, diabetics and people with severe insulin resistance will fall into a catabolic state in which the lions share of the protein they ingest will be subject to gluconeogenesis, i.e. the production of glucose from proteins / their amino acids in the liver. The consequence of the skyrocketing rates of gluco-neogenesis is an increase in blood glucose that will only exacerbate the existing damaging effects of elevated glucose levels in diabetics and people with severe insulin resistance. Since the of gluco-neogenesis depends on the rate of appearance of amino acids in the blood, fast-digesting proteins like whey are more prone to trigger this effect than slow-digesting proteins like meat.

If you don't belong to the previously referred to group of people suffering from type I or severe type II diabetes and/or severe insulin resistance, though, you don't have to worry that high(er) protein diets could mess with your ability to manage your glucose levels | Comment on Facebook!

References:

• Blazquez, E., and C. Lopez Quijada. "The effect of a high-protein diet on plasma glucose concentration, insulin sensitivity and plasma insulin in rats." Journal of Endocrinology 46.4 (1970): 445-451.
• Calbet, Jose AL, and Dave A. MacLean. "Plasma glucagon and insulin responses depend on the rate of appearance of amino acids after ingestion of different protein solutions in humans." The Journal of nutrition 132.8 (2002): 2174-2182.
• Chevalier, Stéphanie, et al. "The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism." Diabetes 55.3 (2006): 675-681.
• Eisenstein, Albert B., Inge Strack, and Alton Steiner. "Glucagon stimulation of hepatic gluconeogenesis in rats fed a high-protein, carbohydrate-free diet." Metabolism 23.1 (1974): 15-23.
• Gannon, M. C., et al. "Effect of Protein Ingestion on the Glucose Appearance Rate in People with Type 2 Diabetes 1." The Journal of Clinical Endocrinology & Metabolism 86.3 (2001): 1040-1047.
• Linn, T., et al. "Effect of long-term dietary protein intake on glucose metabolism in humans." Diabetologia 43.10 (2000): 1257-1265.
• Tremblay, Frédéric, et al. "Role of dietary proteins and amino acids in the pathogenesis of insulin resistance." Annu. Rev. Nutr. 27 (2007): 293-310.
• Unger, Roger H. "Glucagon and the insulin: glucagon ratio in diabetes and other catabolic illnesses." Diabetes 20.12 (1971): 834-838.
• Wahren, J., P. H. I. P. Felig, and L. A. R. S. Hagenfeldt. "Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus." Journal of Clinical Investigation 57.4 (1976): 987.

Nutrition Research Update: Stem Cell Treatment For Type II Diabetes, Probiotics and Weight Loss Reviewed (Twice) and D-Xylose Sweet Poison for Superfluous Body Fat

With the right diet and lifestyle, stem cell treatments, probiotic supplements or xylose-laden "functional foods" wouldn't be necessary in the first place.

You're probably used to it, but I am in the mood for bragging: The SuppVersity is where you'll read about the latest nutrition, exercise and supplement related studies first. In research updates like the one today, I am trying to provide a little more information than in the SV Facebook News, though, where I usually stick only to the main results of studies that have just been published or at least accepted for publication.

In today's installment of what I often call the "Short News", I will discuss three papers that are going to be published in one of the next issues of the peer-reviewed scientific journal Nutrition News.

Studies dealing with a pre-clinical, but promising stem cell therapy for diabetics, the verdict on probiotic supplements (including my evaluation of the scientists' verdict ;-) for weight loss and an update on the effects of the xylitol precursor d-xylose and its effect on mammalian fat cells in vivo.

Read older short news and true or false article at www.suppversity.com:

Pasta "Al Dente" = Anti-Diabetic

Vinegar & Gums for Weight Loss

Teflon Pans Will Kill You!

Yohimbine Burns Stubborn Fat

You Can Wash Pesticides Away

Milk = Poisonous Hormone Cocktail

• Stem Cells as Diabetes Treatment (Xing. 2015) - In software development you'd probably call the latest study from the Cangzhou City Central Hospital an "early alpha version" of an intriguing new way of treating type II diabetes.
  
  In their latest rodent study, Baoheng Xing et al. build on previous experiments in which pancreatic progenitors derived from human embryonic stem cells were shown to be able to effectively treat diabetes in mice (Kroon. 2008). In their study, however, Xing et al. went one step further and developed a system for treating diabetes using human embryonic stem cell–derived pancreatic endoderm in a mouse model of gestational diabetes mellitus.
  

  

  Figure 1: Glucose (a), insulin (b) and body weight (c) levels of wild type (wt) and treated (db/+PE) vs. untreated (db/+) pregnant mice before and during gestation, as well as Kaplan-Meier survival curves of litters show significant improvement right into the normal range in response to treatment (Xing. 2015)

  To this ends, the researchers had human embryonic stem cells differentiate in vitro into pancreatic endoderm, which were then transplanted into db/+ mice suffering from gestational diabetes mellitus.
  
  As the data in Figure 1 goes to show you, the transplant, of which the researchers expect that it could be used in humans, too, greatly improved the glucose metabolism and reproductive outcome of the treated female rats compared with the control groups. With their results Xing et al. do thus contribute to the growing evidence that diabetes may (sooner or later) be a "curable" disease when we are eventually mastering the use of differentiated human embryonic stem cells for treating general and gestational diabetes mellitus patients.
• Probiotics and weight loss - reviewed (Park. 2015): What's the verdict? You will remember that I am still skeptical with respect to the real world benefits of the new en-vogue supplements that contain billions of life or dead bacteria and promise benefits from increased gut health to... you guessed it, the most marketable of all benefits: weight loss!
  
  A recent systematic review by scientists from the Hoseo University and the Keimyung University in Korea presents the first attempt to summarize and critically evaluate the evidence from clinical trials that have tested the effectiveness of probiotics or foods containing probiotics as a treatment for weight loss. Literature searches of electronic databases such as PubMed, Cochrane Library, and EMBASE were conducted. Methodological quality was assessed using body weight and body mass index (BMI). Initial searches yielded 368 articles. Of these, only 9 met the selection criteria. Because of insufficient data, only 4 of the studies were randomized controlled trials (RCTs) that compared the therapeutic efficacy of probiotics with placebo.
  
  As my skepticism would have made me believe, the meta-analysis of these data showed no significant effect of probiotics on body weight and BMI (body weight, n = 196; mean difference, −1.77; 95% confidence interval, −4.84 to 1.29; P = .26; BMI, n = 154; mean difference, 0.77; 95% confidence interval, −0.24 to 1.78; P = .14).
  

  

  Figure 3: It's not like there were no benefits. You just have to look at the right parameters to see them. Studies like Kadooka et al. show that the effects on BMI are small compared to those on metabolically more relevant markers like total fat mass, waist circumference and visceral fat (Kadooka. 2015).

  That does not mean that there are no benefits at all, though. I reviewed the few studies that measured not just body weight and BMI, but also the subjects' body fat levels. This is an important difference, because a focus on BMI ignores potentially health relevant changes in body composition. Changes as they were observed by Kadooka et al. (2013; see Figure 3), for example, who found a significant time x group differences for visceral fat, fat percentage, fat mass, and waist circumference with much less pronounced effects on BMI (too low to influence the result of a systematic review significantly) in their 12-week study. In this context, it is also worth mentioning that Sanchez et al. (2014) observed a significant beneficial effect in obese women (but not man) for whom the consumption of 1.6 × 10^8 colony-forming units of LPR/capsule with oligofructose and inulin made it significantly easier to maintain their body weight after a weight loss intervention. Another benefit that must not be ignored.

A lot of choline and potassium, but also a significant amount of fiber, this simple meal has everything US and other inhabitants of the Westernized fast food world don't get enough of - so why even bother w/ supplements if your diet can have it all? | more

Scrape the probiotics grab the prebiotics: Unlike for probiotics, the evidence for the weight management benefits of various prebiotics (fiber that feeds the bacteria in your gut) is more promising. One has to be careful wrt to making overgeneralized statements based on evidence that has been generated with specific types of fiber, even though probiotic fiber has more to offer than just a weight loss effect: Improvements in blood pressure, blood glucose management and blood lipids are only three additional items on the "benefits of increased fiber intake"-list. Moreover, fiber is one of the nutrients for which westerners are at the highest risk of not getting enough in their fast food diets (learn more) if you want so supplement, "supplement" high fiber foods.

• Overall, I still feel obliged to repeat what I wrote in my recent article on the effects of sweeteners on the microbiome: We still have to learn very much about the effects of probiotics in general and individual types of gut bacteria, in particular, before we can actually give good strain-specific supplement recommendations. It's after all possible that the same strains that work in the obese subjects of studies like Kadooka (2015) won't work or even do the opposite in lean individuals.
• D-Xylose Exerts Epigenetic Anti-Obesity Effects and Stops Fat Cell Growth (Lim. 2015) - Yes, this is not the first study to show that the provision of D-Xylitol or, as in the case of a 2011 study by Amo,et al., its cousin and "artificial sweetener" xylitol can reduce the weight gain due to obesogenic diets. What makes it interesting, though, is that it involved two different, relatively low dosages of D-xylitol as they could easily be added to our own food chain.
  

  

  Figure 4: While the effects on body weight and fat gain were significant, the differences (expressed relative to the rodents on regular chow) are still significant, so even if you replace 5-10% of the sugar in your junkfood diet with the low calorie sweetener (2.4kcal/g), you will get fat. If anything it may completely prevent the increase in liver fat - albeit only if the dosage is high enough and the effects are identical in humans (data from Lim. 2015)

  With only 5% and 10% of the sucrose content of the high fat chow of the rodents in Lim et al.'s latest study being replaced by D-Xylose, the scientists observed
  • significant reductions in weight and more importantly fat gain
  • significant reductions in hepatic steatosis (NAFLD),
  • a reduction of the genes that are responsible for the storage of fat to normal (5%) and sub-normal (10% D-Xylose) levels, and
  • significant reductions in total cholesterol and low-density lipoprotein cholesterol, low-/high-density lipoprotein, and the important total cholesterol/high-density lipoprotein ratio.
  In view of the fact that replacing just a relatively small amount of sucrose in our diet with D-Xylose (and probably xylitol) can ameliorate the weight and adipose tissue gain, normalize blood glucose levels and blood lipid profiles and lower the lipid accumulation in the liver by "regulating expression of lipogenesis- and β-oxidation–related genes" (Lim. 2015), it is probably actually warranted to speculate, just like Lim et al., about a "possible application of d-xylose as a dietary supplement for the prevention of obesity-related metabolic disorders" (Lim. 2015) - even though clinical human trials are still warranted.

My recent article on "Getting Your Macros Straight" may help you improve your diet | learn more 

Bottom line: In spite of the fact that new developments like those discussed above are both exciting and promising, an active lifestyle and a largely unprocessed whole-foods high(er) protein lowe(er -/ compared to the current) carbohydrate diet that derives the lion's share of its fats from low(er) omega-6 foods, olive and other high MUFA oils, alone, would be enough to maintain healthy blood sugar and lipid, as well as body fat levels for most of us.

I mean, if you don't get fat in the first place, you don't have to take probiotic supplements or use stem cell therapy to handle or undo the damage you've done... right? | Comment!

References:

• Amo, Kikuko, et al. "Effects of xylitol on metabolic parameters and visceral fat accumulation." Journal of clinical biochemistry and nutrition 49.1 (2011): 1.
• Kadooka, Yukio, et al. "Effect of Lactobacillus gasseri SBT2055 in fermented milk on abdominal adiposity in adults in a randomised controlled trial." British Journal of Nutrition 110.09 (2013): 1696-1703.
• Kroon, Evert, et al. "Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo." Nature biotechnology 26.4 (2008): 443-452.
• Lim, Eunjin, et al. "d-Xylose suppresses adipogenesis and regulates lipid metabolism genes in high-fat diet–induced obese mice." Nutrition Research (2015).
• Park, Sunmin, and Ji-Hyun Bae. "Probiotics for Weight Loss: A Systematic Review and Meta-Analysis." Nutrition Research (2015).
• Sanchez, Marina, et al. "Effect of Lactobacillus rhamnosus CGMCC1. 3724 supplementation on weight loss and maintenance in obese men and women." Br J Nutr 111.8 (2014): 1507-19.
• Xing, Baoheng, et al. "Human embryonic stem cell-derived pancreatic endoderm alleviates diabetic pathology and improves reproductive outcome in C57BL/KsJ-Lepdb/+ gestational diabetes mellitus mice." Nutrition Research (2015).