— A Narrative Review
Above article became open access, because low carb supporters donated funds.
Click the link below to view the whole article.
Front. Nutr. | https://doi.org/10.3389/fnut.2021.687658
三高族的救星HEALTHY DIET |
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Don't fear fat. Eating saturated fat will not make you fat. Eating refined carbs will.
Low Carbohydrate Dietary Approaches for People With Type 2 Diabetes
— A Narrative Review Above article became open access, because low carb supporters donated funds. Click the link below to view the whole article. Front. Nutr. | https://doi.org/10.3389/fnut.2021.687658
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The earliest change in the pathogenesis of type 2 diabetes mellitus (T2DM) is muscle insulin resistance (IR in short) which could be detected in offsprings of diabetics before they become full-blown diabetics like their parents. Liver insulin resistance develops later when fat accumulates in the liver, as the liver cycle progresses in the “Twin Cycle Hypothesis”. Ironically, this hypothesis was proposed by Radiology Prof Taylor from England, & not any Endocrinologist. When the liver refuses to respond (ie. IR) to insulin action, which is to inhibit glucose production by the liver, excess glucose is poured into circulation. This leads to high fasting glucose levels, which stimulates more insulin production. Insulin stores fat in the liver & the vicious cycle goes on.
The other cycle in the hypothesis is pancreas cycle. When triglyceride (lipid) overflows from liver into blood stream, this state is called hypertriglyceridemia. It is our body’s attempt to transport excess fat from liver to other sites like subcutaneous tissue. When upper limit for fat storage in subcutaneous tissue is reached, fat is stored in other tissues like pancreas. Fat accumulation in islets of Langerhans interferes with its function (insulin production) and this is referred to as lipotoxicity. This leads to loss of first phase insulin response to a glucose load, with resultant postprandial hyperglycemia. This again stimulates more insulin secretion leading to more fat storage & transport to pancreas, forming the pancreas cycle. When a critical level is reached, pancreas fails & full blown T2DM emerges. One important message this hypothesis tells us is that these 2 vicious cycles are reversible! This is quite different from the current mainstream idea that T2DM is a progressive disease requiring ever-increasing medications including exogenous insulin. When Prof Taylor used Magnetic Resonance Imaging (MRI) to follow the T2DM patients who were losing weight, what he found was quite remarkable: when these diabetics lost about 15% of their original weight, their fasting glucose & HbA1c levels returned to non-diabetic levels. This is why Taylor believes the twin cycles are reversible. MRI has the advantage of being able to see the pancreatic fat which cannot be easily detected by ultrasound. Anyone who is interested in nutrition science must read above article, because it sheds light on good science that has been ignored by US dietary guidelines. 180 researchers & scientists from around the world, and their grad students, signed a letter trying to get this paper retracted, and it was a whole year-long battle. But ultimately, the paper survived, with exact corrections, but none of them affected any of the key allegations in the paper. And this paper has now been peer reviewed by pretty much everybody on the planet.
Nutrition coalition shared a paper with me recently & I was surprised to find that current nutrition advise for familial hypercholesterolemia (FH) is evidence-free! I extracted the key points from above paper & pasted below:
Atherogenic dyslipidaemia risk triad: triglycerides, high-density lipoprotein (HDL) and small, dense LDL. LDL-C is contained in heterogeneous particles which range in size and composition from a small, dense, triglyceride (TG) rich LDL (sdLDL) to a large, buoyant, cholesterol-enriched LDL (lbLDL). This distinction between LDL particle subclasses is important because sdLDL, unlike lbLDL, is a component of an atherogenic dyslipidaemia risk triad (ADRT), composed of elevated levels of TGs and sdLDL, in conjunction with low levels of HDL.8–10 23 Each of the three components of the ADRT, individually, has been associated with increased risk of CHD. For example, sdLDL, unlike lbLDL, is a unique marker of CHD risk, independent of LDL-C.24 Another study demonstrated that FH individuals, distinguished solely on the basis of having high TGs (>200 mg/dL), exhibited three times greater occurrence of a myocardial infarction (MI), compared with FH individuals with low TGs (<200 mg/dL).25 It is noteworthy that the association of high levels of TGs in FH with a high rate of MI occurrence was independent of their LDL-C levels (figure 1). Overall, the ADRT is a highly reliable measure of CHD risk in FH, as well as non-FH, individuals. Lipoprotein a Lipoprotein a [Lp(a)] is one of the most robust of all markers of CHD risk in FH and non-FH populations.26 Lp(a) contains a plasminogen-like glycoprotein, known as apolipoprotein (a), which is bound to the apolipoprotein B-100 of an LDL particle. Elevated levels of Lp(a) are more closely associated with CHD than is LDL-C. For example, Seed et al,27 showed that FH individuals with CHD had significantly greater levels of Lp(a) compared with FH without CHD; the association of Lp(a) with CHD in FH was independent of their LDL-C levels (figure 2). Haemostatic balance between coagulation and fibrinolysis A powerful influence on the development of CHD is the interplay between processes that promote clot formation (coagulation) and those that cause clots to lyse (fibrinolysis). There is extensive evidence, at cellular, metabolic and genetic levels of analysis, that the haemostatic balance in FH is shifted toward hypercoagulation. These findings were reviewed by Ravnskov et al,18 who found strong evidence of hypercoagulation, and not LDL-C, as a cause of CHD in FH. A subset of the literature is provided below.
Non-lipid CHD risk factors FH individuals are as susceptible to non-lipid CHD risk factors as non-FH individuals. The following is a subset of the literature that has documented this finding:
This blog is going to be a bit technical & intended for health care professionals who want more in-depth information about biomarkers that predict cardiovascular risk.
Canadian guidelines have included Apo-B as a biomarker to predict CV risk along side LDL-C but the US is lagging behind for reasons that are not clear. Click the word "Apo-B" & see the document about the details. I also have some cartoons that explains biochemical structure of lipoproteins. Click the word "cartoon" to see them. I am very surprised that TG/HDL ratio is so under-used by physicians in Taiwan & in Yangon. I will review a US study with huge sample size which shows the prediction power of TG/HDL ratio.
Methods: Survival analysis was done in 39,447 men grouped by TG/HDL-C ratio cut point of 3.5 and for metabolic syndrome. National Death Index International Classification of Diseases (ICD-9 and ICD-10) codes were used for CVD and CHD deaths occurring from 1970 to 2008. DISCUSSION This study shows that a high TG/HDL-C ratio in men is a predictor of mortality from CHD and CVD. The TG/HDL-C ratio had a significant and higher HR for mortality from CHD and CVD than was found for the TyG index (TG x Glucose). These 2 measures, TG/HDL-C ratio and TyG index, similarly predicted incidence of type 2 diabetes, but the HR associated with a high TG/HDL-C seems to make the ratio a preferred single parameter of measurement. In this study, we also noted that the HRs for prediction of CHD, CVD, and all-cause mortality were similar for the TG/HDL-C ratio and the metabolic syndrome except when the latter was adjusted for non-HDL-C and other factors (Table 2). Kannel et al. questioned whether this ratio is better than the total cholesterol/HDL-C ratio for defining risk for CHD. For the Framingham Heart Study population, these workers found that the TG/HDL-C correlated with insulin resistance (estimated by homeostasis model assessment–insulin resistance) only moderately. Furthermore, these ratios had power to predict CHD only slightly better than did the total cholesterol/HDL-C ratio. (My comment: slightly better means at least as good as TC/HDL ratio which is commonly presented in routine lab reports. However TG/HDL is rarely if ever printed on any lab report that I have ever seen!) 45% of persons with a high TG/HDL ratio did not have metabolic syndrome. Therefore, it independently points to greater risk for CVD. At the same time, the finding of a high ratio calls for more attention to individual metabolic risk factors such as abdominal obesity, hypertension, and dysglycemia. These 45% with high TG/HDL ratio don’t qualify for Met syn because it needs 3 criteria out of 5. Nevertheless, this study shows if ratio is >3.5 they are at higher risk than those <3.5 for mortality from CHD, CVD as well as all- cause! If a doc uses Met Syn criteria to screen for high risk persons, he will miss 45% of those with high risk of dying from all causes (ie. If he ignores those who have only high TG & low HDL). Docs who are brain-washed by statin producers focus on LDL-C only & ignores the importance of TG & HDL which is highlighted by this study with huge sample size & statistical power. I was reviewing a paper by “Cholesterol skeptics” the other day & I doubted whether they are evidence-based. They say, “If high LDL-C causes premature CVD in Familial Hypercholesterolemia (FH), the LDL-C of those with CVD should be higher compared to others, but at least 6 studies of untreated FH individuals have shown no significant differences in LDL-C or age.” I checked one of the references (NEJM 1990;322:1494-1499) they cite & was shocked to find hidden in the article the following facts. See for yourselves & feel free to go to that paper if you, like me, doubted cholesterol deniers.
Univariate comparison revealed five variables in which the group with CHD differed significantly from the group without CHD: age, sex, smoking status, log triglyceride, and log lipoprotein(a). No significant differences were observed between the two groups in serum total cholesterol, HDL cholesterol, or LDL cholesterol. Stepwise multiple-discriminant analysis of only the variables for which differences were significant was carried out post hoc to investigate the independence of these risk factors in predicting CHD among patients with familial hypercholesterolemia (Table 3). Note the P values for Total cholesterol, LDL-C & HDL-C are all >0.5 (no statistical significance). However, that of TG is significant! Check the link below if you want to confirm what I mentioned above: www.nejm.org/doi/full/10.1056/NEJM199005243222104 After years of waiting, another review article appears in peer reviewed journal reminding health care professionals not to be too obssessed with LDL-C.
Click the following link to see the full article. Formos J Endocrinol Metab 2017;8:49-54. This is an excerpt from news media describing the research done by one of the mainstream cancer researchers, Dr Lewis Cantley.
Dr. Cantley was a professor at Tufts University School of Medicine in the '80s when he identified a previously unknown enzyme, phosphoinositide-3-kinase, or PI3K, that would turn out to be a sort of master switch for cancer. The protein's normal function is to alert cells to the presence of insulin, prompting them to pump in glucose, cells' metabolic fuel. This signaling pathway is crucial to cells' growth, proliferation and survival, so it makes sense that malfunctions can cause serious problems. If the pathway runs too slowly, the body becomes insulin-resistant and cells fail to take up enough glucose: this is Type II diabetes. In cancer, however, the pathway shifts into high gear, providing tumors with an overabundant supply of glucose, which drives their growth. It turned out that the gene that encodes PI3K is the most frequently mutated cancer-promoting gene in humans—and in the years since Dr. Cantley's revolutionary discovery, it has been implicated in as many as 80 percent of cancers, including those of the breast, brain and bladder. The pathway has also served as a target for new drugs, including the breakthrough lymphoma and leukemia drug idelalisib, which in 2014 became the first PI3K inhibitor to be approved by the FDA. Dr. Cantley came to Weill Cornell Medicine in 2012, his scientific reputation well-established; he has won a host of prestigious international awards, and his name comes up frequently when colleagues speculate about future Nobel laureates. Since setting up his lab at Weill Cornell Medicine, he has continued to investigate the role of PI3K. One of oncology's major frustrations is that some drugs that aim to inhibit PI3K have been less successful in clinical trials than originally hoped. Blocking the enzyme should impede the signals that allow cancer cells to take in the high levels of glucose they need to survive, but it doesn't always work that way. In many patients, PI3K inhibitors cause blood sugar to spike, suggesting that the drugs meant to starve tumors were telling the liver that the body itself was starving, too. In response, the liver—which stores extra glucose in the form of a compound called glycogen—was sending too much sugar into the blood, which triggered the pancreas to release excess insulin. Meanwhile, these patients' tumors continued to grow. Dr. Cantley and his colleagues wondered whether the excess insulin might be countering the effect of the drugs by reactivating the PI3K pathway in the cancer cells. They theorized that a diet very low in carbohydrates—limiting both sugar and starch, which breaks down into simple sugars in the body—would prevent spikes in blood sugar and might help the drug do its work, starving the tumor while the patient's body fueled itself with fat and protein instead, a state called ketosis. So researchers in Dr. Cantley's lab, including instructor in medicine Dr. Benjamin Hopkins, worked with colleagues at Columbia University Irving Medical Center and NewYork-Presbyterian to test the hypothesis. Using mice that had been genetically engineered to develop pancreatic, bladder, endometrial and breast cancers and treated with a new PI3K inhibitor (which is currently in clinical trials), they demonstrated that spikes of insulin did indeed reactivate the pathway in tumors, countering the anti-cancer effect of the drug. But when the researchers severely restricted the mice's carbohydrate intake, putting them on what's known as a ketogenic diet in addition to the medication, the tumors shrank. (Adding a diabetes drug meant to lower blood sugar levels also helped, but the effects of the diet in conjunction with the PI3K inhibitor were more dramatic.) The encouraging results were published in the journal Nature in July 2018 with Dr. Hopkins as lead author. "The mutations to the PI3K pathway that cause cancer also enhance the ability of insulin to activate the enzyme," Dr. Cantley explains. "Our preclinical research suggests that if somewhere in your body you have one of these PI3K mutations and you eat a lot of rapid-release carbohydrates, every time your insulin goes up, it will drive the growth of a tumor. The evidence really suggests that if you have cancer, the sugar you're eating may be making it grow faster." Is Ketosis Key? The Internet is full of diet advice, and among today's hottest fads is a low-carb regimen popularly known as "keto." It was the most Googled diet trend of 2018, a popular weight loss strategy among celebrities like reality TV star Kourtney Kardashian and basketball icon Lebron James, who sometimes refer to it as "paleo," for its supposed resemblance to the diets of our Paleolithic ancestors. But that's not what clinicians or researchers mean when they talk about a ketogenic diet, explains Dr. Katie Hootman, a registered dietician and director of the Metabolic Research Unit at Weill Cornell Medicine's Clinical and Translational Science Center (CTSC). "The diets on the internet tend to be way too high in protein," she says. "There is a pretty big difference between that and a clinical ketogenic diet, one that's actually intended to get the patient into ketosis." Ketosis, Dr. Hootman explains, is a state in which the body relies on the metabolism of fat as the primary fuel to meet energy demands, rather than glucose, cells' preferred source of energy. From the breakdown of fat, the liver circulates molecules called ketone bodies, which cells use as fuel until carbohydrates become abundant again. This metabolic process evolved to help mammals survive food shortages, but in a clinical context it has been used since the early 20th century to reduce seizures in people with epilepsy. A few studies in the late 20th and early 21st centuries suggested a ketogenic diet might also be helpful against some forms of cancer, but it is only recently that researchers have studied its usefulness in conjunction with anti-cancer drugs. Among the clearest evidence is the Dr. Cantley Lab's mouse study, which Dr. Hootman is now helping to translate to human patients. In the meantime, Dr. Cantley—ever the anti-sugar evangelist—adds that limiting sweets certainly couldn't hurt. Eating less sugar, he says, is clearly beneficial. "It'll help you in so many different ways, with so many different diseases," he says. "And once you don't have that addiction anymore, it's actually quite easy. After all, I've had no trouble doing it for 40 years." Dr. Lewis Cantley has a very simple rule, he says. "I eat fruit, but I don't eat anything that has sugar added to it. And I guarantee everybody would be better off if they ate zero sugar." WHO recommends that populations consume less than 2 g/day sodium as a preventive measure against cardiovascular disease, but this target has not been achieved in any country. In PURE study, less than 1% of general population follow this recommendation. That's ridiculous! 2g sodium / day is approximately 5g NaCl (or 1 teaspoon of salt) and the PURE study is an international prospective epidemiolgy study involving 18 countries with a median follow-up of 8 years. If it is undoable, what good is that suggestion? Furthermore, there is also harm in that suggestion. Please read on to find out.
According to a study published in Lancet, 80% of people from mainland China consume more than 12.5 gm of salt /day whereas 84% of people from other countries have salt intake of 7.5 ~12.5 gm/ day. When we look at cardiovascular [CV] events (eg. Stroke or heart attacks), positive association is seen only in mainland China, which means higher salt intake is associated with stroke. In other countries, those in the highest tertile (one third) of salt intake (more than 12.5g/ day) have non-significant association with CV events. There was no association between salt intake and CV events in the middle tertile (salt intake 10 ~12.5 g/ day). In the lowest tertile (ie. Salt intake less than 10 g/ day), there is inverse association meaning less salt intake is associated with more CV events. One important finding is CV events decreased with increasing potassium intake (K in chemistry) in all countries. Therefore, those in countries other than mainland China, following WHO recommendation of low sodium intake might lead to more CV events. I will cite another study from Lancet which analyzed data from 4 studies and followed people for a mean period of 4 years. N = 133118 (63559 with hypertension & 69559 without hypertension), so a very large study with huge statistical power. Findings: in those people with hypertension, salt intake of more than 17.5 g/day AND less than 7.5 g/ day were both associated with increased risk of death or CV events (stroke or heart attack). Please note, this is the case in hypertensive patients. Those with normal blood pressure have another story: higher salt intake (NaCl more than 17.5 g/day) was NOT associated with risk of death or CV events. Read carefully please, in these people WITHOUT hypertension, salt intake < 7.5g/ day was associated with a significantly increased risk of death or CV events! What all these mean is: following WHO recommendation (salt intake < 5g/day) is likely to increase your risk of death or CV events whether or not you have hypertension. Luckily, only less than 1% of the world population complies to their darn suggestion. This brings up the issue of “salt sensitivity” which is found only in a small % of the population. In these salt-sensitive people, higher salt intake might increase blood pressure, but not in those insensitive to salt. There is also evidence that this salt sensitivity is related to sugar intake, so if you quit sugar or reduce its intake, your sensitivity to salt might improve, so blood pressure may not go up with increased salt intake. |
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