As a borderline pre-diabetic (IFG), I have recently had the (accidental) experience of inducing a temporary lowering of my fasting blood glucose for three weeks that occurred while eating a low-calorie ketogenic diet. My FG went from 90s or 100s down to 60s (and sometimes even high 50s many hours after last meal). Measurement of my beta-hydroxybutyrate (with a freshly-acquired personal meter) concentration somewhat after the 3-wk. interval (and return to my normal FG) gave a 6mmol/L reading -- a starvation level. I would suspect that the study cohort also sustained starvation-level (>3mmol/L) ketosis during their 2-mo. intervention period. After three mo., it's impressive that most still are clinically not diabetic. But I wonder how much below the T2D threshold they were, and whether more will return to T2D OGTT results after more time. My guess is that they will. The long-term anchor in the pathogenesis of T2D seems to be loss of beta-cell volume/mass/function. My own personal experience seems to indicate that certain supplements as well as ketosis can alter beta-cell behavior for some time (weeks or months), but a reversion to hyperglycemia then has occurred. This is my own conclusion as a layman, but it appears that nothing short of full recovery of normal beta-cell tissue will result in normal glucose regulation. Maybe this is possible in years, but I doubt it is in two months. Charles Mobbs at Mt. Sinai in NY has done a lot of interesting work on the effect of ketosis in altering glucose metabolism in many tissues, including the pancreas.View Thread
I would suggest that the difference in the pathogenesis associated with fasting hyperglycemia (or IFG) and insulin resistance (or IGT) in the progression between normal glycemia and T2DM offers a clue.
It appears, from my reading of some of the research, that IFG has a significant associated genetic aging of the tissues while IGT is more significantly acquired. Similarly, IGT is more responsive to intervention (both lifestyle and drug therapy). And the primary defect in IFG involves non-insulin-dependent basal glucose clearance, while that in IGT presumably involves insulin-dependent post-prandial glucose clearance more predominantly.
It is my own theory (or at least personal experience) that insulin resistance can be eliminated solely with diet and exercise -- more or less may be required in different people with different genetics. The same does not appear to be true of fasting hyperglycemia -- at least not in a time period of less than many years, if at all.
I am lean (~10% body fat), but not diabetic (yet). I am about halfway between normal and diabetic in terms of fasting glucose. It's clear, I think, that I am genetically susceptible to becoming diabetic -- I am in my fifties.
On the other hand, I have been overweight (BMI between 25 and 30) for a lot of my previous middle-aged life. I suspect, but can't prove, that this advanced my hyperglycemia more quickly than it would otherwise have progressed had I always remained lean and insulin-sensitive.
Not a very interesting story, nor very unusual I suspect, but there it is.
Also, it seems clear from what I have read that amongst the majority of the population which is not genetically susceptible to diabetes, any individual can nevertheless achieve enormously elevated blood-sugar levels. I have read of many cases > 500mg/dL, and my own uncle has been obese and highly insulin-resistant most of his life. But he, like others in this category, has an overdeveloped capability for insulin secretion and hence frequently has hypoglycemic reactions to heavy-carb meals that drive his blood sugar down to levels < 40mg/dL. In such individuals, merely cleaning up the diet (usually just a bit) usually results in a correction of glycemia very quickly (a few weeks or months at most).
Guenther Boden and others suggest that one of the key genetic differences between those susceptible to and those immune from T2DM is the gradual loss (or perpetual preservation) of the ability of the pancreas to adequately compensate for insulin resistance in the adipocytes (or degradation of the "antilipolytic effect of insulin", as it is usually phrased in the medical literature) to maintain normal plasma concentrations of FFAs/NEFAs. This is another characteristic that seems insensitive to lifestyle intervention, but is quite responsive to TZD therapy.
Hence, I suggest that the many effects of TZDs on the metabolism offer another big clue regarding the pathogenesis of T2DM. Maybe these drugs aren't ideal and have nasty side effects in some, but they certainly seem to offer insight into the deranged metabolism of hyperglycemia and IR.
Finally, while progression from IGT to frank diabetes is largely a continuum, the transition from IFG to diabetes appears to be more discrete. In particular, the regulation of normal plasma FFAs and basal glucose production is maintained in isolated-IFG because the pancreas maintains the ability to compensate for adipocyte and hepatic IR. Only in the final transition to overt diabetes is this feedback loop broken and heavy whole-body insulin resistance quickly supplants normal insulin sensitivity.
The common element between IFG and IGT seems to be susceptibility to loss of pancreatic beta-cell mass, volume and function. Hepatic IR (and probably adipocyte IR) appear to me to be largely genetic. Skeletal-muscle IR is partially genetic but can be readily overcome. Skeletal-muscle non-insulin-dependent glucose transport, etc. seems largely genetic.
It is impossible to overstate the importance of the observation that societies eating a traditional paleolithic diet have remained utterly devoid of modern chronic diseases. A few coastal communities may have eaten a lot of fish (which themselves often contain a lot of saturated fat as well as unsaturated fat depending upon the temperature of the waters they swim in), but the vast majority of humans ate big land animals and had the means to easily kill and collect them -- the anthropological evidence is clear and consistent.
Hence, I suggest that the two most important recommendations of the paleo-diet researchers should be followed:
1. Keep carbohydrate content low (extremely low by modern standards). Especially avoid sugars containing fructose. This avoids overweight, IR and metabolic syndrome. 2. Keep linoleic-acid content low. This means largely avoiding plant food that is calorie-dense, including grains and legumes (which also contain lots of phytochemicals that are chronically toxic to the human metabolism and auto-immune system). Especially avoid refined vegetable (e.g. grain, nut, legume) oils (not including olive oil which comes from fruit and is low in linoleic acid). This avoids systemic inflammation, leaky-gut syndrome, many auto-immune diseases, etc.
How low is "low"? Well, each individual should examine his own metabolic response to diet as he or she ages, and adjust the diet in order to remain lean. Do predators in the wild ever get overweight? Of course not. Do pet dogs and cats (bred from wild carnivores) get fat -- of course they do, because we pet owners feed them "pet food" which is full of cheaply produced carbohydrates -- cattle feed. We humans are just another species of carnivore -- we should eat like a carnivore and ideally feed our carnivore pets this way too -- at least, if we can afford to!
And we should feed our children this way and quit exposing them to hyperglycemia in the womb, so that they are born with severe hyperinsulinemia often leading to obesity and T2DM (so-called adult-onset diabetes) before their reaching the age of ten or twenty.
Sorry for the diatribe, Dr. Dansinger. I guess I drifted off-topic, oh well!
Do I infer from your question that you yourself are having doubts about the "common knowledge"?
If so, welcome to the club
P.S. I was born in the 1950s. Back then, everybody knew that sugars and starches were uniquely fattening and unhealthy. This "common knowledge" was born of centuries of human observation during post-agricultural times.
Loren Cordain is generally a good guy, and the gist of the paleo-diet concept is fundamental to understanding what havoc agriculture and especially the modern food industry has wrought upon human health, although I don't believe in the fundamentalist notion of "eat exactly like a paleolithic man" and Cordain certainly didn't come first to the observation that a paleo diet avoids modern chronic disease. But the idea of sat. fat in the diet inducing down-regulation of LDL receptors is just nonsense, and completely belied by the evidence.
Research on humans is a noble enterprise and difficult, and there should be no shame in getting a few things wrong for a while. In the specific case of demonizing dietary saturated fat (actually, just palmitic acid) Cordain has received a lot of criticism -- unfortunately well deserved, I think. His most distinctive contribution has been in the area of anthropological research in my opinion.
End, last part. Again, sorry for the diatribe. But I've had personal experience with both hyperglycemia and hyperlipidemia, and I hope to pass on what I think is valid knowledge that I have acquired in working to resolve my own problems. I have spent a lot of time and effort on this during the last six months, with some success I believe.View Thread
My last few BP readings were ~95/55 mm-Hg. Unlike LDL-c, BP actually does have a significant correlation to CVD. I haven't had BP readings like this since I was quite young, although I have never been too bad. And my insulin sensitivity is sky-high -- in the elite-athlete category. I do weight-train, but my high dietary intake of saturated fats certainly doesn't seem to be causing any IR.
I am not sure that Loren Cordain believes in the lipid hypothesis (I suspect not), but he does indite palmitic acid alone (amongst the saturated fatty acids commonly found in food) as promoting early-stage (i.e. immature and low-ischemia-risk) arterial plaque by means of being a pro-inflammatory prostaglandin precursor. This is backed up partly by theory and partly by anthropological evidence. Of course, palmitic acid is also the only fatty acid produced endogenously (in the liver) from excess carbohydrate alimentation. Cordain only claims that dietary palmitic acid adds a risk factor for CVD, but does not believe that it alone can induce CVD.
By this reasoning, however, eggs in the diet should also be avoided owing to their high arachidonic-acid content. A tiny segment of the population is actually sensitive to eggs in the diet, apparently due to a resultant increase of AA in the plasma. But almost all people do not have this problem -- the human body is generally very efficient at enzymatic transformation and regulation of metabolism thereby allowing for a lot of dietary variation. Genetic variations from the norm in some individuals are usually responsible for unusual dietary sensitivities.
Ectopic fat in the tissues (i.e. lipotoxicity) is a result of insulin resistance, and IR is induced by excessive carbohydrates in the diet (which probably causes damage via chronic hyperinsulinemic effects). Some individuals are more prone than others to IR, via genetically-sensitive aging effects in the tissues. My own iIFG condition is an example -- the detailed research on fasting hyperglycemia illustrates this. But, in general, the human species is not evolved to handle much carbohydrate in the diet. And this is not surprising, since not much was available before the age of agriculture and industry.
Naturally, most ectopic fat in the insulin-resistance body will be found to be saturated. After all, most of the human-body tissues are composed mostly of saturated fatty acids and the human metabolism will convert dietary fat to such if necessary to achieve the right balance. Krill we are not!
Again, in contrast to the mainstream notion (or propaganda), overweight is caused by IR (not vice versa). For anyone reasonably well-schooled in the metabolism of IR this is intuitively obvious (for example, insulin-resistant individuals lose the ability to oxidize fatty acids in skeletal muscle almost entirely due to lipotoxic effects, whereas the ability to oxidize glucose is largely maintained). It also is consistent with the careful research in prospective epidemiology -- IR precedes overweight by many years and precedes hyperglycemia by even more time. In close relatives and children of type-2 diabetics IR appears very early, while individuals are still lean and have normal glycemia.
In addition to lipotoxicity (resulting from elevated plasma FFAs that are always present in proportion to overweight), the other very significant associated condition that is often present in metabolic syndrome (or IR) is systemic (whole-body cellular-level) inflammation. Damaged adipocytes with excessive macrophages generate cytokines that appear to cause this inflammation. I find absolutely absurd the notion that saturated fat in the diet could be harmful. After all, the human species has evolved over its entire history to survive on large warm-blooded animal meat. The fat content of this prey is predominantly saturated (as in our own tissues).
I believe that the further improvement in the other lipids, and particularly the triglycerides, is consistent with my theory that my abnormally high baseline VLDL-remnant lifetime has been reduced by the statin. Despite a huge amount of reluctance and skepticism on my part, I will probably continue with the statin therapy as long as the side effects remain tolerable. I find the fundamental mechanism by which the statins work in the body to be frightening, however. The mainstream notion that these drugs are benign is absurd, and there is a lot of experience to demonstrate otherwise. The change in my own liver and muscle enzyme levels (while taking the statin) also suggest otherwise.
LDL-c in itself has very low correlation with CVD -- arguably not reliably statistically significant. If particle size is considered, that's a different story. But this has been partially understood since the late 1940s when the early ultracentrifuge work on blood lipids was done. Krauss, Packard and other contemporary researchers have expanded the understanding, but of course clinical measurement of lipid subfractions is still prohibitively expensive (despite NMR methods that have drastically reduced costs). If the only available tool is a hammer ........ everything begins to look like a nail.
Furthermore, ratios of triglycerides to lipoproteins are pretty reliable indicators of subfraction proportions in those same lipoprotein particles anyway. The research shows this consistently.
Of course, it's well understood and acknowledged that the lipid subfractions go to hell with a high-carb diet. That's certainly been my own experience, and I dare say that in my earlier days (before I became self-educated) my diet was vastly more healthy than that of most Americans. It was lower-than-average in carb's, higher-than-average in whole foods, and contained virtually no sugar. I now think that the effect of my not-so-bad diet of earlier times was exacerbated by a genetic susceptibility to diabetes and hypercholesterolemia -- since diabetes is really more of a lipid disease endocrinologically anyway (a la Denis McGarry's famous 1992 paper in Science -- "What if Minkowski Had Been Ageusic? ..."), I suspect that the two may be related as well. I recommend all to Gary Taubes' masterpiece on the horrendous history of dietary research in the last half of the 20th century -- "Good Calories, Bad Calories". Frankly, anyone who has not carefully read this book is not serious with regard to the subject -- I don't care what the other qualifications, especially including PHDs and MDs, are. The history fully explains the genesis and growth of the mistaken mainstream notions about fat and saturated fat and various arbitrary categories of fat in the diet -- it's a history of malign interests, corruption, incompetence and politics and a series of excuses for the dismal failure of an evolving lineage of lipid hypotheses to be confirmed in studies of human metabolism. A bunch of enormously expensive, taxpayer-funded studies disprove a hypothesis and then it is adjusted. And then the same fate awaits the newly adjusted hypothesis and it is again adjusted. And so on. I now eat a lot of animal meat, eggs, cheese, and (with some meals) a small amount of vegetables that are very low in density of sugars and starches (i.e. high-fiber). I sometimes eat a mix of tree nuts and peanuts -- this is mainly convenient for carry-around (away from the kitchen) food. The nut/legume mix completes the set of amino acids and is moderate in carb content -- it's about the most carb-intensive food that I ever eat. On a given day I might eat only eggs and meat and the only effect it seems to have is that I'll be likely to eat less -- fat is satiating and protein is even more so and even more long-lasting.
I am not going to bother to find an answer, because I have done a tremendous amount of reading on the subject. A lot of doctors may believe it, but it's been thoroughly disproven by a lot of studies and it never made any theoretical sense anyway. And it's important to remember, only one instance of violation of a scientific hypothesis fully disproves it. Admittedly, humans are difficult to experiment upon, and so there is often some question about the reliability of even the most careful study on human subjects. But when study after study after study over many years disproves the hypothesis, it's time to move on. I am an engineer and scientist, and I develop physical products that rely upon the laws of nature -- if I accidentally violate the laws of nature through lack of understanding an immediate and harsh punishment is imposed; the darned thing doesn't work! And I then must figure out why and adjust my understanding to the actual laws of nature, but fast. In my world it's hard to carry on the fraud so prevalent in the world of people, politics and medicine. My discipline is fairly intolerant of ignorance and incompetence.
I have hypercholesterolemia (probably polygenic) without the use of a statin. I have experience experimenting on my own body. I know how it responds to diet, and have read of the experience of lots of others (including many, many clinicians) whose results match my own.
I only reached truly hypercholesterolemic LDL-c concentrations (~260mg/dl) after going to a very low-carb diet. I believe that I know why -- LDL receptors in the liver are responsible for the clearance of both VLDL remnants (i.e. LDL) and chylomicron remnants from the plasma. In going to a low-carb diet my dietary fat intake increased, and hence so did my plasma chylomicron load. My LDL-receptor capacity is genetically compromised, and hence a higher chylomicron load further reduced my liver's ability to clear VLDL remnants (hence further increasing my LDL-c).
Up-regulation of LDL receptors is one of two things that statins do well, and the only thing that they were actually designed for. In most people this is entirely unnecessary. Even for myself, it is questionable whether primary prevention using statins will be of benefit. For the general population the vast number of studies over the years have disproven any benefit of statins for primary prevention. For those with hypercholesterolemia no study has been done (with a group not pre-selected for CVD).
One can come up with a theoretical argument (i.e. unproven hypothesis) that reducing the lifetime of LDL particles in the plasma will reduce CVD risk. Nevertheless, the epidemiological history of familial hypercholesterolemia shows that for most of the last two centuries individuals with genetic FH had LOWER risk of CVD -- about half of that of the general population in the 19th century. Put that in your pipe and smoke it, Dr. Watson!
Prior to going low-carb, I had metabolic syndrome (i.e. insulin resistance and its sequelae) to an increasing degree as I got older (when I was young I ate like a pig and always stayed lean and physically/athletically fit). After going low-carb I have maintained a 10% body-fat composition with relative ease, and I eat liberally. My non-LDL lipids have improved enormously:
Tg: 55mg/dL, HDL-c: 87mg/dL, and LDL: 154mg/dL
The triglycerides and HDL-c were already good before I started the statin and after I had started a low-carb diet, but they got better with the statin. The LDL-c was reduced by ~40% (I take the minimum recommended dose of statin).
In this context, "basal" is the same as "fasting". Normal basal/fasting BG is ~75mg/dL. Diabetic (by clinical definition) is 126mg/dL or more.
Hence, significantly above 75mg/dL is "degraded". The diabetes research community is pushing to have the ADA lower threshold for "pre-diabetes" (based upon IFG -- so-called "impaired fasting glucose") reduced from the present 100mg/dL to 90mg/dL, because it is well understood at this point that anyone who has a true FBG of 90 or more is well along in the progression of diabetes and should be made aware of it.
Basal glucose metabolism is, in my opinion, significantly distinct from post-prandial metabolism. Ralph DeFronzo and his group have found that the primary defect (i.e. cause) in fasting hyperglycemia is in the skeletal-muscle non-insulin-dependent pathway (which is responsible for ~85% of glucose uptake under fasting conditions). An aging of the tissues, involving gene expression, gradually reduces the glucose uptake at normal fasting concentrations -- this results in a higher fasting level in homeostasis (or equilibrium). On the other hand, post-prandial response is highly dependent upon the insulin-dependent pathways in various tissues.
However, as loss of pancreatic function (i.e. insulin-secretory capability) always occurs in true diabetic progression, in an isolated-IFG (i.e. I have no whole-body insulin resistance or IGT -- so-called "impaired glucose tolerance" -- which is the other category of pre-diabetes) case such as myself there is an effect upon post-prandial response. For me, it is primarily a loss of acute or 1st-phase insulin response, resulting in a higher BG in the first hour or so after a meal (until the 2nd-phase insulin response kicks in). According to DeFronzo I have lost about 60% of my overall post-prandial insulin capability. This is probably due to a combination of loss of beta-cell mass/volume (including the vesicles that are used to store insulin for the 1st-phase response) and an apparent effect of elevated FBG in reducing the sensitivity of beta cells to BG concentration. Hence, there is probably both a permanent and a recoverable component to the "degradation" of pancreas function. Recovery of some of my insulin secretion would occur if I could lower my fasting BG.
Thanks for the tips, Dr. Dansinger. I think I am OK regarding particle size -- my last HDL-c = 87mg/dL and triglycerides = 55mg/dL. I haven't had NMR-measured subfractions, but with a Tg/HDL ratio < 1 I am confident that there is no degradation of particle size as in metabolic syndrome and T2DM.
I take ~2g EPA/DHA and 5000IU vitamin-D3 daily too.
Overweight, IGT and T2DM all come with elevated plasma FFA caused by IR in the adipocytes (and associated lipids degradation), but IIFG does not. Possibly the degradation of basal glucose regulation I have has resulted from metabolic syndrome that I have previously had.
If that's the case then I may be able to arrest the degradation by sticking with my current diet and exercise program. Maybe the basal regulation will eventually even improve, but if so I am guessing that will take years to become noticeable.
Thanks again for your last response. I haven't checked back in for a while and just now have read it.
I think you understand my conundrum -- what is best for me to do now that I recognize my hyperglycemia?
You might be interested in the fasting-insulin/glucose readings that I had done recently, at your suggestion. They were: FI: 2 mclU/ml, FG: 79 mg/dL
My normal FG is ~100 mg/dL -- I know that this reading was abnormally low, apparently because of some exercise (shoveling snow) done the evening prior. My HbA1c reading done at the same time was 5.6%. Recent OGTT readings were: 0-hr. 99 mg/dL, 2-hr. 91 mg/dL
My crude interpretation of all this is that my insulin sensitivity is probably even higher than normal, and that my primary problem (at this point, anyway) is loss of insulin secretion. A paper by DeFronzo et al ( http://www.ncbi.nlm.nih.gov/pubmed/18492770 ) indicates that for IIFG with FG in the 95-100 mg/dL range there is ~60% loss of pancreatic function (i.e. IS). So that's where I am at, I guess.
I wonder how I might arrest and even reverse the loss of beta-cell function, and if my own pathogenesis is purely genetic (i.e. aging of the tissues via changing genetic expression) at this point, or not.
The results of the various studies of TZD treatment of pre-diabetes are intriguing. If DeFronzo's theory of the primary defect in IIFG is correct then TZDs would seem to be my only hope of actual reversal (i.e. lowering of FG), within the scope of current knowledge. Outside of a research study, however, I recognize that few if any clinicians would choose to prescribe a TZD at my present level of hyperglycemia. I don't particularly like the idea of taking a drug, but if the progression is insensitive to anything else it might be worth considering.
I guess I probably have many years of time before progressing to diabetes, in the worst case, and hopefully the research will generate more understanding of the etiology and treatment of fasting hyperglycemia.View Thread
I think that a big reason most PCPs don't make specific lifestyle recommendations is that they disagree with or are not confident in the mainstream medical notions of what is a healthy diet.
Since I believe almost all of these mainstream notions are DEAD wrong, I sympathize with this. My own PCP at one time advised me to lose weight, but never commented upon how to do it.
With respect to exercise, it's relatively ineffective in the presence of significant whole-body insulin resistance and a high-carbohydrate diet at achieving leanness. On the other hand, once the IR is eliminated then exercise works well at maintaining and increasing leanness and insulin sensitivity.
I suspect many experienced PCPs know that recommending exercise is unlikely to produce results because of the above-described problem for overweight individuals as well as other factors.
People need to become self-educated. If they have the discipline to do this, the rest of it will come in due time.View Thread
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