The ‘X’ Factor – T2D 21

posted in: Diabetes | 40

Searching for the X factor

Hyperinsulinemia plays the dominant role in provoking obesity and fatty liver disease, but what causes it? Insulin is intimately related to our diet, so that was naturally the first place to look. Highly refined and processed carbohydrates, such as sugars, flour, bread, pasta, muffins, donuts, rice and potatoes are well known to raise blood glucose and insulin production. This became known as the carbohydrate-insulin hypothesis, and forms the rational basis for many of the low carbohydrate diets such as the Atkins diet.

These are not new ideas, but very old ones. The first low carbohydrate diet dates all the way back to the mid 19th century. William Banting (1796–1878) published in 1863 the pamphlet Letter on Corpulence, Addressed to the Public, which is often considered the world’s first diet book. Weighing 202 pounds (91.6 kilograms), Banting had been trying unsuccessfully to lose weight by eating less and exercising more. But, just as today’s dieters, he was unsuccessful.xfactorpost1

On the advice of his surgeon, Banting tried a new approach. He strenuously avoided all breads, milk, beer, sweets and potatoes that had previously made up a large portion of his diet. William Banting lost weight, and successfully kept it off. For most of the next century, diets low in refined carbohydrates were accepted as the standard treatment for obesity.

For all the success of low carb diets, the carbohydrate insulin hypothesis remains incomplete. High dietary intake of refined carbohydrates is an important contributor to high insulin levels, but not the only contributor. There are many other significant influences. For this, we need to understand insulin resistance.

Insulin Resistance – The Major Player

Insulin acts like a key to open a gate for glucose to enter the cell for energy. In the insulin resistance state, normal levels of insulin no longer open this gate and glucose piles up outside in the bloodstream.insul-resistance

To compensate, the body produces more insulin to ‘overcome’ this resistance and force the blood glucose inside the cell. This normalizes blood glucose levels at the cost of persistent hyperinsulinemia. We care about insulin resistance so much because this hyperinsulinemia will drive overall weight gain. But how does this insulin resistance develop in the first place?

Does Obesity cause IR?

Type 2 diabetes is a disease of high insulin resistance. Obesity typically precedes the diagnosis of type 2 diabetes by a decade or more, so many presume that obesity itself causes insulin resistance. Decreased insulin resistance often accompanies weight loss. Insulin resistance gradually increases with obesity and further with pre-diabetes and type 2 diabetes. Obese, but otherwise normal (non-diabetic) patients have substantially increased insulin resistance compared to lean patients. Insulin resistance increases as you progress through the spectrum of obesity, pre-diabetes and then type 2 diabetes.

Understanding how obesity actually causes insulin resistance proved difficult. The first suspect was elevated fatty acids in the blood, which are increased with obesity. Insulin activates LPL, moving those fatty acids into adipocytes for storage. Fatty acid levels should not stay high unless insulin is not working properly. In other words, insulin resistance causes high fatty acid levels, rather than the other way around. This is reinforced by the fact that infusions of free fatty acids into the blood do not raise insulin resistance.

So, if fatty acids were not the causal factor, what was? Adiponectin, involved in fatty acid oxidation, was identified in 1995. However, the role it plays in obesity and IR is still unknown. Resistin, discovered in 2001, was given its name in the mistaken belief that it was the long-lost hormone that caused insulin resistance. Other factors such as interleukin-6, tumor necrosis factor, retinol-binding protein 4 and plasminogen-activating factor has all been investigated as a contributing hormone, but all have been found inadequate.

Unable to find the hormonal mediator of insulin resistance despite 35 years of intensive and dogged research, it is best to consider that perhaps obesity does not cause insulin resistance. After all, obesity and insulin resistance can be related in three possible ways. First, obesity might cause IR. However, this does not explain the importance of central obesity, or how type 2 diabetes can develop in normal weight patients. Insulin resistance may cause obesity, but this is unlikely since obesity typically pre-dates insulin resistance. Decades of intense research yields no definitive proof exists that either is true.xfactorpost2

A third, more likely possibility exists. The same fundamental root cause may underlie both obesity and insulin resistance and possibly other closely associated diseases. The past twenty years had identified syndrome X, now known as the metabolic syndrome (MetS).

Metabolic Syndrome

Our understanding of the metabolic syndrome began in the 1950s, when high triglycerides were noted to be highly associated with CV disease. In 1961, Dr. Ahrens showed that this abnormality was primarily related to excess dietary carbohydrates rather than dietary fat, as widely expected at the time.

Around the same time, early insulin assays confirmed that many people with relatively minor blood glucose elevations had severe hyperinsulinemia. This was understood as a compensatory mechanism to the elevated insulin resistance. In 1963, the observation that patients with heart attacks often had both high triglycerides and hyperinsulinemia first linked these two diseases.

High blood pressure (hypertension) was associated with hyperinsulinemia as early as 1966 (9). By 1985, researchers showed that much of essential hypertension, so called because the underlying cause had not been identified, was also closely associated with high insulin levels.

By the 1980s all the essential features of metabolic syndrome were identified and established – central obesity, insulin resistance, dyslipidemia (high triglycerides and low HDL) and hypertension. Dr. Gerald Reaven of Stanford University introduced this concept of a single syndrome in his Banting Medal address of 1988, one of the highest profile academic lectures in all of diabetic medicine, calling it ‘Syndrome X’.

The ‘X’ moniker was chosen since it is commonly used in algebra to denote this single unknown variable, emphasizing that this syndrome shared a common underlying pathophysiology as yet unknown. These were not all individual risk factors, but one unified, critically important syndrome.

The 2005 National Cholesterol Education Program (NCEP) Adult Treatment Program III (ATP III) defines the metabolic syndrome as three of the following five conditions:

  • Abdominal obesity – Men over 40 inches, women over 35 inches
  • High Blood Glucose – over 100 mg/dL or taking medication
  • High Triglycerides – > 150 mg/dL or taking medication
  • Low High Density Lipoprotein (HDL) – <40 mg/dL (men) or <50 mg/dL (women) or taking medication
  • High Blood pressure – >130 mmHg systolic or >85 diastolic or taking medications

Each additional component of metabolic syndrome increases the risk of future cardiovascular disease. The metabolic syndrome identifies patients with shared group of risk factors that all have a common origin. Insulin resistance, central obesity, high blood pressure and abnormal lipids all reflect a single underlying problem, the unknown X. While obesity is commonly associated, the metabolic syndrome could also be found in approximately 25% of non-obese individuals with normal glucose tolerance levels.

High levels of Low Density Lipoprotein (LDL or ‘bad’ cholesterol) are pointedly NOT one of the criterions of the metabolic syndrome. Many doctors and professional guidelines obsess about LDL, and resort to prescribing statin medications to lower it. High LDL is not part of constellation of the metabolic syndrome, and may not have the same origins.

The prevalence of metabolic syndrome in the United States varies from 22% to 34% depending upon the specific criteria. This is not a rare disease, but instead one that affects close to 1/3 of adult population of North America. This constellation increases the risk of heart disease by almost 300%. Metabolic syndrome also increased the risk of stroke, cancer, NASH, PCOS, and obstructive sleep apnea. Even more worrisome, this MetS is increasingly being diagnosed in children.

Recent research has supported and extended this concept of a single syndrome with a common cause. Other metabolic abnormalities, including endothelial dysfunction, increased inflammation, sympathetic tone and coagulation have been noted. All the major diseases of the 21st century were all related to a common cause. But what was it?xfactor

Insulin resistance became established as the central, essential feature of the metabolic syndrome. For this reason, the name Insulin Resistance Syndrome has also been applied and the hyperinsulinemia is understood as a compensatory mechanism. But this does not further our understanding. If insulin resistance causes syndrome X, what causes insulin resistance?

Dr. Reaven hypothesized that chronically hyperinsulinemia was not so innocent. Hyperinsulinemia may cause hypertension through salt and water retention. Hyperinsulinemia stimulates triglyceride synthesis in the liver, which are secreted into the bloodstream as VLDL. Hyperinsulinemia causes obesity. Hyperinsulinemia was causing insulin resistance.


40 Responses

  1. Fantastic explanation of the deduction of the causal factors associated with T2 diabetes. Understanding how the system works and issues that arise within it really helps to motivate me in taking the steps necessary to lose the weight I need to. FInding your work and reading your articles has given me a new lease on life.

  2. Off Topic .. but ..

    Dr Fung have you tried dry fasting? Have you thought about writing about dry fasting?

    Thanks in advance

    • Yes, I would like to hear Dr. Fung’s thoughts on dry fasting as well.

      • To both honeycomb and john,
        You can go on, in the “ask the experts” section, and ask your question directly to Dr Fung. He has a section dedicated to him on that website. I’ve done it myself and was very pleased at quality of his answers and timeliness, too.

    • He talks about it in his latest book and doesn’t recommend it.

    • From what I’ve read so far at Dr. Fung’s old book & blogs and other Doctor’s recommendation re: fasting, the difference between Water Fasting to Dry Fasting is the same as Healthy Fasting to Starvation. Depending on the length of fasting, dehydration can set in and that’s not where you want to be.

  3. So how do people eat high carb vegan diets and are skinny and healthy?

    • While some people can eat a high carb vegan diet and remain skinny (and maybe healthy, maybe not), not everyone can. It all depends on your degree of insulin resistance.

    • sten bjorsell

      Patrick “So how do people eat high carb vegan diets and are skinny and healthy”.
      1/ Have never heard of anyone that have cured metabolic syndrome that way. I.e. you must be healthy to start
      2/ You must never overeat

      It is very hard but possible to not overeat on such diets. Naturally it works well in overall shortages, but life span is usually not very long. For instance Indian researcher S.L. Malhotra found 12 years shorter life span and 7 times higher incidence of heart disease in Indian railway workers on mainly low fat vegetarian diet compared to those having access to milk fat and meat. This was in the 1960’s when nearly all were slim. Not yet any diabetes-2 then as very common in India today.

    • Patrick, our bodies seem to be able to tolerate a wide variety of diets for a time and still allow people to appear skinny and healthy. Detailed tests might show a different picture as the drop out rate for vegans (and vegetarians) is very high, with most citing health as the reason. Those that are left are the best motivated and perhaps the best suited to the diet. Many ex-vegetarians are quiet about changing their diet because of the disapproval, and even ostracism, received from more committed or successful vegetarians.

      I think it’s possible to eat a very good vegetarian diet and a terrible diet that includes meat, but I also think it’s possible to eat a terrible vegetarian diet and a good one including meat. Many vegetarians I know seem to eat lots of pasta and use vegetable oil, neither of which I want in my food, and most don’t look at all healthy. And it’s much harder for vegans, particularly long term.

      There have been a number of reports in Europe of children brought up by vegan parents being taken into hospital and intensive care because of serious nutrient deficiency. More sensible vegans tend to take a lot of supplements. I think it is very difficult to make a health case for veganism, but easier for well-informed vegetarian diet. These are essentially moral positions with most health claims standing little scrutiny.

      Vegetarian websites regularly claim that eating meat causes diabetes by a bafflingly implausible path. I doubt Dr Fung will be supporting this theory any time soon.

    • Dr Fung actually talks about this in Obesity Code. This is one factoid that led him to believe it is not solely eating processed foods that is unhealthy but rather the persistent and high insulin levels. Consequently, one should not eat between meals as those of us baby boomers remember our mothers (yes, back then we were raised by our parents) disallowing snacking as it would spoil our appetites.

    • i’ve read many vegans who complain that they think they are eating a good diet but continue to gain weight. Its all the degree of insuling resistance, same as some people can get better with lchf diets , others have to fast short periods, very resistant people have to do long fasts.

  4. These posts bother me because they isolate a problem or highlight one but then don’t offer a solution. Perhaps there isn’t one, but that would be good information also. I feel like we’re getting half the story here. If it’s all unknown does that mean our efforts to lose weight are futile since we’re not treating the underlying Syndrome X?

    • If you are eating Low Carb and/or Fasting, you ARE addressing the underlying Syndrome X. When you lower your insulin levels, you lower your chances for Syndrome X and the diseases associated with it.

      • Exactly! The ‘X Factor’ is hyperinsulinemia. Treat that and you treat the syndrome.

    • sten bjorsell

      Maybe you did not read the last line in the post: “High insulin causes insulin resistance”.
      To reduce it, read Jason’s earlier great posts. Intermittent fasting -IF- seems to be the quickest lasting way to get results.
      But also reduce carbs and insulinogenic foods and increase healthy fats like butter and coconut fat that do not easily become rancid. The “glycemic index” is close, else google “insulin index”. Start eating more fats before IF as it makes it easier to fast.

    • Nicole sapp

      I agree. It doesn’t mention what you do about syndrome x or really if the know the cause. I did a little digging and found out that a specific gene mutation may be the ultimate cause. This gene mutation causes inefficient processing of certain chemical signals which effect your ability to do certain things. I.end. detox for instance. Then that overload of toxins doesn’t let the body function normally leading to insulin resistance.

    • Nicole sapp

      But the cause may be different for different people.

  5. How will physical activity lower hyperinsulinemia? It does cure Diabetes…

  6. John Schiffel

    Wondering why a fasting insulin level isn’t ordered more often by physicians. Wouldn’t that be a clear marker of insulin resistance?

    • Post-glucose insulin vastly more useful – hence all the Kraft stuff. He eschewed fasting insulin – pretty much dismissed it – shows why in early chapter of his book.

      Rosedale mentioned that he always ran fasting insulin (radioimmunoassay). He mentioned that many labs discontinued radioimmunoassay, and then the fasting insulin results bounced all over the place. Another reason why fasting insulin is dodgy — remember Dr. Kraft had the immunoassay all the way – that’s why his work is so crucial. And he dismissed FI even though he had a great assay at play…

      Elevated triglyceride/HDL ratio is a proxy for insulin resistance.

      Dr. Jason Fung: “Serum insulin fluctuates too much to be useful.”

      Maybe now with poor assays and with what I mentioned above i.e. limitations of ‘fasting’ readings…  I would not overly trust HbA1c as early flag unless high 5’s or over 6… (indirect measure of long term insulin stimulation).

      Random, non-fasting tests in general – gives much better indication of the metabolic state.

      Catherine Crofts: “A lot of my thesis was about telling “signal” from “noise” and insulin has to be the most frustratingly fickle protein I have ever had to work with.  We are so used to working in a static system and since most of the normal measures we use, (such as fasting blood glucose, HbA1c, TG etc ) are sufficiently stable that we can use them in a static system. Ideally , though, these measures should be tracked over time.”

      And she verified Kraft’s work re: FI

      I think it’s just easier to use the triglyceride/HDL ratio as a marker of insulin resistance.

      • John Schiffel

        Thanks for taking the time to share and pointing me in a better direction, Gary. A little googling quickly confirms the validity of your comments. Dr. Joseph R. Kraft’s book looks interesting: Diabetes Epidemic and You. I’m going to pull out the results of last lipid panel and calc TG/HDL; looks like anything over 2.75 deserves followup.

        BTW, heard anything about the time line for the new book by D. Ron Rosedale?

  7. Can metformin reduce blood pressure in patients who do not have a particularly elevated blood sugar level. I have BS level at circa 5.6, have normal weight (80kg at 6ft height) but BP of 150/90 and wondered whether metformin might help rather than other medication.

    • Barry, unless the benefits are crystal clear, I’d much rather avoid drugs and their unpredictable consequences. Diet, sensible fasting, exercise and lifestyle are the way to go.

      Lowering moderately-high blood pressure with drugs is questionable, particularly for mild to medium readings (140 – 159) systolic.

      The following extracts are from ‘Does Treating High Blood Pressure Do Any Good?’ by Dr Kendrick (on

      “Nine thousand people were treated for raised blood pressure for five years. At the end of the study five more people were alive in the treatment arm than the placebo arm. A result so deeply unimpressive that it fitted comfortably within the possibility of it being purely a chance finding. Or, to put it another way, this study failed completely to reach the holy grail of medical studies – statistical significance.

      “It seemed from this very large, long-term study, that lowering mild/moderately raised blood pressure was of no benefit. Certainly not when you set it against billions of dollars it costs, and years of potential side-effects. I do remember thinking at the time. Well, that should cause a massive re-think in the whole area. But it did not. Not even slightly. This result was basically swept aside and ignored.”

  8. Rajesh Pankaj

    Bravo Dr. Fung!

    One more Gem is out from your knowledge treasure. I am really getting educated here.

  9. its something to do with high concentrations of glucose in the duodenum , seems to cause upregulation of glucose transporters in that section of the GI tract aswell as growth of the pancreas ( pancreas has insulin receptors on it which cause growth in a autocrine loop )

    The fact that gastric bypass resolves hyperinsulinemia very quickly might suggest there exists some kind of important cross-talk between intestine and pancreas/liver axis that regulates fasting insulin levels.

  10. John Voyles

    While I did not check his sources, Gary Taubes in “Why We Get Fat” mentions how treatment for obesity in the early 20th Century consisted of placing patients on complete bed rest, and HFLC diets. This is remarkable, given the nutritional and physiological state of the art of that time? But it suggests a practical, results-based approach that was not influenced by special interests motivated more by profit, than seeking best practices for obesity treatment? I keep posting these articles on Facebook, hoping that some might read past the hype that commercialized health advice showers upon us?

  11. sten bjorsell

    Gastric bypass operation forces a 5 day fast. A day before, during and days after to allow to heal up. A 3 day fast lowers insulin substantially and it is kept down when followed up with foods that do not promote insulin. Insulin is promoted by foods with high insulin index multiplied by the quantity of it. GBP patients have normalized insulin and FBG after those 5 days of fasting connected with the operation, followed by eating dismal quantities of food for weeks after, keeping them “off insulin” no matter what food they eat.
    Most if not all GBP patients are taken off their DB-2 medications during/ immediately after operation.

    Since the GBP benefits on DB-2 result from fasting long before any eating starts after GBP operation it is safe to say that the GBP operation had no part in restoring insulin sensitivity = curing diabetes type 2, the procedure invoking the 5 day fast however did it, alone. And insulin is then kept low after GBP/fasting through the minimal portion intake GBP forces.
    But same benefits can also be achieved through very low insulin index foods; something that even GBP patients today are advised to not spoil 1/ the benefits of the operation for themselves 2/Provide long term better statistics for the operation.
    When potential GBP patients are given above info before they decide, naturally many fewer will choose the GBP way.

    Dawn phenomenon, a sign of diabetes-2.
    5 days fasting gives a fatty expanded liver time to empty and reduce in weight/fats, ensuring that morning blood sugar for instance is normalized immediately after a GBP. Read Jasons very good post about dawn phenomenon, explaining why a fatty and enlarged liver causes morning blood sugar to rise as soon as insulin falls in the early morning hours.
    So called “Physiological insulin resistance” is nothing more than a large fatty liver, not reversed by low carb eating alone that many of us experienced. Mine went with a five day fast after reading the Jason Fung posts. Not bad for well over 65 !

  12. Nancy Fryhover

    Sten, are you saying your fatty liver went away after a 5 day fast?

  13. Hi Dr. Fung. Great post.

    I’m curious about your thoughts on practical approaches to help prevent syndrome X in children. It seems reasonable to avoid snacking and minimizing consumption of sugars and processed grains. I’m concerned about any effect on growth and development though by implementing fasting of any significant duration. Anyway, I’d love to see a post on preventing childhood obesity.

  14. I’m a girl, 20 years old. My goal is to lose weight (I’m about 90 lbs overweight) and also reverse my prediabetes (I’m not on any medication but i’m prettu sure I am borderline diabetic). I want to start doing 13h of fasting. I like to workout in the mornings. Is it best to do cardio while fasting, or after breaking the fast? Fasted cardio leads to muscle loss so..
    And will fasted cardio have any effect on blood sugar?

    • M, Rod’s quite right. I exercise a couple of hours before I end my fast, usually at the 16 hour point, and it’s surprisingly easy. I eat low carb and found fasting pretty easy because I’m not stimulating my appetite with sugar and refined carbs. Don’t fear high-fat food as long as the fat is natural. I don’t touch vegetable oils.

      Best wishes.

    • sten bjorsell

      Agree with Rod. Energy is first taken from glycogen stored in muscles and from glycogen in the liver, then from fat stored in the liver. Liver will lose weight and shrink! If overweight I guess it will take days before much fat in fatty tissues is metabolized. When around 90% of body fat is consumed, muscle will be sacrificed, but this can take over 100 days fast at normal weight. The world’s water fasting record is around 380 days…. Run as much as you like to speed up weight loss and you are building muscle during fasting! Interval training “HIIT” is however much more effective for both.

  15. @M: Kudos to you for being proactive. You’ve found the right Doctor and the right blog to help with your weight and health concerns! Read *everything* on this site–starting with the series on fasting. Save your money and don’t bother buying buying books.

    One of the things that you’ll learn early in your reading is that you don’t have much to worry about re: losing muscle from exercising in the fasted state. As you’ll soon see in your reading, many world class athletes actually prefer to exercise in the fasted state.

    So exercise away… and get started on your reading assignment!

  16. I run every day at varying lengths and intensity – and have been doing 16/8 fasting for about 10 months – I never eat breakfast and instead drink coffee – lately with butter and/or coconut oil (I don’t know if I’m still technically in fast mode or not). My body now loves working out in a fasted state. My race times (half marathon and 10k) continue to improve. Already rather lean, I’ve nevertheless lost a couple of inches around my waist. Also I notice a quicker healing/recovery time – almost 7 months without missing a day of running. I’m 68 years old – which is a shocker to some folks who meet me. I read and re-read Fung and explain to whoever will listen – especially family and friends. I give away copies of Obesity Code or just direct folks to the blog. As you know, it’s sad out there as you see your friends with metabolic syndrome. Fung offers health and hope.

  17. After a long period of fasting could a diabetic have paleo dieta Rich in startch vegetables, no startch vegetables, green leaf, fruits, Meat, ChicKen, fish, eggs?

Leave a Reply