Insulin toxicity – T2D 37

posted in: Health and Nutrition | 34

Insulin Toxicity

The rosiglitazone debacle and the shocking 22% increased risk of death found in the ACCORD study focused researchers on the potentially harmful effects of some of these blood glucose lowering medications. Insulin was the oldest and most powerful and the time had come to consider the paradigm of insulin toxicity.

Making the diagnosis of hyperinsulinemia has always been problematic for several reasons. Insulin levels vary widely throughout the day and in response to different foods. Release of insulin, like all hormones, is pulsatile, meaning that two measurements may widely differ even if taken within minutes of each other. A fasting insulin level solves some of these problems, but it varies widely between people and tends to reflect underlying insulin resistance.

Hyperinsulinemia had been considered a potential problem even as far back as 1924. As insulin assays became available in the 1960’s it was clear that insulin resistance and hyperinsulinemia were closely associated. It has long been assumed that insulin resistance provokes the hyperinsulinemia, but the reverse is also true – hyperinsulinemia may cause insulin resistance.

Recently, more data has become available to substantiate these concerns. Once researchers started to look, the evidence that hyperinsulinemia was a problem was everywhere. It has been strongly associated with cancer, heart disease, stroke, type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver, obesity and Alzheimer’s dementia.

Insulin Resistance

Ectopic fat, the accumulation of fat in places other than fat cells, plays a critical role in the development of insulin resistance. Fatty liver contributes to hepatic insulin resistance, and fatty muscle contributes to insulin resistance in the muscles. Even in the presence of severe obesity, insulin resistance does not develop in the absence of ectopic fat accumulation. This explains how an estimated 20% of obese individuals may have no insulin resistance and normal metabolic profiles.

A hypothesis first proposed in the 1950’s by Jean Vague, visceral, or central obesity is more metabolically damaging. Since then, many studies have confirmed this hypothesis. Thus, abdominal obesity rather than body mass index forms part of the criteria for metabolic syndrome. Thus, normal weight subjects may develop type 2 diabetes if the fat is deposited in the organs instead of in the fat cells.

In the absence of insulin, these ectopic fat deposits, and hence the insulin resistance cannot develop. Indeed, accumulated fat deposits melt away under conditions of sustained low insulin levels. Insulin is required to convert excess calories to fat and also to sustain it as fat.

As previously discussed, hyperinsulinemia underlies all of the metabolic syndrome and its consequences and forms a large portion of the toxicity of insulin.


Atherosclerosis, sometimes called ‘hardening of the arteries’ is the precursor to heart attacks, strokes, and peripheral vascular disease. Since the earliest days of insulin treatment, it has been noted that it has been linked to the development of atherosclerosis. Animal studies had demonstrated as early as the 1949 that insulin treatment cause early atherosclerosis, which could be reversed by preventing the excessive insulin.

Atherosclerosis is an inflammatory process that develops through several stages – initiation, inflammation, foam cell formation, fibrous plaque formation and then advanced lesions. Insulin facilitates atherosclerosis along every step of this pathway. Furthermore, insulin receptors are found inside human plaque and experimentally, insulin stimulates the growth of plaque, contributing to the progression of atherosclerosis.

Cardiovascular Disease

Concerns about insulin toxicity are not new. In 1970, the UGDP raised concerns that sulphonylurea medications, which stimulate insulin production, increased risk of cardiovascular disease. This led the Federal Drug Administration to issue a warning about this potential increase in cardiovascular deaths. However, since therapeutic options were limited at the time, SUs became widely prescribed for treatment despite these reservations.

The Quebec Cardiovascular Study established hyperinsulinemia as a known risk factor for heart disease as early as 1996, although this was felt to reflect the underlying insulin resistance and largely ignored. However, the evidence that insulin toxicity was a factor continued to accumulate, particularly in the treatment of type 2 diabetes, where treatment doses were sometimes high.

Reviewing over 12,000 newly diagnosed diabetic patients in Saskatchewan from 1991 to 1996, researchers found was a ‘significant and graded association between mortality risk and insulin exposure level”, even after adjustment for other factors. Simply put, the higher the insulin dose, the higher the risk of dying. It wasn’t a trivial effect, either. The high-insulin group had a 279% higher risk of death compared to those that did not use insulin.

British researchers soon found similar results. The UK General Practice Database from year 2000-2010, which contained medical records of over 10 million people, identified over 84,000 newly diagnosed diabetics. Compared to metformin treatment, the use of SU was associated with a 75% higher risk of death. Insulin was even worse, more than doubling the risk. The same held true for heart attacks, strokes, cancer and kidney disease.

Newly diagnosed diabetics in The Health Information Network (THIN) group doubled their risk of cardiovascular disease with the use of insulin and risk increased by 55% with SUs. With increasing duration of treatment, risk increased in lockstep.

In patients not taking medications, a lower A1C is clearly associated with less risk of heart attack and death. Insulin is a powerful blood glucose lowering medication. Its usefulness assumed that this would protect organs, but this was not really true.

Real world records from the the United Kingdom General Practice Research Database from 1986 to 2008, identified over 20,000 patients who had added insulin to their diabetes medication. Patients with the lowest A1C expected the best survival, but the exact opposite was true!

Patients with the ‘best’ blood glucose control had the worst outcomes. Patients achieving an A1C of 6.0%, considered ‘excellent’ control, fared just as poorly as those patients with an A1C of 10.5%, considered ‘uncontrolled’ diabetes. The glucotoxicity paradigm utterly failed to explain this phenomenon. If most of the damage from diabetes was being caused by the high blood glucose, then those with the lowest A1C should have the best outcomes. But they did not.

This was not an isolated finding as study after study showed the same results. A 2011 study confirmed that both low and high blood glucose carried excess risk of death and insulin use was associated with a mind-boggling increased 265% risk of death.

A Cardiff University study reviewed data from almost 10% of the UK population from 2004-2015 and found that lower A1C was associated with elevated mortality risk, driven mainly by a 53% increased risk with the use of insulin. In fact, in this study, no other medication increased the risk of death.

Metformin is the standard first line medication for type 2 diabetes. Adding insulin, compared to SUs increased the risk of heart disease or death by 30%. In a Dutch database, high daily insulin doses were associated with three times the high cardiovascular risk. In heart failure patients, insulin use is associated with more than four times the risk of death.

Metformin versus SU

Both metformin and SUs effectively control blood glucose, but they differ in one important respect. SUs increase the body’s secretion of insulin, where metformin does not. Is this important?

The Veteran Affairs database in the United States contained over 250,000 newly diagnosed type 2 diabetics. Starting treatment with SUs had a 21% higher risk of cardiovascular disease compared to metformin. The UKPDS had also showed that metformin is particularly beneficial in obese type 2 diabetic patients compared to insulin or SU. Other studies estimated the use of SUs increased the risk of heart attack or death by 40-60%.

The experience in the United Kingdom was no different, where the use of SUs increased the risk of heart attack or death by a disconcerting 40%. Furthermore, these risks increased in a dose dependent manner. Simply put, the higher the dose of SU, the greater the risk.

These results were finally confirmed in a 2012 randomized, controlled trial, the gold standard of evidence based medicine. Initial therapy with SU increased vascular disease risk by 40% despite equal blood glucose control. This agreed perfectly with the earlier estimates. Cardiovascular disease is by far the leading cause of death in type 2 diabetes, so the importance of this study cannot be underestimated. Two drugs, controlling blood glucose equally could have widely divergent effects on cardiovascular health. The main difference? One stimulated insulin and caused weight gain, where the other did not.

Excessive insulin is toxic, particularly in a setting of type 2 diabetes, where baseline insulin is already very high. With hindsight, this problem becomes perfectly obvious. The high blood glucose was only a symptom of the underlying disease of type 2 diabetes, which is characterized by hyperinsulinemia and insulin resistance. Giving more insulin will lower the blood glucose, but worsen the underlying hyperinsulinemia.

Giving more insulin successfully masked the hyperglycemia, but worsen the hyperinsulinemia. We were treating only the symptoms but not the actual disease. We were pretending that the symptom was the actual disease.

The situation is analogous to alcoholism. Patients with alcohol dependence often develop severe withdrawal symptoms upon abstinence. This syndrome, called delirium tremens includes tremor and even generalized confusion.

Giving alcohol can effectively reduce the symptoms. However, the underlying disease of alcoholism is not improved, but actually made worse. You can’t treat alcoholism with alcohol and expect positive results. In the same manner, you can’t treat hyperinsulinemia with insulin.


The association between diabetes and risk of cancer has been well established. Diabetics are at increased risk of many different cancer types, including all the most common ones such as breast, colon, endometrial, kidney and bladder cancer. Obesity, pre-diabetes and type 2 diabetes are all associated with increased risk of cancer suggesting that factors other than the increased blood glucose plays a major role in the development of cancers.

All three conditions are linked by the presence of hyperinsulinemia and insulin resistance. Insulin is a well-known growth factor that induces cells to undergo division, which drives tumor growth. For example, women with the highest insulin levels carry a 2.4 fold higher risk of breast cancer. Obesity itself may play a role, but hyperinsulinemia is associated with increased risk of cancer, regardless of weight status. Lean and overweight women, when matched for insulin level, exhibit the same risk of breast cancer.

Single gene mutations that increased insulin effect significantly raise the risk of cancer. Pioglitazone, a drug that increased insulin effect was linked to increased incidence of bladder cancer.

The choice of diabetic drug treatment significantly influences the risk of cancer, reaffirming the large role of hyperinsulinemia. Insulin use raises the risk of colon cancer by approximately 20% per year of therapy. A review of the UK General Practice database revealed that, compared to metformin, insulin increased the risk of cancer by 42%, and SUs by 36%. A review of the 10,309 newly diagnosed diabetics in the Saskatchewan population disclosed that use of insulin increased risk of cancer by 90% and SUs by 30%.

Once cancer has been established, the high blood glucose can enable faster growth Cancer cells are known to be glucose avid, with limited metabolic flexibility in using other fuels such as free fatty acids when glucose supplies are low. Cancer cells are highly metabolically active, requiring large supplies of glucose to proliferate.


According to the Center for Disease Control, in the year 2013, the top three causes of death in the United States were:

  1. Heart Disease 23.7%
  2. Cancer 22.8%
  3. Chronic lung disease 5.7%

Heart disease and cancer far outpace all other causes of death by a wide margin. They are linked in one significant way. Hyperinsulinemia and insulin toxicity.

34 Responses

  1. Jason,

    Is waist-to-height ratio over 50% a good predictor of, or does it correlate with insulin resistance?

    Of course, there are those who are skinny-fat with insulin resistance and those obese without. Would these be outliers?

    Does sarcopenia increase the risks of IR? If so, are we too myopically measuring or focusing bodyfat, but ignoring declining lean muscle mass? And if so, should doctors be prescribing resistance training to stimulate muscle re-growth?

  2. One more….

    Does diet-cola stimulate insulin?


      “Let me put it this way. Reducing dietary sugars is certainly good. But it doesn’t mean that replacing sugar with completely artificial, manmade chemicals of dubious safety is a good idea. I mean, pesticides and herbicides are also considered safe for human consumption. That doesn’t mean we should be going out of our way to eat more of them. (Anti-organic foods? Extra pesticides for worm free apples!)”

    • BernardP

      In his book “The Obesity Code”, Dr. Fung cites studies that show that artificial sweeteners ** do ** stimulate an insulin response. There seems to be a conditioned response to sweet taste, even in the absence of sugar.

      The Obesity Code is a must read… Also an easy and fun read.

    • Yes, and good question. As BernardP indicates, Dr. Fung’s book says that the insulin response mechanism is not well understood and that artificial sweeteners cause about 60% of the insulin that would be produced after the consumption of pure sugar. As Dr. Fung’s work shows, much better results are obtained by focusing on reduction of insulin instead of focusing on blood sugar.

    • I am struck by the number of people responding to these blog entries that have read neither Obesity Code nor Complete Guide to Fasting. Neither book is expensive. However, for those disinclined to read much, if not all of OC, is part and parcel of Dr Fung’s six part series Aetiology of Obesity. Aside from this six part series there are many others well worth of your consideration.

    • Jamie, it is my experience Dr Fung does not engage in dialog with posters here. Many people ask him questions and I haven’t seen him answer in, likely, 18 months if not more. Artificial sweeteners do spike insulin, although they don’t raise blood sugar.

      Your questions might well be answered by judicious use of google. Filter the hits to only those found on the NIH site. This is the internet, there are all sorts of wild beliefs masquerading as facts.

    • Yes, because of cephalic stage insulin spiking due to the aspartame in Coke lite.

    • Once more….Marks Daily Apple…a resource I consider generally authoritative and suffused with some humility…

      Does sucralose (aka Splenda) affect insulin?

      Sucralose activates the sweet receptors in taste buds, and some in vitro studies have shown that sucralose can stimulate the release of incretin hormones, which increase the secretion of insulin, via the sweet taste receptors in enteroendocrine cells (located in the gut). An in vivo study of sucralose infusions into the gut, however, showed that it does not stimulate the incretin hormones GLP-1 or GIP, does not release insulin, and does not slow gastric emptying.

      Another in vivo study, this time using healthy human subjects, got similar results: oral dosing of sucralose did not induce a cephalic insulin response, nor did it affect GLP-1. Not even appetite was affected.

      The commercial version of sucralose, Splenda, is cut with dextrose as a bulking agent. Dextrose is essentially glucose, which certainly elicits an insulin response, so there’s definitely the potential for a slight insulin response to Splenda, but there’s not much if any evidence that sucralose has an independent in vivo effect on insulin.

      Recently, a review of in vivo studies concluded that “low-energy sweeteners” do not have any of the effects on insulin, appetite, or blood glucose predicted by “in vitro, in situ, or knockout studies in animals.” As far as the clinical studies go, I think I’d have to agree. Am I going to use the stuff? No; there are other potential negative effects to artificial sweetener usage, including gut flora disturbances, the promotion of psychological dependencies on sweets, and long term safety issues, but I think it’s important to be clear on where the science lies. So far as I can tell, according to the literature there isn’t an appreciable insulin effect from most sweeteners.

  3. In the case of T1 diabetes, where insulin must be administered, is concerning to me. But given their only source of insulin is exogenous, it can be easily measured. I wonder is there is some level that should not be exceeded. I would also think that it would be wise to eat lower carb so one would need less insulin bolus to offset the rise in blood glucose?

    • Pete, IF I remember correctly, a study of T1 diabetics found that the less insulin they used overall, the better their health. I do not have a citation for you, sorry, but believe you are thinking on the correct path

    • Stephen T

      Pete, this short Ted-x talk is by a professor of bio-chemistry and type 1 diabetic. She compares her reaction to the standard awful advice and a low-carb approach. It’s well worth a view.

  4. David Sander

    So it appears that the two best treatment modes for diabetic patients or those with metabolic syndrome are a seriously low carb diet and any method of improving insulin sensitivity. Insulin sensitivity is improved by adding fiber, taking fish oil, use of high doses of niacin and chromium GTF, consuming blueberries, grapes, broccoli, and other insulin sensitivity improving foods.

    • BernardP

      Dr. Funk might differ about grapes, which he calls “little packets of sugar.” As for improving insulin sensitivity, fasting is the golden standard. However, my own experience shows that a strong majority of people are afraid of fasting and don’t want to try it, even once.

    • …. Insulin sensitivity is improved by adding high doses of niacin ??? is the opposite !!

      • David Sander

        It is more effective if you combine Chromium GTF with niacin. This helps the body to regulate blood sugars better which has to be a good thing.

        • What is the dose of these drugs ?

          • David Sander

            The research says that chromium doses in the 500 mcg to 2000 mcg range and 100 mg of niacin. Personally I found that taking 800 mcg of chromium with 250 mg of niacin BID vastly improved my blood sugar control, I’m a hypoglycemic and can really use the reduced variation of blood sugar for things like not falling asleep in meetings. I have recently boosted chromium to 1500 mcg to see if it helps weight loss but the results are too early to report. There is a China research using 100 mg of niacin and 500 mcg of chromium twice a day but I can’t find the specific paper. Chromium GTF is very nontoxic and some research has exceeded 2000 mcg.
            Anderson RA, Cheng N, Bryden NA, et al. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes. Diabetes. 1997;46:1786-1791.
            Albarracin CA, Fuqua BC, Evans JL, et al. Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes. Diabetes Metab Res Rev. 2007 May 16. [Epub ahead of print]
            A personal logger:

    • Mike is correct, Niacin promotes insulin resistance.

    • Maura Santangelo

      One of the best way to improve insulin sensitivity is exercise and fasting, I would start with those before supplementing with any chemicals…

  5. I am diabetic for 11 years. I am on LCHF for 9 months. Waist reduced from 36 to 31 inches. My height is 5’6″. My basal insulin is only 2 mcu/ ml. There was good improvement in bg in the beginning. Say 180 to 100 fbs. But when i stopped SU and kept only met, it started shooting up. After fasting this ramadhan for 27 days, today i checked my fbs. Alas! 284.
    Waist , weight and fasting insulin are at the lowest.
    How can this be explained?

    • Hello,
      I was told by the lab that the fbs is “valid” after an 8 to at most 12 hour fast. After that the results are not reflective of what the test is testing? I became non-diabetic through intermittent fasting. And indeed I had a high fbs after a 36 hour fast that I thought would be low. Since then I always do the test the morning after a normal evening meal, and it has never spiked.
      In general I have paid less and less attention to the bg one-off readings, and focus on the less fickle Habc1 readings which in my case have remained low, non-diabetic since after 6 months of IF.

  6. Question: The study re: atherosclerosis – if blood sugars normalize, excess insulin is reduced or eliminated, then atherosclerosis can be reversed? Does IF help reverse atherosclerosis?

    • Again, google is your friend. From a Harvard Medical School article – no but a vegan diet can slow it. This is echoed in another 12 yr study stressing very low fat and statin drugs could ‘reverse’ it somewhat. Again, google is your friend.

      I would guess straight IF, likely no. Having said that, you could IF on a low fat diet taking statin drugs.

      • Walt,
        Google is only your friend if you apply critical/skeptical thinking to what it spits out. There are many foods which are vegan but which have highly athrogenic properties (added sugars, grains,vegetable oils, industrial foods) and some foods which are animal-based but which seem to consistently produce health improvements to markers for heart disease (quality eggs), so any “study” that showed what you say would have to reconcile these things. There are some animal-based foods that could be a problem for some people, like meats cooked at high temperature, A1 milk possibly, or over consumption of muscle meats, but those issues are easily fixed. I wouldn’t believe any source on any topic without thoroughly researching, but Harvard in particular has a habit of saying things in the abstract that conflicts with the actual data in the study. There was another example of that last year (which may have been from Harvard) where the data said unprocessed meat was not a health risk, but the abstract only addressed the data from processed meat (some of which may be a legitimate problem.)
        Proper IF also produces many positive changes in well-established health markers (as Dr. Fung has described) so if did not benefit heart health then that would have to be explained.
        There has been a lot written and observed about reversing artery damage and I think the best summary is that removing things that damage the arteries and eating a nutrient-rich diet will allow at least significant improvement in many people.

      • Stephen T

        Walt, my brother was taking statins and losing his memory and suffering severe muscle cramps as a result.

        Statins are linked to cancer, increased diabetes, muscle damage, memory loss, reduced libido and other side effects. They deplete CoQ10, a crucial vitamin-like anti-inflammatory. They produce no life extension in primary care (not high risk).

        The low-fat diet and statins are good suspects for the increase in dementia, according to Stephanie Seneff from MIT and many others.

        The whole cholesterol theory of heart disease is nonsense sustained solely by pharma because of the profit it generates. It can’t be reconciled with facts from the real world:

        • France has the highest rate of saturated fat consumption in the world and a heart disease rate one third of the UK’s. Many other countries show similar results, including Switzerland, Sweden, Norway, Holland, Belgium, Germany, Spain and Iceland. (WHO figures.)
        • Switzerland has the second highest rate of saturated fat consumption in the world and the second lowest rate of heart disease.
        • Lithuania’s population consumes half France’s level of saturated fat, yet has a rate of CHD nine times higher. This is one of many similar examples. The WHO figures in Europe show a clear relationship between higher saturated fat consumption and lower heart disease.
        • In America of 137,000 people, in 541 hospitals, who’d had a heart attack, 78% had below average cholesterol. (American Heart Journal, 2009.)

  7. David Sander

    IF should be a help, but it should not be the only tool in your tool box. Being diabetic causes a number of biological stresses on the body that contribute to starting heart disease. One of these is the reduction of making MK4 vitamin K2 which results in the MGP proteins that scavenge calcium from that arteries being unable to work. As a result arteries start to accumulate calcification and heart disease progresses. Reversing this takes multiple nutrients, Vitamins D3 and Retinol A both boost and improve production of MGP and a supplement of MK4 vitamin K2 is needed to boost carboxylation of the MGP. This results in a strong soft tissue calcium removal process and incidental rebuilding of the bones.
    Nitric oxide generation is important to the health of the lining of the arteries, you can read more about this in Dr Louis Ignarro’s books on heart disease.
    Reducing carbohydrate intake is important to normalized blood sugars so you should be doing this too.

  8. Dr Fung,

    Can you explain why my blood sugar goes up during fasting, Anywhere between 130-155 mg/dl. I’m type 2 diabetic, 57 yrs old, 215 lbs, 5’11”, taking Metformin for at least 10 years. I’m very insulin resistant (history of diabetes in my family). I’m having a hard time understanding what my body is doing. I fast daily 12 to 24 hrs. Been LCHF for about 4 months. My main reason for going keto is to help with my insulin resistance.

    Thank you,


    • Dr Shivanand Nelogal

      My story is also same like you. My fasting is up but HBA1c is 6. Probably it is due to dawn phenomenon.That says still we have lot of visceral fat to be burnt.

    • Stephen T

      Paul, you should seek further confirmation or do more reading, but I believe that when you fast your body uses its stores of glycogen, so it is released as glucose. Your body won’t burn fat until the glucose is used and your insulin drops. I think low carb and fasting are the right route, but if you’re insulin resistant it may be more difficult . In your position, I think I’d join Dr Fung on Diet Doctor for a while, so you can directly ask questions and get the answers from an expert. He doesn’t answer questions on here.

      Best wishes.

  9. Perhaps we should all do alternate day water fasting, and eat a moderate, healthy diet on the other days, and stop measuring blood sugar, etc., etc.. I am convinced that the most important thing is the forced abstinence from food on a regular basis for the improvement of health, weight loss, improvement of liver, heart, kidney conditions, together with hormone regularisation. I am hoping to reabsorb floppy skin and cellulite after weight loss. Perhaps I am a dreamer, any info on this?

    • Mary,

      For the skin and cellulite, I would add weightlifting. Also, Dr. Cate Shanahan has had some interesting comments on cellulite possibl being at least partially due to diet heavy in PUFAs, if I remember correctly, so you might want to avoid those and check out her work.

  10. This link, and a little self-experimenting, may help:

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