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Insulin Resistance As An Endocrine Disorder

Discussion in 'Scientific Studies' started by haidut, Mar 2, 2017.

  1. haidut

    haidut Member

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    This argument has flared up so many times on this forum and I doubt we have reached any agreement. I am on the side that insulin resistance and obesity are endocrine disorders. There is a group here that maintains that it is the obesity that really triggers it all. This study discusses some of the arguments that I have made in the past - i.e. that overactivation of the HPA drives the whole pathology. Unfortunately, the study claims it is down to genetic defects and does not go into detail as to what other metabolic/environmental factors could cause the overactivation of HPA. Suffice it to say chronic stress is now established as a primary cause. I would like to see a future study address hypothyroidism as perhaps the primary direct cause, which chronic stress leads to.
    @Westside PUFAs, @paymanz, @ecstatichamster, @Drareg

    Neuroendocrine perturbations as a cause of insulin resistance. - PubMed - NCBI

    "...Newly developed methodology has made it possible to determine more precisely the neuroendocrine abnormalities in abdominal obesity including increased cortisol and adrenal androgen secretions. This is probably due to a hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, amplified by inefficient feedback inhibition by central glucocorticoid receptors, associated with molecular genetic defects. Secondly, secretion of gender-specific sex steroid hormones becomes inhibited and the sympathetic nervous system activated. At this stage the HPA axis shows signs of a 'burned-out' condition, and cortisol secretion is no longer elevated. Cortisol counteracts the insulin activation of glycogen synthase in muscle, the insulin inhibition of hepatic glucose production and the insulin inhibition of lipolysis in adipose tissue, leading to the well-established systemic insulin resistance caused by excess cortisol. This is exaggerated by increased free fatty acid mobilization, particularly with a concomitant elevation of the activity of the sympathetic nervous system. Furthermore, capillarization and fiber composition in muscle are changed. These are the identical perturbations responsible for insulin resistance in recent reviews. The diminished sex steroid secretion in abdominal obesity has the same consequences. It is thus clear that insulin resistance may be induced by neuroendocrine abnormalities, such as those seen in abdominal obesity. These endocrine perturbations also direct excess fat to visceral fat depots via mechanisms that are largely known, indicating why abdominal obesity is commonly associated with insulin resistance. This possible background to the most prevalent condition of insulin resistance has been revealed by development of methodology that allows sufficiently sensitive measurements of HPA axis activity. These findings demonstrate the power of neuroendocrine regulations for somatic health.
     
  2. Drareg

    Drareg Member

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    I was just speculating,didn't really have a side but it makes sense if you are born into a poor epigenetically inclined environment that starts it all off.
    It should still however be possible with modern foodstuffs to start it off even with a good womb to start,alcohol consumption for example in early to late teens is quite common,contraception with teenage girls is being handed out at younger ages.
     
  3. paymanz

    paymanz Member

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    No it can't be obesity that triggers it all the time, but obesity surely is a factor,by increasing FFA and inflammation.

    That article is very interesting,it takesntime to digest it,but its very good.

    So cortisol causes IR by increasing FFAs,

    FFAs cause IR through randle cycle and inflammatory signals.

    But cortisol it self is also anti inflammatory, shutting down immune system.

    So cortisol not only through FFAs , but also by inhibiting glycogen synthesis(in muscles), and other mechanisms that they have mentioned inhibit insulin action.
    ----------

    But cortisol is important, for negative feedback to shutdown the HT respond to stress,

    And there is IR in patients with low cortisol too(burned out!?), so maybe the lack of negative feedback cause that?!
     

    Attached Files:

  4. paymanz

    paymanz Member

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    Ray:

    "Hypoglycemia intensifies inflammatory reactions, and insulin can reduce inflammation if sugar is available. Obesity, like diabetes, seems to involve a cellular energy deficiency, resulting from the inability to metabolize sugar.


    ,..Sucrose (and sometimes honey) is increasingly being used to reduce pain in newborns, for minor things such as injections (Guala, et al., 2001; Okan, et al., 2007; Anand, et al., 2005; Schoen and Fischell, 1991). It's also effective in adults. It acts by influencing a variety of nerve systems, and also reduces stress. Insulin is probably involved in sugar analgesia...."
     
  5. Koveras

    Koveras Member

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    You guys might like this one

    Thyroid Function in Human Obesity: Underlying Mechanisms.

    "Obesity is associated with several metabolic and endocrine disorders; and changes in plasma concentrations, secretion patterns, and clearance of various hormones are observed in obese patients. In this context, recent research has shown that overweight can influence the function of the thyroid gland, usually leading to increased thyrotropin concentrations and changes in the ratio between the hormones triiodothyronine and thyroxine, though within the normal range. The etiology of these changes is still unclear; however, several mechanisms have been proposed including the adaptive process to increase energy expenditure, hyperleptinemia, changes in the activity of deiodinases, the presence of thyroid hormones resistance, chronic low-grade inflammation, and insulin resistance. Although the clinical implications have not been clarified, studies suggest that these changes in the thyroid function of obese individuals may contribute to the worsening of metabolic complications and the development of diseases in the thyroid gland."

    Screen Shot 2017-03-02 at 6.54.14 PM.png
     
  6. Ella

    Ella Member

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    Haidut thanks for that review paper. I maintain that it is stress that triggers HPA dysregulation. I started my research career in trying correlate stress in the pathogenicity of an eye disease at a time that people did not believe such a thing as stress existed.

    I found it interesting that many of the young people with the eye condition had experienced on-going stress of some sort. Type A individuals, high achievers, sexual abuse during childhood. Those that manifested the condition at a young age of 8 - 10 years where extremely poor eaters. It is very rare to have the condition at this age. One mother was demented that her son would only eat white pasta and white rice and nothing else. No sauce of any kind. This is a very delicate age where extremely good nutrition is required. I remember one 8 yr old boy was on the chubby side. The ones that experienced the most trauma were the obese ones - the sexual abused ones. There is quite a bit of research on autoimmunity and trauma in childhood. The obesity connection intrigued me the most. They weren't all fat, there were also the very skinny. My colleage had this amazing german made equipment that was able to scan the body for energy levels. So it seems that there was some sort of biphasic mechanism going on with the thyroid. Either they had low functioning or hyper functioning. We are talk energy here.

    The following from that review paper:

    Estrogen


    Oophorectomy in female rats is followed by systemic and muscular insulin resistance, localized mainly to glucose transport. This is fully restituted by administration of 17-β-estradiol102, indicating that estrogens are involved in the regulation of systemic insulin sensitivity in women. It may therefore be likely that the progressive estrogen deficiency with menopause is involved in the relative insulin resistance of that condition103, although other factors are probably involved as well.

    This confuses me the most about estrogen. Women who produce too much testosterone become insulin resistant, however, they are muscular and certainly do not display central obesity - very little fat. Peat says estrogen is a problem when it is allow to accumulate and not removed by the liver. I understand the problem with xenoestrogens and how they confused signal transduction pathways, but how do we explain the fact that loss of ovaries coincides with insulin resistance, central obesity and glucose dysregulation in post menopausal women. If fat cells produce estrogen from the aromatisation of testosterone then we would expect with increased obesity (fat cells) an increase also in insulin sensitivity. How then does 17-beta-estradiol reverse the systemic and localised insulin resistance and glucose transport?

    Is there something we are missing in our understanding of estrogen? Is it possible to target estrogen too aggressively?

    Interplay Between Insulin Resistance and Estrogen Deficiency as co- Activators in Carcinogenesis
     
  7. Westside PUFAs

    Westside PUFAs Member

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    That study says similar things to something I've posted before:

    The Inflammatory Syndrome: The Role of Adipose Tissue Cytokines in Metabolic Disorders

    As far as IR and T2D, I don't think it's that complicated. Type 1 may be complicated but type 2, no. Type 1 may be complicated because the person has to figure out how much insulin they need to inject into their blood every day for the rest of their lives. There are even machines that people wear on their waists to inject it for them now. But that's type 1. Not type 2. What other hormone is there to take besides insulin when one is a type 2? There's a lot of evidence that none is the answer because it can be reversed by diet and lifestyle. Insulin resistance is type two diabetes and type two diabetes is insulin resistance. The important part is that insulin resistance, also known as type two diabetes, is a temporary state.

    Somethings I've written before:

    "That is being a type two diabetic. Type two diabetes is insulin resistance and insulin resistance is type two diabetes. It's a temporary state. If a type two diabetic eats something that doesn't cause their glucose to go too high too quickly and stay too high, then they are not a type two diabetic in that moment. They are only a type two diabetic when their glucose stays high for too long. Type two diabetes does it's damage in it's temporary, not constant, state, which is high glucose that is not getting used quickly enough. It's the repeated high extracellular glucose that causes damage. Inside the cells, glucose is quickly transformed into a different molecule (glucose-6-phosphate) by an enzyme called hexokinase.. The intracellular concentration of glucose therefore remains very close to zero as long as the hexokinase remains active. Lower the fat, improve glucose utilization, cure type two diabetes/insulin resistance. The fat comes from ingesting dietary fat or liberated free fatty acids from one's own fat tissue, which is why when one loses excess fat tissue, type two diabetes is cured. Of course even if one lost fat tissue, they can still eat high fat to put themselves in a temporary insulin resistant state."

    "The glucose number is not as important as how someone feels. Blood glucose rises and falls constantly for anyone and everyone because that's the nature of being human. But the healthier you are, the more you are able to handle going longer without eating because you store glycogen more efficiently and can use your glycogen more efficiently so your blood glucose will be utilized better than someone less healthy. That is the nature of being a hungry human, we get low blood glucose, so we need to eat glucose. Protein is mostly used for other things and fat can only be burned by muscles (but it is mostly stored right away in adipose tissue unless you’re being very active in that moment). The red blood cells and the brain can not burn fat. They need glucose. Ketones are not fat and the red blood cells can not burn ketones either. They always need glucose. If one feels really bad from either hypo or hyper glycemia then that is the problem. It's all about timing and thats exactly what Metformin hydrochloride does, it controls the timing of glucose so yes it reverses the temporary T2D state. The damaging action of the glucose is temporary until the levels go back to normal. A fat sick person will get damaged little by little daily until something worse happens like nerve damage. Yes blood tests are important but the glucose test isn't in this context because the problem isn't the glucose, it's fat that is blocking insulin from using the glucose efficiently. That fat can come from one's own adipose tissue and it can also come from the diet. This is what happens when you lower the dietary fat:

    "OBJECTIVE:
    The purpose of this study was to determine the health effects of a high carbohydrate, low fat multi-cultural traditional diet, The Hawaii Diet, fed ad libitum to an adult population.

    METHODS:
    Twenty-two adults recruited from various cultural backgrounds in Hawaii were fed, without calorie or portion size restriction, the Hawaii Diet for 21 days. The Hawaii Diet, based on familiar traditional foods from different cultures, is high in complex carbohydrate (77% of calories), low in fat (12% of calories), and moderate in protein (11% of calories). Participants were encouraged to eat to satiety.

    RESULTS:
    There was a significant weight loss on The Hawaii Diet averaging 10.8 lbs (23.8 kg) (P < .0001). Blood pressure was decreased from an average of 136.0/82.7 mm Hg to 125.5/78.9 mm Hg yielding a significant decrease of 10.4 mm Hg for systolic (P < .01). Beginning diastolic levels were normal so decreases in these values were not significant. Average lipid values also decreased with total serum cholesterol being significantly reduced from 205.3 to 156.9 mg/dl (P < .0001); LDL from 125.9 to 94.9 mg/dl (P < .001); and HDL from 38.3 to 31.3 mg/dl (P < .0005). Triglycerides (238.7 to 152.2 mg/dl) and the Chol:HDL ratio (5.8 to 5.2) improved at marginally significant levels (P < .08). There was also a significant reduction in blood glucose levels from 112.2 to 91.5 mg/dL (P < .01).

    CONCLUSION:
    The Hawaii Diet consisting of high carbohydrate, low fat ethnic meals appears to have a beneficial influence on weight loss and in decreasing systolic blood pressure, total cholesterol, LDL, and blood glucose values. Marginal improvement occurred for triglyceride levels. There was also a significant drop in HDL levels, however, the Chol:HDL was ratio did not increase. Further studies of longer duration with a control group should be conducted to test the effectiveness of The Hawaii Diet in maintaining these health benefits over a longer period of time."

    The Hawaii Diet: ad libitum high carbohydrate, low fat multi-cultural diet for the reduction of chronic disease risk factors: obesity, hypertension... - PubMed - NCBI

    When they said "marginal improvement occurred for triglyceride levels," that's because the fatter you are, the more triglycerides you'll have, until you get to baseline, by losing all excess adipose tissue.

    "People keep focusing on the level of glucose but let's get to the root of the problem. That's the key. Type two dibetics take a drug called Metformin hydrochloride. In type 2 diabetes, muscle cells become resistant to the action of insulin. Insulin is the main hormone responsible for controlling the level of sugar (glucose) in the blood. It makes cells in the body remove sugar from the blood. When the cells are resistant to insulin this makes blood sugar levels rise too high. Metformin hydrochloride is a type of anti-diabetic medicine called a biguanide. It works in a number of ways to lower blood sugar levels in people with type 2 diabetes. Firstly, it increases the sensitivity of muscle cells to insulin. This enables these cells to remove sugar from the blood more effectively. Secondly, it reduces the amount of sugar produced by cells in the liver. Finally, it delays the absorption of sugar from the intestines into the bloodstream after eating so that there is less of a spike in blood sugar levels after meals."

    "The fact remains, almost everyone with real type two diabetes, (type two, type two, type two, how many times do I have to say type two?), has excess adipose tissue. After eating a meal, their blood sugar remains high and overtime it causes damage to nerves which is why they go blind or lose a foot, starting with the toes. That is type two diabetes. It is not really a "disease" is the classic sense. It's a symptom of poor diet and lifestyle combined with excess fat, and it can be turned around in a day. They take Metformin. Metformin helps the body to control blood sugar in several ways. It helps type 2 diabetics respond better to their own insulin, lower the amount of sugar created by the liver, and decreasing the amount of sugar absorbed by the intestines. It does all of that but it doesn't treat the cause of the problem. The diet that gives you type two diabetes is the diet that makes you fat. If you put these people on a low fat, high fiber, natural starch diet, insulin resistance goes away and T2D is gone as long as keep the excess fat off and life a good lifestyle."
     
  8. Ella

    Ella Member

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  9. OP
    haidut

    haidut Member

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    The ovaries are the female gonads. They are the primary source of progesterone and also serum estrogen. So, when you remove them, both progesterone and estradiol plummet. However, unlike progesterone, many other tissues (in both males and females) can produce estrogen and in postmenopausal females and older males fatty tissue produces a lot of estrone, which gets converted into estradiol peripherally. Also, women with PCOS do not really have symptoms of hyperandrogenism. The hirsutism is caused by estrogen and DHEA. These women have in the past been successfully treated with strong androgens like DHT or even androsterone. If their condition was hyperandrogenic, those treatments would have badly deteriorated their condition but they actually improved it by opposing estrogen. PCOS is an estrogen and adrenal driven condition. Calm the adrenals and PCOS disappears. Thyroid and progesterone tend to work remarkably well, as do anti-prolactin drug which calm the pituitary.
     
  10. OP
    haidut

    haidut Member

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    That part is key. As long as they keep the excess fat off, which for those formerly diabetic people means chroic dieting and/or exercise. Healthy people do not have to perform these heroic feats to stay away from type II diabetes. So, bottom line is that their endocrine disorder is probably still raging and they keep diabetes at bay by virtue of these extreme measures. The moment they stop following them they become diabetic again. To me cure is permanent, no need to maintain an extreme lifestyle to keep the disease of coming back. If they have to continue this restricted lifestyle then they are in remission and not cured.
     
  11. Dante

    Dante Member

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    Did the treatment with DHT, androsterone cause virility? Don't FtM people use these in their transition ?
    Plus , Ella said "Oophorectomy in female rats is followed by systemic and muscular insulin resistance, localized mainly to glucose transport. This is fully restituted by administration of 17-β-estradiol" - is this only applicable to female rats not humans?
     
  12. paymanz

    paymanz Member

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    Thanks,very interesting...
     
  13. Ella

    Ella Member

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    Why is it different in females humans??
     
  14. Drareg

    Drareg Member

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    Im getting the impression Peat is patiently observing deiodinase and how it may be influenced by flavones,terpenes etc before writing or speaking about them. They might pop in a newsletter soon.
    They appear significant to say the least.
     
  15. Ella

    Ella Member

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    Haidut why would they have to be chronically dieting and/or exercising. If we get rid of the fat in adipose tissue our metabolisms are primed to run at a higher rate, Pufa's are restricted, inflammatory amino acids kept low; the weight is not likely to increase so why will the diabetes come back? I think the diabetes will come back if the extreme stress comes back to throw everything out of kilter. I think the chronic dieting will bring back the diabetes. Stress made me fat not calories. If I had been eating more calories I might have faired better.

    Now that I lost weight, I can eat loads and the weight does not come back on. So is it the calories or is it the weight?

    Am I doomed to a life of calorie restriction and running on a treadmill? Tell me it can't be so.:nonono
     
  16. OP
    haidut

    haidut Member

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    It's not my statement, it's from WestSide's quotes. I think the extreme stress can give you diabetes I. Diabetes II is more of a hypometabolism issue, also related to stress but also to chronic low-grade inflammation driven by many factors but mainly PUFA.
    Once you lose the excess weight, if it was done through dieting and exercise, you will likely downregulate RMR. That is another very controversial topic on this forum, but that's the side I stand on. If that happens, then you will have to eat less (or keep exercising) or you will start putting weight on even if you are not very stressed. The idea is to restore metabolism and HPA flexibility, not battle weight as if it is the main issue. Weight is just a symptoms of bad environmental conditions to which you adapted.
     
  17. Ella

    Ella Member

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    Forgive me, I rest assured that you have not deserted us hopefuls.
     
  18. Drareg

    Drareg Member

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    In many cases it takes time for the fat to build up,a few years in some cases,acknowledging it takes time to loose it is something not acknowledge by most people,they are expected to go doing extreme training regimes to loose the weight in a few months.
    Is it not more reasonable to find out how long it took to put the weight on and then inform them of a similar length of time to loose while following a good diet.

    Is there a speed at which the body preferentially burns fat and does this speed get effected as the extreme stress increases and decreases or does the mechanism of mobilisation not change with speed,does more cortisol get used as speed increases etc?
    For example does extreme fitness training push PUFA through first to try stop the extreme level of stress,slow you down?
    Body is like no way pal,not happening,hibernate and we will do this slowly.
     
  19. OP
    haidut

    haidut Member

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    It's quite possible - the body trying to downregulate your extreme zeal for losing weight when dieting/exercising. The same thing happens in thyroid downregulation due to exercise - i.e. to slow you down so you don't end up consuming all of your tissues. The exercise is a forceful (and thus often unhealthy) metabolism booster. As such, it is quite natural that the body will downregulate the endogenous/unforced metabolism to compensate.
     
  20. Drareg

    Drareg Member

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    In some cases the preference for burning PUFA is possibly an opportunity to get rid of it so the body takes it.
     
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