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A Few More Thoughts on Diabetes

After reading some more hyperlipid I have begun to question whether it is the adipose tissue or the liver that goes first in the pathogenesis of diabetes. One way to imagine the progression of diabetes is that through heavy fructose consumption, the liver becomes damaged and stops being able to manage glucose in the blood thus leading to elevated blood glucose levels. The pancreas thus overproduces insulin in an attempt to compensate for this and this process, which is simultaneous with hyperphagia due to disruption to leptin by excess fructose and toxin exposure, leads to the insulin resistance of fat cells and thus elevated NEFAs in the blood.

I have heard that elevated NEFAs appear before elevated BG so I would guess that these processes happen simultaneously but that the adipose tissue fails first as a result of hyperphagia and that this causes the pancreas to overcompensate with insulin hastening the arrival of hepatic insulin resistance soon thereafter. In any case, the factors that cause this remain the same, fructose and other dietary toxins that promote hyperphagia. The question is whether fructose or the hyperphagia that high fructose consumption can induce is the primary factor in this process. If it is the former then hepatic insulin resistance should happen first, if it is the latter then adipose insulin resistance should happen first. These are likely simultaneous processes where one has more susceptibility to what is happening and becomes insulin resistant first.

EDIT: I think that perhaps the way it works is something like this. Fructose damages leptin and this causes hyperphagia. Hyperphagia forces the body to fatten to avoid lipotxicity. At some point, the body refuses to fatten any longer and so the fat cells become insulin resistant and elevated NEFAs is the consequence. The pancreas secretes more insulin in response to the elevated NEFAs. The liver, simultaneous with this, is getting damaged by fructose leading to non-alcoholic fatty liver disease and once the pancreas goes into overdrive to control the elevated NEFAs, hepatic insulin resistance occurs and the liver stops being able to ration out glucose and process fructose well. Now you also have elevated blood sugar levels and the pancreas is going nuts with insulin production. Now you have diabetes. So far this is what makes the most sense to me.

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Filed under: Diabetes, Hormones, Insulin, NEFAs, Obesity, Pathogenesis

2 Responses

  1. tracker says:

    ///”The pancreas secretes more insulin in response to the elevated NEFAs.”///

    I wasn’t aware that insulin is secreted in response to non esterified fatty acids… Lippincott’s Illustrated biochemistry text says that insulin is synthesized and released in response to three things: 1. glucose 2. amino acids and 3. gastrointestinal hormones, with glucose being the primary trigger of insulin response.

    ///”Now you also have elevated blood sugar levels and the pancreas is going nuts with insulin production. Now you have diabetes.”///

    I’m assuming you mean type 2 diabetes. Your statement is incorrect. Or rather it would be correct if you added a step in-between the over production of insulin, and the diabetes part. Obese people have elevated insulin response (p. 342 Lippincott), because they’re insulin resistant. This does not by default lead to diabetes. So long as you can continue to put away fat into the fat cells, you will probably not develop diabetes. It’s only when your fat cells become insulin resistant AND your pancreas reaches the point that it cannot produce enough insulin to force the fat into the fat cells, that you become diabetic. That’s why not every obese person is diabetic. Some are lucky (perhaps in that they have good genetics) and will never develop diabetes. My grandmother is an example of this. She was always obese and yet never developed diabetes. I too once weighed 270 lbs and my sugar levels were always normal. On the other end of the bell curve, you have people who will get type 2 diabetes no matter what they do. If they’re careful, they may be able to delay it.

    I like hyperlipid’s blog too, it’s very interesting stuff. It does seem that fructose is very bad for you. Cooking my liver is not my idea of a good time.

    • jingo says:

      In response to your first criticism, perhaps I am incorrect in my assessment. My logic for insulin being increased in response to NEFAs is that the increase in NEFAs in the blood would create a state in which the inhibition of lipolysis is desired and would thus lead to an elevation of insulin levels in the body. This assumption may be incorrect. In that case, however, once adipose tissue becomes insulin resistant and is unable to store any more fat cells thus causing NEFAs to rise in the blood, what occurs in response?

      In response to your second, I am working with the assumption that your adipose tissue has reached its maximal point and thus become resistant as one of the first steps in the cascade leading to diabetes. This would necessarily imply that the pancreas is unable to force fat cells into additional adipose tissue. I don’t really see a conflict here.

      I also agree that each person has a different threshold after which they can no longer store adipose tissue and may become diabetic depending on genetic factors.

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