β-Cell dysfunction vs insulin resistance in type 2 diabetes

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β-Cell dysfunction vs insulin resistance in type 2 diabetes


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Old 03-17-2013, 00:04   #1
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Default β-Cell dysfunction vs insulin resistance in type 2 diabetes

This paper is quite interesting. It was published in the journal Medicographia, Vol 33, No.1, 2011. I got the link to this paper from The Carb-Sane Asylum, the blog of Carbsane (Evelyn). There is a pdf version of the aforementioned issue of the journal where you can read other interesting papers on diabetes besides the one that I mentioned. Here is the link to the pdf version of the journal.

Quote:
The idea that type 2 diabetes (T2DM) is mainly due to insulin resistance stems from the 1930s, but became dominating from the 1980s. However, evidence since the 1960s indicates that insulin response to glucose is markedly diminished from the earliest signs of glucose intolerance. Insulin pump treatment induces near-normoglycemia in T2DM with doses similar to type 1 diabetes, indicating that hyperglycemia is caused by lack of insulin, insulin resistance acting as an amplifier. Insulin secretion is genetically controlled. T2DM risk gene polymorphisms hint toward mechanisms of reduced insulin secretion in diabetes-prone subjects, in whominsulin response decreases as the number of diabetic alleles increases. I hypothesize that the genetic background of the β cell determines its adaptation capacity to increased insulin demand imposed by augmented caloric intake and insulin resistance; failure to adapt eventually leads to T2DM. Therefore, I regard the “prediabetic” β cell as a normal cell with limited adaptability, diabetes risk being entirely context-dependent (nutritional load and insulin sensitivity). Once hyperglycemia is established, β cells are exposed to continuous nutrient stimulation, with consequent oxidative and endoplasmic reticulum (ER) stresses. The result is increasing functional deficiencies and β-cell apoptosis, hence reduced β-cellmass. Some of itsmechanisms are discussed. An intriguing as yet unanswered question is whether the mechanisms of β-cell deficit in the diabetic environment operate before hyperglycemia in overfed, insulin-resistant subjects. Therapeutic agents preventing β-cell oxidative and ER stress could stop the progression and perhaps initiation of T2DM.
Quote:
Conclusions

Is T2DM a disease of insulin deficiency or insulin resistance? Obviously both. Nevertheless, I am comforted in my nearly 50-year-old belief in the primacy of insulin deficiency for the pathogenesis of T2DM by the consensus that has emerged in the last decade over the fact that hyperglycemia is not possible in the absence of β-cell deficiency. Compared to the near-total lack of insulin of the type 1 diabetic, the β-cell deficiency of the type 2 diabetic patient is modest, and therefore would not be sufficient to lead to the full diabetic state in such a high proportion of subjects without additional environmental factors. This is a classic gene-environment interaction. It is a fascinating idea that, had the whole genome association studies been performed immediately after World War II in the undernourished populations of Europe and Asia, none of the polymorphic genes being hotly investigated today would have been found to be associated with type 2 diabetes. Indeed, these polymorphic alleles seem to render the cell somewhat less efficient, ie, place it at the lower end of normal variation in terms of its functional adaptability and resistance to stress; nevertheless, these cells are normal until faced with unreasonable demands. I think too much emphasis is put on insulin resistance; I believe that the greatly augmented caloric intake, ie, the greatly increased nutrient flux in the cell, is the real problem, insulin resistance acting as a potent amplifier. The consequence of this thought is that the risk for an individual to develop T2DM would be inversely correlated with the magnitude of adaptability of his cells and directly correlated with the degree of caloric intake/ insulin resistance to which he would be exposed. Thus, the “stronger” the cell, the greater the degree of obesity that can be tolerated while maintaining normal glucose tolerance. There are cases of lean, insulin-sensitive T2DM, as there are cases of diabetes with severe insulin resistance and extreme hyperinsulinemia. However, these are rare. For the majority of type 2 diabetics, to prevent hyperglycemia and its consequences either food intake has to be reduced drastically, or the cell enforced to cope with the increased workload. Neither seems easy. Almost all research today on the cell in connection with T2DM deals with the cells’ reaction to various stresses, ie, the glucolipotoxicity situation. That this is most relevant to the fate of the cell in the diabetic environment, and therefore to diabetes progression, is clear. A legitimate question does arise, however: Are the various mechanisms of -cell stress discussed above (and in the literature) responsible also for the initiation of hyperglycemia? In other words, is -cell stress a secondary reaction to diabetes (glucolipotoxicity), almost a complication of the disease, or is it the etiopathogenic event that leads to the gradual impairment of glucose homeostasis until glucose intolerance and diabetes appear? This is an important question that awaits its solution through future research.
In my personal case, I believe my insulin response curve might lie in between the blue and green traces of figure 2 of the paper.

Read on, the paper is informative and interesting.

Regards,
Rad

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Old 03-17-2013, 05:24   #2
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I don't see where he really says anything new. He acknowledges that hyperglycemia precedes beta cell degradation. If that's not insulin resistance before beta cell death, I don't know what is.

Interestingly, although he obsesses over the genetic factor, at the same time he totally acknowledges diet as the proximate cause or trigger for T2.

Quote:
T2DM risk gene polymorphisms hint toward mechanisms of reduced insulin secretion in diabetes-prone subjects, in whom insulin response decreases as the number of diabetic alleles increases. I hypothesize that the genetic background of the β cell determines its adaptation capacity to increased insulin demand imposed by augmented caloric intake and insulin resistance; failure to adapt eventually leads to T2DM.
Oops! Did he not just place hyperglycemia (obviously caused by insulin resistance) BEFORE beta cell degradation?

Then, actual onset is caused by diet:

Quote:
I hypothesize that the genetic background of the β cell determines its adaptation capacity to increased insulin demand imposed by augmented caloric intake and insulin resistance; failure to adapt eventually leads to T2DM.
Calories? Really? How do mere "calories" impact the glucose metabolism system again? It's too much GLUCOSE, obviously. If he'd said that, it would have been right on.

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