β-Cell dysfunction vs insulin resistance in type 2 diabetes: the eternal “chicken and egg” question
OK Gang. The first of the two reviews on the changing paradigms on the etiology of type 2 diabetes. This one thanks to Craig in CT.
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-cell mass. Some of its mechanisms 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.
When I first read this, it was that emphasized passage that caught my eye. The timeline was interesting as well, as it reminded me of this paper, Insulin: understanding its action in health and disease, that refers to:
... a 20 yr ‘black age’ of endocrinology (between approximately 1960 and 1980), where leading scientists—through extrapolating beyond their new discoveries—confused scientific thinking and teaching.
This is the period, BTW, from which most of a certain science journalist's understanding of endocrinology is gleaned.
When one reads studies like the one from my last post, it can be downright depressing ... does the pancreas poop out that quickly? Well, on the encouraging side, we have a plethora of evidence that it can be reversed. This is why the insulin pump comment jumped out at me. So take a look at this paper this weekend gang. I'd love to discuss it and it's implications.