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【Diabetologia】高血糖与高胰岛素血症——胰岛素
The complex metabolic disturbances seen in diabetes are not just related to alterations in glucose homeostasis, but also include changes in fat and protein metabolism. Each change cannot be considered in isolation, since changes in one of these factors will lead to alterations in another. In the insulin-resistant state, glucose levels increase and there is also relative hyperinsulinaemia, which is exacerbated by a reduction in insulin degradation under these conditions. The process of insulin metabolism starts with binding of insulin to its receptor on the cell surface. The insulin receptor is then internalised into endosomes and degradation begins [1]. Insulin degradation occurs by the action of insulin-degrading enzyme (IDE) [2], which is responsible for the majority of cellular insulin metabolism (reviewed in [1]). Although the majority of IDE is cytosolic, it is also found in endosomes, peroxisomes and mitochondria [3–5]. It is present in all cell types, not just those responsive to insulin, and in all organisms, from yeast to mammals [1, 6], suggesting that IDE has functions in addition to its degradative one. There is increasing evidence of a regulatory role for IDE in a variety of cell functions. Some of these include regulation of the proteasome [7–9], androgen and glucocorticoid receptors [10], peroxisome [3], myoblast differentiation [11], lymphocyte antigen presentation [12] and yeast bud site selection [13].
Insulin metabolism is altered in patients with type 2 diabetes, and human genetic studies have linked polymorphisms in the gene encoding IDE to an increased risk of type 2 diabetes [14] and of Alzheimer’s disease [15, 16]. Knockdown of Ide in mice causes insulin resistance and hyperglycaemia, and plaques similar to those seen in Alzheimer’s disease are also found [17]. The Goto–Kakizaki (GK) rat has a mutation in IDE that causes altered cellular insulin degradation [18] in addition to other characteristics typical of type 2 diabetes.
Despite the obvious importance of IDE in the control of insulin metabolism and other metabolic processes, the metabolic control of IDE has not been extensively studied. It has been shown that certain NEFA inhibit IDE [19] and that other small molecules may interact with and inhibit IDE activity [20, 21]. But more information on the control of IDE is needed.
In this issue of Diabetologia, Pivovarova et al. [22] present the results of a study of the effects of glucose and insulin exposure on the activity and levels of IDE. They show that insulin increases the activity of IDE in extracts of cells that have been treated for 24 h with 10 mol/l of insulin. If the glucose concentration is increased from 1 g/l (5.55 mmol/l; ‘normal’ glucose) to 4.5 g/l (25 mmol/l; ‘high’ glucose), the increase in IDE activity promoted by insulin is abolished. This suggests that the reduction in insulin metabolism seen in cases of type 2 diabetes may be due to an effect of hyperglycaemia. How this insulin-induced increase in IDE activity occurs is unknown. The authors measured both mRNA and protein levels, and neither were altered by insulin under conditions of normal glucose concentrations. These findings suggest a change in the kinetic properties of the enzyme, such as the K m or V max, which could be measured in future experiments in enzyme preparations isolated from cells treated with glucose and/or insulin. Increasing the glucose levels per se did not change the expression of IDE mRNA. The addition of insulin to the high-glucose conditions increased levels of IDE mRNA by approximately 30% relative to the levels in the non-insulin-treated cells under high-glucose conditions. Since neither the levels nor the activity of the protein are altered, this difference does not appear to be biologically significant. Hyperglycaemia and hyperinsulinaemia:is insulin-degrading enzyme the missing link?
高血糖与高胰岛素血症——胰岛素降解酶是其中缺少的一环吗？
1.The complex metabolic disturbances seen in diabetes are not just related to alterations in glucose homeostasis, but also include changes in fat and protein metabolism. Each change cannot be considered in isolation, since changes in one of these factors will lead to alterations in another. In the insulin-resistant state, glucose levels increase and there is also relative hyperinsulinaemia, which is exacerbated by a reduction in insulin degradation under these conditions. The process of insulin metabolism starts with binding of insulin to its receptor on the cell surface. The insulin receptor is then internalised into endosomes and degradation begins [1]. Insulin degradation occurs by the action of insulin-degrading enzyme (IDE) [2], which is responsible for the majority of cellular insulin metabolism (reviewed in [1]). Although the majority of IDE is cytosolic, it is also found in endosomes, peroxisomes and mitochondria [3–5]. It is present in all cell types, not just those responsive to insulin, and in all organisms, from yeast to mammals [1, 6], suggesting that IDE has functions in addition to its degradative one. There is increasing evidence of a regulatory role for IDE in a variety of cell functions. Some of these include regulation of the proteasome [7–9], androgen and glucocorticoid receptors [10], peroxisome [3], myoblast differentiation [11], lymphocyte antigen presentation [12] and yeast bud site selection [13].
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作者:admin@医学,生命科学 2010-10-10 17:11
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