Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?
Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?
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DOI：
10.1007/s00125-005-1949-2
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发表时间：
2005-11-01
期刊：
影响因子：
8.2
通讯作者：
Butler, PC
中科院分区：
文献类型：
--
作者：
Meier, JJ;Bhushan, A;Butler, PC
目的/假设：1型糖尿病被广泛认为是由于胰岛素分泌β细胞的不可逆损失。然而，在一些长期患有1型糖尿病的人中可以检测到胰岛素分泌，这表明存活的β细胞数量很少，或者β细胞受到持续的自身免疫破坏而持续更新。本研究的目的是评估这些可能性。材料与方法：对42名1型糖尿病患者和14名非糖尿病患者的胰腺切片进行了β细胞、β细胞凋亡和复制、T淋巴细胞和巨噬细胞的存在评估。还定量了导管周围纤维化的存在和程度。结果：在88%的1型糖尿病患者中发现了β细胞。β细胞的数量与病程（范围4-67岁）或死亡年龄（范围14-77岁）无关，但在平均血糖较低的个体中较高（p < 0.05）。1型糖尿病患者β细胞凋亡的发生率是对照组的两倍（p < 0.001），但两组中β细胞复制都很罕见。1型糖尿病中β细胞凋亡的增加伴随着巨噬细胞和T淋巴细胞的增加以及导管周围纤维化的显著增加（p < 0.001），这意味着多年的慢性炎症，与β细胞的持续供应一致。结论/解释：大多数长期1型糖尿病患者的β细胞持续被破坏。β细胞死亡增加的潜在机制可能涉及持续的自身免疫和葡萄糖毒性。根据定义，尽管细胞凋亡仍存在，但β细胞的存在意味着即使在长期存在的1型糖尿病之后，也必须伴随新的β细胞形成。我们的结论是，1型糖尿病可以通过靶向抑制β细胞破坏来逆转。
Aims/hypothesis: Type 1 diabetes is widely held to result from an irreversible loss of insulin-secreting beta cells. However, insulin secretion is detectable in some people with long-standing type 1 diabetes, indicating either a small population of surviving beta cells or continued renewal of beta cells subject to ongoing autoimmune destruction. The aim of the present study was to evaluate these possibilities. Materials and methods: Pancreatic sections from 42 individuals with type 1 diabetes and 14 non-diabetic individuals were evaluated for the presence of beta cells, beta cell apoptosis and replication, T lymphocytes and macrophages. The presence and extent of periductal fibrosis was also quantified. Results: Beta cells were identified in 88% of individuals with type 1 diabetes. The number of beta cells was unrelated to duration of disease (range 4-67 years) or age at death (range 14-77 years), but was higher (p < 0.05) in individuals with lower mean blood glucose. Beta cell apoptosis was twice as frequent in type 1 diabetes as in control subjects (p < 0.001), but beta cell replication was rare in both groups. The increased beta cell apoptosis in type 1 diabetes was accompanied by both increased macrophages and T lymphocytes and a marked increase in periductal fibrosis (p < 0.001), implying chronic inflammation over many years, consistent with an ongoing supply of beta cells. Conclusions/interpretation: Most people with long-standing type 1 diabetes have beta cells that continue to be destroyed. The mechanisms underlying increased beta cell death may involve both ongoing autoimmunity and glucose toxicity. The presence of beta cells despite ongoing apoptosis implies, by definition, that concomitant new beta cell formation must be occurring, even after long-standing type 1 diabetes. We conclude that type 1 diabetes may be reversed by targeted inhibition of beta cell destruction.