Fourlanos S, Narendran P, Byrnes G B, Colman P G, Harrison L C
Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Diabetologia. 2004 Oct;47(10):1661-7. doi: 10.1007/s00125-004-1507-3. Epub 2004 Oct 6.
AIMS/HYPOTHESIS: Glucose homeostasis is determined by an interplay between insulin secretion and insulin action. In type 1 diabetes, autoimmune destruction of pancreatic beta cells leads to impaired insulin secretion. However, the contribution of impaired insulin action (insulin resistance) to the development of type 1 diabetes has received little attention. We investigated whether insulin resistance was a risk factor for progression to type 1 diabetes.
Islet-antibody-positive first-degree relatives of type 1 diabetes probands were followed for 4.0 years (median). Insulin secretion was measured as first-phase insulin response (FPIR) to intravenous glucose. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-R). We compared subjects who progressed (n=43) and subjects who did not progress (n=61) to diabetes, including 21 pairs matched for age, sex, islet antibodies and FPIR.
Progressors had higher insulin resistance relative to insulin secretion at baseline (median HOMA-R : FPIR 0.033 vs 0.013, p<0.0001). According to Cox proportional hazards analysis, islet antibody number, FPIR, fasting plasma glucose, fasting serum insulin, HOMA-R and log(HOMA-R : FPIR) were each predictive of progression to diabetes. However, log(HOMA-R : FPIR) (hazard ratio 2.57 per doubling, p<0.001) was the only metabolic variable independently associated with progression. In the matched comparison, progressors had higher fasting glucose, fasting insulin, HOMA-R and HOMA-R : FPIR, both at baseline and during the follow-up pre-clinical phase.
CONCLUSIONS/INTERPRETATION: Relatives positive for islet antibodies who progress most rapidly to diabetes have a subtle disturbance of insulin-glucose homeostasis years before the onset of symptoms, distinguished by greater insulin resistance for their level of insulin secretion. Taking steps to reduce this insulin resistance could therefore delay the development of type 1 diabetes.
目的/假设：血糖稳态由胰岛素分泌与胰岛素作用之间的相互作用决定。在1型糖尿病中，胰腺β细胞的自身免疫性破坏导致胰岛素分泌受损。然而，胰岛素作用受损（胰岛素抵抗）对1型糖尿病发生发展的影响却很少受到关注。我们研究了胰岛素抵抗是否是进展为1型糖尿病的危险因素。
对1型糖尿病先证者的胰岛抗体阳性一级亲属进行了4.0年（中位数）的随访。胰岛素分泌通过对静脉注射葡萄糖的第一相胰岛素反应（FPIR）来测量。胰岛素抵抗通过胰岛素抵抗稳态模型评估（HOMA-R）来估计。我们比较了进展为糖尿病的受试者（n = 43）和未进展为糖尿病的受试者（n = 61），其中包括21对在年龄、性别、胰岛抗体和FPIR方面匹配的受试者。
进展者在基线时相对于胰岛素分泌具有更高的胰岛素抵抗（中位数HOMA-R：FPIR为0.033对0.013，p<0.0001）。根据Cox比例风险分析，胰岛抗体数量、FPIR、空腹血糖、空腹血清胰岛素、HOMA-R和log（HOMA-R：FPIR）均能预测糖尿病进展。然而，log（HOMA-R：FPIR）（每增加一倍风险比为2.57，p<0.001）是唯一与进展独立相关的代谢变量。在匹配比较中，进展者在基线和随访临床前期的空腹血糖、空腹胰岛素、HOMA-R和HOMA-R：FPIR均较高。
结论/解读：胰岛抗体阳性且进展为糖尿病最快的亲属在症状出现前数年就存在胰岛素-葡萄糖稳态的细微紊乱，其特征是相对于胰岛素分泌水平具有更高的胰岛素抵抗。因此，采取措施降低这种胰岛素抵抗可能会延缓1型糖尿病的发生。
