Interaction between insulin and inuli-like-growth factor in the pathogenesis of childhood diabetes mellitus.

胰岛素和菊粉样生长因子在儿童糖尿病发病机制中的相互作用。

• 批准号: 11670750
• 负责人: AMEMIYA Shin
• 金额: $ 2.3万
• 依托单位: 山梨医科大学
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670750/
• 关键词: Diabetes mellitus; Insulin; Insulin-like-growth factor; Insulin resistance; Free insulin-like-growth factor; Neuro D; Insulin-like-growth-factor binding proteins; Childhood and adolescence; 遊離型インスリン様成長因子-I; ハイブリッド受容体; 受容体

We aimed to clarify the interaction between insulin and inuli-like-growth factor in the pathogenesis of childhood diabetes mellitus.1.According to Brgman's Minimal Model analysis, insulin sensitivity (SI) and first phase insulinresponse (FPIR) shows a curvilinear relationship as an disposition .index (DI). Even if patients with obese type 2 diabetes had been controlled in near-normoglycemia, the levels of FPIR did not recover by the expected level of DI in non-diabetic subjects. This finding suggests an irreversible change in pancreatic β cell function in Japanese obese type 2 diabetes..2.In obese adolescents the increased level of Insulin-like-growth-factor I (IGF-I) may be observed in the relation on increased insulin levels. We demonstrated that low SI groups, simple obesity and obese type 2 diabetes with fair and good glycemic control, had low free IGF-I even with high total IGF-I, thus indicating that low free/total IGF-I may be a factor for insulin resistance. Since obese groups … More with hypogonadism such as Prader-Willi and Bardet-Biedle syndromes showed also as absolutely low level of free/total IGF-I in relation to low total IGF-I, it may be an parameter for diabetic susceptibility, whereas it may play some role in growth-hormone independent growth.3.We have demonstrated that a weaning effect of subcutaneously administered insulin results in an increased level of IGFBP-1, which in turn cause an decrease in free IGF-I due to the binding. In nondiabetic subjects a nocturnal rise of IGFBP-1 was observed, resulting in decreasing free IGF-I . Since this rise started as early as 1 am, insulin resistance observed during night may be caused by a decrease in free IGF-I instead of anti-insulin hormones. Further nocturnal hypoglycemia may be physiologically prevented by this mechanism before adolescent period.4.Low carbohydrate-diet resulted in insulin resistance in animal, as well as in healthy volunteers, indicating an importance in dietary habit consuming appropriate carbohydrate contents. In relation to free IGF-I, low carbohydrate-diet-induced insulin resistance remains to be investigated especially focused on increased signal transduction for IGFBP-1.5.An involvement of Neuro D in the susceptibility to type 1 diabetes has been demonstrated in Japanese with HLA DRB1^*0901., probably due to enhanced apoptosis by autoimmune susceptibility., since Danish populatoion with the same SPN in Neuro Dwas reported to be protective if they have a specific HLA genotype, HLADR3/4 Less

本研究旨在阐明胰岛素和胰岛素样生长因子在儿童糖尿病发病机制中的相互作用。1.根据Brgman最小模型分析，胰岛素敏感性(SI)和第一时相胰岛素反应(FPIR)作为倾向性指数(DI)呈曲线关系。即使肥胖型2型糖尿病患者被控制在接近正常的血糖水平，非糖尿病受试者的FPIR水平也没有恢复到预期的DI水平。这一发现提示日本肥胖型2型糖尿病患者胰腺β细胞功能发生了不可逆转的改变。2.在肥胖青少年中，胰岛素样生长因子I水平的升高可能与胰岛素水平的升高有关。结果显示，血糖控制良好的低SI组、单纯性肥胖和肥胖型2型糖尿病患者，即使总IGF-I较高，但游离IGF-I仍较低，提示低游离/总IGF-I可能是胰岛素抵抗的一个因素。由于肥胖群体…更多的性腺功能减退症，如Prader-Willi和Bardet-Biedle综合征，也显示出与低总IGF-I相关的绝对低水平的游离/总IGF-I，它可能是糖尿病易感性的一个参数，而它可能在生长激素非依赖性生长中发挥一定的作用。3.我们已经证明，皮下注射胰岛素的脱机效应导致IGFBP-1水平升高，进而由于结合导致游离IGF-I水平下降。在非糖尿病受试者中，观察到夜间IGFBP-1升高，导致游离IGF-I减少。由于这种上升早在凌晨1点就开始了，夜间观察到的胰岛素抵抗可能是由于游离IGF-I减少而不是抗胰岛素激素造成的。在青春期之前，这种机制可能会从生理上预防进一步的夜间低血糖。4.低碳水化合物饮食导致动物和健康志愿者的胰岛素抵抗，这表明饮食习惯中摄入适当的碳水化合物很重要。关于游离IGF-I，低碳水化合物饮食诱导的胰岛素抵抗仍有待研究，特别是IGFBP-1.5信号转导增加。在携带HLADRB1**0901的日本人中，已证明Neuro D参与了1型糖尿病的易感性，这可能是由于自身免疫易感性增强了细胞凋亡。由于有报道称，在Neuro Dwas中具有相同SPN的丹麦人如果具有特定的HL A基因，HLADR3/4较少。

项目成果

Kobayashi K,Amemiya S et al: "A role of free insulin-like growth factor-I in dawn phenomenon in children and adolescents with type 1 diabetes mellitus."Endocr J. 47(suppl). S91-S93 (2000)

Kobayashi K、Amemiya S 等人：“游离胰岛素样生长因子-I 在 1 型糖尿病儿童和青少年黎明现象中的作用。”Endocr J. 47（增刊）。

Kobayashi K: "Pathogenic factors of Glucose Intolerance in Obese Japanese Adolescents With Type 2 Diabetes."Metabolism. 49. 186-191 (2000)

Kobayashi K：“患有 2 型糖尿病的肥胖日本青少年葡萄糖不耐症的致病因素。”代谢。

Mie Mochizuki,Shin Amemiya et al: "The Association of Ala45Thr Polymorphism in NeuroD with Child-onset type 1a Diabetes in Japanese."Diab Res Clin Prac. (in press). (2001)

Mie Mochizuki、Shin Amemiya 等人：“NeuroD 中 Ala45Thr 多态性与日本儿童发病 1a 型糖尿病的关联。”Diab Res Clin Prac。

Kaneko T et al: "The long term effect of low-carbohydrate/ high-fat diet on the development of diabetes mellitus in spontaneously diabetes rats."Diabetes metabolism. 26. 459-464 (2000)

Kaneko T 等人：“低碳水化合物/高脂肪饮食对自发性糖尿病大鼠糖尿病发展的长期影响。”糖尿病代谢。

Kobayashi K, Amemiya S, Mochizuki M, Kobayashi K, Matsushita K, Sawanobori E, Ishihara T.Higashida K, Shimura Y, Kato K, Nakazawa S: "Association of angiotensin converting enzyme (ACE) gene polymorphism with lipid profiles in children and adolescents with

Kobayashi K、Amemiya S、Mochizuki M、Kobayashi K、Matsushita K、Sawanobori E、Ishihara T.Higashida K、Shimura Y、Kato K、Nakazawa S：“血管紧张素转换酶 (ACE) 基因多态性与儿童和脂质谱的关联