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

我们的目的是阐明胰岛素和土菊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）和第一阶段胰岛素反应（FPIR）呈曲线关系即使肥胖 2 型糖尿病患者已将血糖控制在接近正常水平，FPIR 水平也没有恢复到预期水平。非糖尿病受试者的 DI。这一发现表明日本肥胖 2 型糖尿病患者的胰腺 β 细胞功能发生了不可逆转的变化。2.在肥胖青少年中，胰岛素样生长因子 I (IGF-I) 水平升高可能是由于我们观察到胰岛素水平升高的关系，表明低 SI 组、单纯性肥胖和血糖控制良好的肥胖 2 型糖尿病组，即使总 IGF-I 较高，游离 IGF-I 也较低，因此表明血糖控制水平较低。游离/总 IGF-I 可能是胰岛素抵抗的一个因素，因为患有性腺功能减退症的肥胖群体（例如 Prader-Willi 和 Bardet-Biedle 综合征）也表现出相对于总 IGF 水平较低的游离/总 IGF-I 水平绝对低。 -I，它可能是糖尿病易感性的一个参数，而它可能在不依赖生长激素的生长中发挥一定作用。3.我们已经证明，皮下注射胰岛素的断奶效应会导致IGFBP-1 水平增加，从而导致游离 IGF-I 由于结合而减少。在非糖尿病受试者中，观察到 IGFBP-1 夜间升高，导致游离 IGF-I 减少，因为这种升高很早就开始了。凌晨 1 点，夜间观察到的胰岛素抵抗可能是由于游离 IGF-I 的减少而不是抗胰岛素激素的减少引起的，在青春期之前，这种机制可以在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以及健康志愿者的胰岛素抵抗，这表明摄入适当碳水化合物含量的饮食习惯的重要性相对于游离IGF-I，低碳水化合物饮食诱导的胰岛素抵抗仍然存在。有待研究，特别关注 IGFBP-1.5 信号转导的增加。在日本，HLA DRB1^*0901 已证明 Neuro D 参与 1 型糖尿病易感性，可能是由于自身免疫增强细胞凋亡易感性。，因为据报道，神经 D 中具有相同 SPN 的丹麦人群如果具有特定的 HLA 基因型，则具有保护性，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）。

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。

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。

Kaneko T, Wang P-Y, Wang Y, Sato A: "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、Wang P-Y、Wang Y、Sato A：“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