【作者】 宋薇；

【导师】 李桂梅；

【作者基本信息】 山东大学 ， 儿科学（内分泌）（专业学位）， 2019， 博士

【摘要】 前言近十年来1型糖尿病的患病率在全世界范围呈上升趋势,而1型糖尿病是儿童糖尿病发病最主要的原因,占糖尿病总数的5-10%,1型糖尿病患儿多血糖控制较差,不能采用单独口服降糖药物治疗,需要终生注射胰岛素以维持生命,而且胰岛素比其他口服降糖药更容易引起低血糖,即良好的血糖控制带来更多低血糖的发生,通常当接近正常的糖化血红蛋白时,低血糖的发生率是普通的三倍以上,这更增加了血糖控制的难度。长期的高血糖和代谢紊乱导致严重的并发症,1型糖尿病患者的寿命与普通人群相比减少了 11-13年,1型糖尿病的并发症的发生率可高达96.5%。1型糖尿病主要的死亡原因就是心血管并发症,其发生的基础是动脉粥样硬化,可起始于出现临床症状前十几年,儿童时期的动脉粥样硬化可以被逆转。目前有研究发现,在不降低血糖的情况下,二甲双胍对1型糖尿病患者心血管有益,提示其心血管保护作用可能并非是由其降低血糖产生的,可能是独立于其降糖作用之外的。二甲双胍保护心血管机制是专属于糖尿病的,即通过抑制高血糖产生的非酶糖基化产物的形成阻止糖尿病血管病变。AGEs可直接与血管壁中的蛋白形成共价交联,刺激内皮细胞过度表达黏附分子,导致血管结构和功能的损害,从而引发血管病变。此外AGEs还能引起血管内皮细胞膜上阴离子多糖蛋白的降解,致使血管通透性增大破坏血管内皮的屏障作用。AGEs还可以通过与AGEs受体作用,引起血管通透性增加,进而使单核细胞趋化蛋白1、血管细胞黏附分子1过度表达,导致单核细胞对内皮细胞的黏附性增强,从而损伤血管内皮结构,AGEs可诱导血管平滑肌细胞增殖、形成活性氧簇,诱导核因子κB转导通路的激活,从而使炎症因子的表达增加,促进动脉粥样硬化的发展。二甲双胍可能是通过清除丙酮醛,使晚期糖基化终末产物减少来达到保护心血管的作用。对于1型糖尿病儿童来说,长期血糖不良的T1DM可能会影响线性生长,会导致发育迟缓,代谢控制良好的儿童的线性生长趋于正常。而TlDM中发现的血清胰岛素样生长因子-1(IGF-1)水平的降低被认为是这些糖尿病儿童中生长异常的原因。IGF-1的异常是由于门静脉中胰岛素浓度低。在血浆中,IGF-1与胰岛素样生长因子结合蛋白(IGFBP)结合。IGFBP在肝脏中产生并被胰岛素急性调节,从而允许胰岛素调节IGF-1的生物活性。虽然低IGF-1水平归因于胰岛素分泌减少,但胰岛素对IGF-1合成没有直接影响,但也表明胰岛素对其的作用是间接的。尽管在血糖控制不佳的1型糖尿病出现了这些异常,以前的研究也支持IGF-1水平与糖化血红蛋白(HbAlc)之间存在负相关性,但近期多项研究发现1型糖尿病患者的IGF-1水平低但与HbAlc水平无关。严格的血糖控制和外源性胰岛素只能减弱这些影响,但是并不能完全逆转它。本研究主要包括四部分:第一部分ApoE小鼠诱导成幼年1型糖尿病模型,观察期幼年动脉粥样硬化的程度。第二部分ApoE小鼠诱导成幼年1型糖尿病动脉粥样硬化模型,应用二甲双胍干预有效。第三部分二甲双胍对保护1型糖尿病心血管的作用机制的研究。第四部分主要研究1型糖尿病儿童的长期血糖控制不良其身高是否受损,是否是其胰岛素样生长因子-1的改变影响了身高。第一部分关于幼年1型糖尿病动脉粥样硬化模型的建立的探讨研究目的建立1型糖尿病幼年动脉粥样硬化模型。研究对象和方法动物饲养与处理ApoE基因敲除雄性小鼠36只,4周龄,18只小鼠腹腔注射STZ,连续注射5天,观察2周,用剪刀剪去适量小鼠尾巴测血糖。两次非空腹血糖水平≥llmmol/L的小鼠为糖尿病模型诱导成功,随机入糖尿病组。剩下的18只入对照组。动物取材(1)普通饮食喂养4周后,对小鼠禁食12小时,饮水不做限制;小鼠被处安乐死。对照组和模型组各随机抽取1只,确定造模是否成功。(2)将小鼠麻醉,小鼠取血。生化指标检测:集中应用全自动生化分析仪测定血糖、甘油三酯、低密度脂蛋白胆固醇的指标。(3)取血后,小鼠采血后用PBS进行灌注,分离获得整体主动脉,主动脉是切除从主动脉根部到腹部,进行油红0染色后拍照,并用Image-ProPlus6.0.软件对斑块面积进行定量分析。然后从主动脉瓣开始以100μ m为间距切取连续8张厚度为8μm的切片,通过HE染色观察动脉粥样硬化的程度。研究结果打药前的基线血糖是5.33±0.24 mmol/1,入组前糖尿病组与非糖尿病组的血糖有统计学差别。糖尿病组中入组时和4周后处死时体重无明显增长。糖尿病组存在动脉粥样硬化。非糖尿病组未观察到明显的斑块。研究结论ApoE-/-小鼠1型糖尿病模型及其幼年动脉粥样硬化造模成功。第二部分二甲双胍对1型糖尿病幼年动脉粥样硬化干预效果的研究研究目的观察二甲双胍是否可以干预ApoE-/-雄性小鼠1型糖尿病幼年动脉粥样硬化。研究对象和方法动物饲养与处理ApoE基因敲除雄性小鼠36只,4周龄,18只小鼠腹腔注射STZ,连续注射5天,观察2周,用剪刀剪去适量小鼠尾巴测血糖。两次非空腹血糖水平≥11mmol/L的小鼠为糖尿病模型诱导成功,随机入糖尿病组(1、2、3组)。剩下的18只入对照组(4、5、6组)。1组为1型糖尿病二甲双胍治疗组,2组为1型糖尿病辛伐他丁干预组,3组1型糖尿病对照组,4组为非糖尿病二甲双胍干预组,5组非糖尿病辛伐他丁干预组,6组为非糖尿病空白对照组。1组,4组分别给予二甲双胍l00mg/kg/day灌胃4周,2组,5组分别给予辛伐他丁 5mg/kg/day灌胃4周,3组,6组采用生理盐水灌胃4周。动物取材(1)普通饮食喂养4周后,对小鼠禁食12小时,饮水不做限制;小鼠被处安乐死。对照组和模型组各随机抽取1只,确定造模是否成功。(2)将小鼠麻醉,小鼠取血。生化指标检测:集中应用全自动生化分析仪测定血糖、甘油三酯、低密度脂蛋白胆固醇的指标。(3)取血后,小鼠采血后用PBS进行灌注,分离获得整体主动脉,主动脉是切除从主动脉根部到腹部,进行油红0染色后拍照,并用Image-ProPlus6.0.软件对斑块面积进行定量分析。然后从主动脉瓣开始以100μ m为间距切取连续8张厚度为8 μ m的切片,通过HE染色观察动脉粥样硬化的程度。研究结果打药前的基线血糖是5.33±0.24 mmol/1,糖尿病二甲双胍治疗组与非糖尿病二甲双胍干预组,入组前的血糖有统计学差别。糖尿病各亚组中入组时和治疗4周后处死时体重无明显增长。糖尿病二甲双胍治疗组、糖尿病盐水干预组和糖尿病辛伐他汀治疗组存在动脉粥样硬化。非糖尿病辛伐他汀组和非糖尿病盐水组未观察到明显的斑块。非糖尿病二甲双胍组附壁血栓形成趋势,管腔内血小板梁形成。研究结论二甲双胍可以防治1型糖尿病动脉粥样硬化。第三部分二甲双胍延缓1型糖尿病动脉粥样硬化作用机制的研究研究目的应用ApoE小鼠诱导成幼年1型糖尿病模型,观察期幼年动脉粥样硬化的程度,并应用二甲双胍干预并探讨其相应的机制。研究对象和方法动物饲养与处理ApoE基因敲除雄性小鼠36只,4周龄,18只小鼠腹腔注射STZ,连续注射5天,观察2周,用剪刀剪去适量小鼠尾巴测血糖。两次非空腹血糖水平≥11mmol/L的小鼠为糖尿病模型诱导成功,随机入糖尿病组(1、2、3组)。剩下的18只入对照组(4、5、6组)。1组为1型糖尿病二甲双胍治疗组,2组为1型糖尿病辛伐他丁干预组,3组1型糖尿病对照组,4组为非糖尿病二甲双胍干预组,5组非糖尿病辛伐他丁干预组,6组为非糖尿病空白对照组。1组,4组分别给予二甲双胍l00mg/kg/day灌胃4周,2组,5组分别给予辛伐他丁 5mg/kg/day灌胃4周,3组,6组采用生理盐水灌胃4周。动物取材(1)喂养4周后,对小鼠禁食12小时,饮水不做限制;小鼠被处安乐死。对照组和模型组各随机抽取1只,确定造模是否成功。(2)将小鼠麻醉,小鼠取血。生化指标检测:集中应用全自动生化分析仪测定血糖、甘油三酯、低密度脂蛋白胆固醇的指标。应用ELISA检测血浆CEL和CML水平。(3)取血后,小鼠采血后用PBS进行灌注,分离获得整体主动脉,主动脉是切除从主动脉根部到腹部,进行油红0染色后拍照,并用Image-ProPlus66.0.软件对斑块面积进行定量分析。然后从主动脉瓣开始以100μ m为间距切取连续8张厚度为8um的切片,通过HE染色观察动脉粥样硬化的程度。免疫组化法测和Western Blot检测主动脉eNOS蛋白和AMPK蛋白的表达进行定量。研究结果打药前的基线血糖是5.33±0.24 mmol/l,糖尿病二甲双胍治疗组与非糖尿病二甲双胍干预组,入组前的血糖有统计学差别。糖尿病各亚组中入组时和治疗4周后处死时体重无明显增长。糖尿病二甲双胍治疗组CEL和CML较糖尿病辛伐他汀治疗组明显降低。糖尿病二甲双胍治疗组CEL和CML较糖尿病盐水组低,差异有统计学意义。糖尿病二甲双胍治疗组CEL和CML较非糖尿病辛伐他汀治疗组明显升高。糖尿病二甲双胍治疗组CEL和CML较非糖尿病二甲双胍治疗组高,差异有统计学意义。糖尿病二甲双胍治疗组、糖尿病盐水干预组和糖尿病辛伐他汀治疗组存在动脉粥样硬化。非糖尿病辛伐他汀组和非糖尿病盐水组未观察到明显的斑块。非糖尿病二甲双胍组附壁血栓形成趋势,管腔内血小板梁形成。非糖尿病辛伐他汀治疗组和糖尿病辛伐他汀治疗组ApoE-/-小鼠血管内皮细胞中均检测到 eNOS 的表达(0.0497±0.0152 vs 0.0398±0.0131,P<0.05)。非糖尿病二甲双胍组eNOS表达(0.0133±0.0019)与非糖尿病盐水组(0.0172±0.0013)类似(P=0.3),但均低于糖尿病辛伐他汀治疗组,差异有统计学意义(P<0.05)。糖尿病二甲双胍组和糖尿病盐水组eNOS均无明显的表达,均较之前的各组低。六组AMPK没有明显的表达。研究结论二甲双胍可以防治1型糖尿病动脉粥样硬化,其可能通过清除丙酮醛,使晚期糖基化终末产物减少而非降低血糖来达到的作用。第四部分1型糖尿病患儿身高与胰岛素样生长因子-1相关性的研究研究目的评估1型糖尿病儿童的身高是否受损,并探讨1型糖尿病患儿中IGF-1SDS与HSDS之间是否存在关联。方法本研究为横断面研究。从2016年12月至2018年8月,招募了在山东省立医院的糖尿病门诊进行定期随访的72名中国T1DM患儿。此外,还招募了在山东省立医院儿童保健门诊接受常规健康检查的儿童作为健康对照组。结果本次研究一共有72名T1DM儿童,和190名健康儿童入组。在T1DM组平均基线HSDS为0.49,在对照组为0.05,有统计学差异。T1DM组中的女孩HSDS也明显高于对照组女孩HSDS。T1DM组中的THSDS高于对照组THSDS。T1DM组中的男孩THSDS明显高于对照组中的男孩THSDS。但女孩的THSDS在T1DM组与对照组之间无明显差异。所有入组的儿童HSDS均高于THSDS。T1DM组中的IGF-1水平明显低于对照组。同样T1DM组中的IGF-1SDS水平明显低于对照组。此外,在分别比较男孩和女孩的IGF-1SDS时仍然有显著差异。在血糖控制良好组HSDS比THSDS高0.48SDS,在健康儿童组中的HSDS 比THSDS高0.32SDS。血糖控制良好组与健康对照组中IGF-1SDS的值差异有统计学意义。在血糖控制良好组中的FPG和糖化血红蛋白也高于相应的健康对照组。C肽和胰岛素水平在血糖控制良好组也明显低于相应的健康儿童组。T1DM男孩与T1DM女孩的IGF-1SDS无明显差异。T1DM女孩中的胰岛素剂量明显高于T1DM男孩。但T1DM患儿中,不同胰岛素类型的亚组中胰岛素用量存在显著差异。在所有入组的儿童中,HSDS与C肽、胰岛素、IGF-1水平以及IGF-1SDS呈正相关。在所有入组儿童,IGF-1SDS与糖化血红蛋白、C肽和胰岛素水平呈显著相关。在对照组中IGF-1SDS与C肽、胰岛素水平呈正相关。C肽水平与胰岛素剂量显著负相关,在T1DM组中IGF-1和胰岛素剂量显著正相关。结论1.T1DM患儿的GH/IGF-1轴受损,但是他们的身高是未受损的。2.T1DM患儿IGF-1水平和身高不随糖化血红蛋白降低而升高。3.C肽水平和胰岛素类型对T1DM患儿身高无影响。4.大剂量的胰岛素可以使T1DM儿童有较高的IGF-1水平和高身高。更多还原

【Abstract】 BackgroundThe prevalence of type 1 diabetes mellitus(T1DM)among pediatric populations has been increasing globally over the last decade.Type 1 diabetes is the main cause of diabetes in children,accounting for 5-10%of the total number of diabetes.Type 1 diabetes children have poor glycemic control and cannot take the oral hypoglycemic drugs alone with lifelong insulin injections.Insulin is more likely to cause low blood glucose than other oral medications.The better glycated hemoglobin,the more hypoglycemia.The incidence of hypoglycemia is three times than ordinary time.This increases the difficulty of blood glucose control.Long-term hyperglycemia and metabolic disorders lead to serious diabetic complications.Compared with the general population,the life expectancy of patients with type 1 diabetes is reduced by 11-13 years,and the incidence of complications of type 1 diabetes can be as high as 96.5%.The main cause of death in diabetes is cardiovascular complications,which are based on atherosclerosis.At present,there is definite evidencethat metformin can delay atherosclerosis in type 1 diabetes mellitus at the same glycated hemoglobin.The cardiovascular protective effect may be extra and not be its lower blood sugar way.Metformin’ s protective cardiovascular mechanism is specific to diabetes.It prevents diabetic vascular disease by inhibiting the formation of non-enzymatic glycosylation products produced by hyperglycemia.AGEs have strong reactivity and the ability of continuous cross-linking,which can directly form covalent cross-linking with the proteins in the blood vessel wall,stimulate the endothelial cells to over-express adhesion molecules,and lead to damage of the vascular structure and function causing vascular lesions.In addition,AGEs can also cause degradation of anionic polyglycoproteins on the vascular endothelial cell membrane,leading to increased vascular permeability and destruction of vascular endothelial barrier function causing vascular permeability increase,which make excessive expression of vascular cell adhesion molecule 1 and the monocyte chemotactic protein 1 in mononuclear cells.As a result,the adhesion of monocytes to endothelial cells is enhanced,thereby damaging the vascular endothelial structure.AGEs can induce the proliferation of vascular smooth muscle cells and the formation of reactive oxygen species,and induce the activation of nuclear factor κ B transduction pathway,thereby increasing the expression of inflammatory factors and promoting the development of atherosclerosis.Metformin may have a protective effect on the cardiovascular system by scavenging MGO and reducing AGEs.Long-term poor metabolic control may affect linear growth,whereas good metabolic control tends to normalize linear growth.In T1DM,a decrease in serum insulin-like growth factor-1(IGF-1)has been consistently reported,and may be the cause of growth abnormalities Insulin has the crucial role of regulating growth factors and linear growth.Moreover,there is strong evidence that insulin may indirectly affect IGF-1 synthesis.Insulin alters the concentration of IGF-binding proteins(IGFBPs),which regulate IGF-1 bioactivity.Through upregulation of hepatic GH receptor expression,insulin increases hepatic sensitivity to GH stimulation,thereby increasing IGF-1 production.In T1DM,with insufficient insulin action in the liver due to lack of endogenous insulin in the portal vein,dysfunction of the GH/IGF-1 axis may be present.Although these abnormalities have been described in patients with poor glycemic control,the results of previous studies support the existence of a negative association between IGF-1 and glycated hemoglobin Alc(HbAlc).However,one study found that the IGF-1 level in patients with T1DM was low,but did not correlate with HbAlc.Strict glycemic control by subcutaneous injections of exogenous insulin attenuates these abnormalities,but does not completely reverse them.This study consisted of four parts:part one:ApoE mice were induced into juvenile type 1 diabetes model,and the degree of juvenile atherosclerosis was observed.In the second part,ApoE mice were induced into juvenile type 1 diabetes mellitus model,and metformin was used for intervention,and it was found that there was already early atherosclerosis,and metformin was effective for intervention.The third part is the role of metformin in preventing atherosclerosis by removing the late glycosylation products.The fourth part mainly studies whether the height of children with type 1 diabetes is impaired due to long-term poor blood glucose control,and whether the change of insulin-like growth factor-1 affects the height.Part 1 Establ ishment of juvenile atherosclerosis in type 1 diabetes mellitusObjectivesWe used ApoE-/-mice to induce juvenile atherosclerosis of type 1 diabetes mellitus model.Subjects and MethodsAnimal model18 Male ApoE gene knockout mice at age of 4 weeks were injected with STZ for 5 consecutive days and observed for 2 weeks.Appropriate amount of tail was cut off to measure blood glucose.The mice with two times of FPG≥llmmol/L were successfully induced into the diabetes model and randomly enrolled to the diabetes group.The remaining 18 were enrolled in the control group.Experimental animal materials(1)After feeding for 4 weeks,the mice were fasted for 12 hours with no restriction on drinking water.The mice were euthanized.Each one of the control group and the model group was randomly selected to determine whether the model was successful.(2)Mice were anesthetized and taken blood.Biochemical criterion determination:FPG,glycosylated hemoglobin,triglyceride,and low-density lipoprotein cholesterol were determined by centralized automatic biochemical analyzer.(3)After blood collection,the whole aorta was obtained.The aorta was removed from the aortic root to the abdomen,oil red 0 staining was performed,and the plaque area was quantitatively analyzed with image-proplus 6.0.ResultsThe baseline blood glucose before injection was 5.33±0.24 mmol/1.There was a statistically significant difference in blood glucose at enrollment between the diabetic treatment group and the non-diabetic group.There was no significant weight gain at enrollment and after 4 weeks in diabetes group.Atherosclerosis was found in diabetic group.No significant plaque was observed in the non-diabetic group.ConclusionType 1 diabetes mellitus and its juvenile atherosclerosis were successfully established.Part 2 Effect of metformin on juvenile atherosclerosis in type 1 diabetes mellitusObjectivesobserved the degree of juvenile atherosclerosis,and used metformin to intervene it.Subjects and MethodsAnimal model18 Male ApoE gene knockout mice at age of 4 weeks were injected with STZ for 5 consecutive days and observed for 2 weeks.Appropriate amount of tail was cut off to measure blood glucose.The mice with two times of FPG≥11mmol/L were successfully induced into the diabetes model and randomly enrolled to the diabetes group(groups 1,2,and 3).The remaining 18 were enrolled in the control group(groups 4,5 and 6).Groups 1 and group 4 received 100mg/kg/day metformin for 4 weeks.Group 2 and group 5 received 5mg/kg/day simvastatin.Group 3 and group 6 received normal saline for four weeks.Experimental animal materials(1)After feeding for 4 weeks,the mice were fasted for 12 hours with no restriction on drinking water.The mice were euthanized.Each one of the control group and the model group was randomly selected to determine whether the model was successful(2)Mice were anesthetized and taken blood.Biochemical criterion determination:FPG,glycosylated hemoglobin,triglyceride,and low-density lipoprotein cholesterol were determined by centralized automatic biochemical analyzer.(3)After blood collection,the whole aorta was obtained.The aorta was removed from the aortic root to the abdomen,oil red 0 staining was performed,and the plaque area was quantitatively analyzed with image-proplus 6.0.ResultsThe baseline blood glucose before injection was 5.33±0.24 mmol/1.There was a statistically significant difference in blood glucose at enrollment between the diabetic metformin treatment group and the non-diabetic metformin intervention group.There was no significant weight gain at enrollment and after 4 weeks in each subgroup of diabetes.Atherosclerosis was found in diabetic metformin group,diabetic saline intervention group and diabetic simvastatin group.No significant plaque was observed in the non-diabetic simvastatin group and the non-diabetic saline group.In the non-diabetic metformin group,mural thrombus formation trend and intraluminal platelet beam formation were observed.ConclusionMetformin can delay atherosclerosis in type 1 diabetes mellitus.Part 3 The mechanism of metformin delaying juvenile atherosclerosis in type 1 diabetes mellitusObjectivesIn this study,we used ApoE-/-mice to induce juvenile type 1 diabetes mellitus model,observed the degree of juvenile atherosclerosis,and used metformin to intervene,and explored the corresponding mechanism.Subjects and MethodsAnimal model18 Male ApoE-/-mice at age of 4 weeks were injected with STZ for 5 consecutive days and observed for 2 weeks.Appropriate amount of tail was cut off to measure blood glucose.The mice with two times of FPG≥llmmol/L were successfully induced into the diabetes model and randomly enrolled to the diabetes group(groups 1,2,and 3).The remaining 18 were enrolled in the control group(groups 4,5 and 6).Groups 1 and group 4 received 100mg/kg/day metformin for 4 weeks.Group 2 and group 5 received 5mg/kg/day simvastatin.Group 3 and group 6 received normal saline for four weeks.Exper imental animal mater ials(1)After feeding for 4 weeks,the mice were fasted for 12 hours with no restriction on drinking water.The mice were euthanized.Each one of the control group and the model group was randomly selected to determine whether the model was successful.(2)Mice were anesthetized and taken blood.Biochemical criterion determination:FPG,glycosylated hemoglobin,triglyceride,and low-density lipoprotein cholesterol were determined by centralized automatic biochemical analyzer.Plasma CEL and CML levels were detected by ELISA.(3)After blood collection,the whole aorta was obtained.The aorta was removed from the aortic root to the abdomen,oil red 0 staining was performed,and the plaque area was quantitatively analyzed with image-proplus 6.0.The expressions of eNOS and AMPK proteins in aorta were quantitatively detected by immunohistochemistry and Western Blot.ResultsThe baseline blood glucose before injection was 5.33±0.24 mmol/1.There was a statistically significant difference in blood glucose at enrollment between the diabetic metformin treatment group and the non-diabetic metformin intervention group.There was no significant weight gain at enrollment and after 4 weeks in each subgroup of diabetes.Compared with the simvastatin treatment group,the CEL and CML in the diabetic metformin treatment group were significantly lower.There was a statistically significant difference between CEL and CML in the diabetic metformin group and the diabetic saline group.Compared with the non-diabetic simvastatin treatment group,CEL and CML in the diabetic metformin treatment group were significantly higher.CEL and CML in the diabetic metformin treatment group were higher than those in the non-diabetic metformin treatment group,and the difference was statistically significant.Atherosclerosis was found in diabetic metformin group,diabetic saline intervention group and diabetic simvastatin group.No significant plaque was observed in the non-diabetic simvastatin group and the non-diabetic saline group.In the non-diabetic metformin group,mural thrombus formation trend and intraluminal platelet beam formation were observed.eNOS expression was detected in vascular endothelial cells in both the non-diabetic simvastatin treatment group and the diabetic simvastatin treatment group(0.0497±0.0152 vs 0.0398 ± 0.0131,P<0.05).The expression of eNOS in the non-diabetic metformin group(0.0133±0.0019)was similar to that in the non-diabetic saline group(0.0172±0.0013)(P=0.3),but both were lower than that in the diabetic simvastatin treatment group,and the difference was statistically significant(P<0.05).There was no significant expression of eNOS in the diabetic metformin group and the diabetic saline group,both of which were lower than the previous groups.There was no significant expression of AMPK in the six groups.ConclusionMetformin can delay atherosclerosis in type 1 diabetes mellitus.by removing MGO to reduce tAGEs not lowering blood glucose.Part 4 The association of height and insulin-1 ike growth factor-1 in children with type 1 diabetes mellitusObjectivesThe purpose of this study was to assess the height of children with type 1 diabetes is impaired and to explore the association between IGF-1SDS and HSDS.Subjects and MethodsThis study was cross-sectional.Seventy-Two Chinese children with T1DM,who regularly attended the Diabetes clinic in Shandong Provincial Hospital(Jinan,China)for follow-up,were recruited from December 2016 to August 2018.In addition,190 healthy Chinese children of similar age,sex,and body mass index(BMI),attending the Childcare clinic in Shandong Provincial Hospital for health examination,were recruited as healthy controls.ResultsThe data of 72 children with T1DM without signs and symptoms of diabetes complications,and 190 healthy children were analyzed.Baseline clinical data showed no significant differences between the two groups.The average baseline HSDS was 0.49 in the T1DM group and 0.05 in the control group.This difference was significant.A significant increase in HSDS was observed in girls with T1DM,compared with girls in the control group.The HSDS was also higher in boys with T1DM than in boys in the control group;however,this difference was not statistically significant.The mean THSDS was higher in the T1DM group than in the control group.The THSDS was significantly higher in boys with T1DM boys than in boys in the control group;however,there was no difference between girls with T1DM and girls in the control group.The HSDS was higher than the THSDS in all recruited children.The IGF-1 level in the T1DM group was significantly lower than that in the control group.A similar difference was observed for IGF-1SDS;moreover,the difference remained significant when considering boys and girls separately.The HSDS and THSDS of the good glycemic control group were higher than those of the healthy control group,but these differences were not statistically significant.The HSDS was higher than THSDS by 0.48 SDS in the good glycemic control group and by 0.32 SDS in the healthy control group.There was a significant difference in IGF-1SDS between the good glycemic control group and the healthy control group.As expected,FPG and HbAlc remained higher in the good glycemic control group than in the healthy control group.The C-peptide and insulin levels were lower in the good glycemic control group than in the healthy control group.No difference was observed in the insulin dosage,HSDS,or IGF-1SDS between good glycemic control group and the poor glycemic control group.No difference in IGF-1SDS was observed between girls with T1DM and boys with T1DM.A significantly higher insulin dosage was observed in girls with T1DM than in boys with T1DM.There was a significant difference in the insulin dosage among the T1DM subgroups based on the types of insulin.The HSDS was positively correlated with C-peptide,insulin,and IGF-1 levels,as well as IGF-1SDS in all recruited children.The IGF-1SDS was also significantly correlated with HbAlc,C-peptide,and insulin levels in all recruited children.As expected,IGF-1SDS was also positively correlated with C-peptide and insulin levels in the control group.As expected,C-peptide level significantly increased with reduction in the insulin dosage,and there was an interaction between IGF-1 and insulin dosage in the T1DM group.Conclusions1.GH/IGF-1 axis is impaired in T1DM children without complications,but their height is not impaired.2.Height and IGF-1 in in T1DM children do not increase by reducing HbAlc.3.C-peptide and insulin types do not affect the height in T1DM children.4.High.dosages dose of insulin may induce high levels of IGF-1 and tall stature in T1DM.更多还原