胰淀素及其基因突变与2型糖尿病骨密度的相关性研究
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摘要
目的胰淀素(amylin),又称胰岛淀粉样多肽(islet amyloid polypeptide, IAPP)在2型糖尿病(T2DM)患者的胰岛淀粉样蛋白及正常的胰岛细胞中发现,是胰岛β细胞分泌的一种天然肽类激素,与2型糖尿病胰岛素抵抗和胰岛细胞功能障碍有关。有研究发现IAPP基因Ser20Gly突变可导致糖耐量减退,影响糖尿病的进程。近年研究还发现,IAPP可作为一种成骨细胞促分裂剂和降钙素样骨吸收抑制剂,在骨代谢方面起着重要作用。该基因S20G突变在云南2型糖尿病患者中是否存在,对骨代谢是否有影响仍不清楚。本文的研究目的有以下几点：
1.探讨空腹血清IAPP水平与2型糖尿病患者骨密度的相关性；
2.观察云南汉族人群中是否存在IAPP基因Ser20Gly突变；
3.IAPP基因Ser20Gly突变是否与2型糖尿病及其骨密度相关。
方法入选对象268例,无血缘关系,右利手,其中2型糖尿病(T2DM)149例,非糖尿病(ND)119例；测定血清IAPP、血脂、肝肾功、钙磷水平；测定血糖、胰岛素,C肽浓度；测定左前臂(尺桡骨远端)骨密度；胰淀素基因突变测定：样本为288例云南人,无血缘关系,其中T2DM 167例,ND 121例。应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP), MspI酶切法筛查突变,部分样本PCR产物进行DNA测序分析。
结果1.T2DM组中骨质疏松症的发生率(28.3%)高于ND组(3.4%),P<0.001。
2.本组所有研究对象左前臂骨密度(T值)与年龄、性别、BMI、IAPP相关(P<0.05),其中与年龄、性别呈负相关,与BMI、IAPP呈正相关；T2DM组校正性别、BMI、GFR、糖尿病病程、高血压病程、吸烟等因素后,T值与年龄呈负相关(r=-0.062,P<0.001),与IAPP呈正相关(r=0.027,P<0.01)；ND组校正性别、GFR后,T值与年龄呈负相关(r=-0.035,P<0.001),与IAPP呈正相关(r=0.018,P<0.01),与BMI呈正相关(r=0.099,P<0.01)。3.对所有研究对象进行Logistic回归显示IAPP每减少1μl/ml,骨质疏松症发生率将增加10.2%。
4.应用PCR-RFLP在T2DM中发现胰淀素基因Ser20Gly突变1例,DNA测序分析证实该突变携带者为杂合子(A/G型),占0.6%,非T2DM中未发现该基因变异。5.IAPP基因Ser20Gly突变在T2DM组及ND组中发生率无显著性差异(P>0.05)。
结论校正性别、BMI、GFR、糖尿病病程、高血压病程、吸烟等因素后,空腹血清IAPP与2型糖尿病患者骨密度正相关,提示IAPP可能是T2DM骨代谢的一个保护性因素。云南汉族人群存在IAPP基因Ser20Gly低频突变,但是未发现该突变与云南人T2DM相关联,亦未发现该突变与T2DM患者骨密度相关。
Amylin (islet amyloid polypeptide, IAPP) expression was found in the islets amyloid of patients with type 2 diabetes mellitus(T2DM), as well as in the islet beta cells of normal pancreas It is a polypeptide hormone produced in islet beta cells and may lead to the insulin resistance and beta-cell dysfunction. In some studies, positive association was found between IAPP gene Ser20Gly mutation and inpaired glucose tolerance in Japanese population, but the frequencies of Ser20Gly mutation and its association with T2DM in YunNan Han population is unknown. On the other hand, IAPP plays a critical role in bone metabolism. It can stimulate the proliferation of osteoblastic and may acts as an inhibitor of bone reabsorption, In this study, we aim to investigate the relationships of serum IAPP levels and IAPP gene S20G mutation with bone mineral density of patients with T2DM.
Objective
1. To study the association between the serous IAPP levels and the bone mineral density of T2DM's patients.
2. To the evaluate the frequencies of the IAPP gene S20G mutation in Yunnan Han ethnic population.
3. To investigate the association between IAPP gene S20G mutation and bone mineral density of T2DM's patients.
Method In the first part of the study,266 unrelated YunNan Han individuals (T2DM 149, non-diabetes 119) with right dominant hand were included in this study. Height, weight, waist circumference, hip circumference, fasting IAPP, blood glucose, insulin, C-peptide, lipid, blood calcium, phosphate and the function of the liver and kidney were measured. Bone mineral density was measured with dual X-ray absorptiometry of the left fore arm. In the second part of this study,167 T2DM and 121 non-diabetes (ND) were enroled, all of them are unrelated Han race and resident in YunNan province. IAPP Ser20Gly mutation was examined by PCR-RFLP method.10% PCR products were randomly selected to perform direct DNA sequencing.
Result
1. The incidence rate of osteoporosis is 27.5% in T2DM and 3.4% in ND, that higher in T2DM than ND (P＜0.001).
2. In all subjects, T-score of the left forearm is association with age, sex, BMI, and IAPP. T-score is negatively associated with age, and positively associated with BMI, IAPP. In T2DM, after adjusting for sex, BMI, diabetes duration, hypertension, and cigrarette smoking, T-score was negatively associated with age(r=-0.062, P＜0.001) and positively with IAPP(r=0.027, P＜0.01). After adjusting for sex and GFR, T-score in ND was negatively significantly associated with age r=-0.035, P＜0.001),and positively associated with IAPP (r=0.018, P＜0.01) and BMI(r=0.099, P＜0.001).
3. In all subjects, logistic analysis indicates that every increment of 1μl/ml of IAPP may lead to 10.2% risk reduction of osteoporosis.
4. Only one Ser20Gly heterozygotic mutation was found in T2DM subjects, no Ser20Gly mutation was observed in ND group. The frequency of IAPP Ser20Gly mutation is 0.6% in T2DM group and no significant differences was found between T2DM and ND group. (Fisher two-tailed exact, P＞0.05).
Conclusions After correction for sex, BMI,GFR, diabetic duration, hypertension duration, and cigarette smoking, fasting serum IAPP level is positively associated with bone mineral density in T2DM patients, suggesting JAPP might be a protective factor for bone mass metabolism in T2DM. Low frequency of IAPP gene Ser20Gly
mutation was found in YunNan Han T2DM, but no positive association was observed
between this mutation and T2DM, as well as with bone mineral density.
1.探讨空腹血清IAPP水平与2型糖尿病患者骨密度的相关性；
2.观察云南汉族人群中是否存在IAPP基因Ser20Gly突变；
3.IAPP基因Ser20Gly突变是否与2型糖尿病及其骨密度相关。
方法入选对象268例,无血缘关系,右利手,其中2型糖尿病(T2DM)149例,非糖尿病(ND)119例；测定血清IAPP、血脂、肝肾功、钙磷水平；测定血糖、胰岛素,C肽浓度；测定左前臂(尺桡骨远端)骨密度；胰淀素基因突变测定：样本为288例云南人,无血缘关系,其中T2DM 167例,ND 121例。应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP), MspI酶切法筛查突变,部分样本PCR产物进行DNA测序分析。
结果1.T2DM组中骨质疏松症的发生率(28.3%)高于ND组(3.4%),P<0.001。
2.本组所有研究对象左前臂骨密度(T值)与年龄、性别、BMI、IAPP相关(P<0.05),其中与年龄、性别呈负相关,与BMI、IAPP呈正相关；T2DM组校正性别、BMI、GFR、糖尿病病程、高血压病程、吸烟等因素后,T值与年龄呈负相关(r=-0.062,P<0.001),与IAPP呈正相关(r=0.027,P<0.01)；ND组校正性别、GFR后,T值与年龄呈负相关(r=-0.035,P<0.001),与IAPP呈正相关(r=0.018,P<0.01),与BMI呈正相关(r=0.099,P<0.01)。3.对所有研究对象进行Logistic回归显示IAPP每减少1μl/ml,骨质疏松症发生率将增加10.2%。
4.应用PCR-RFLP在T2DM中发现胰淀素基因Ser20Gly突变1例,DNA测序分析证实该突变携带者为杂合子(A/G型),占0.6%,非T2DM中未发现该基因变异。5.IAPP基因Ser20Gly突变在T2DM组及ND组中发生率无显著性差异(P>0.05)。
结论校正性别、BMI、GFR、糖尿病病程、高血压病程、吸烟等因素后,空腹血清IAPP与2型糖尿病患者骨密度正相关,提示IAPP可能是T2DM骨代谢的一个保护性因素。云南汉族人群存在IAPP基因Ser20Gly低频突变,但是未发现该突变与云南人T2DM相关联,亦未发现该突变与T2DM患者骨密度相关。
Amylin (islet amyloid polypeptide, IAPP) expression was found in the islets amyloid of patients with type 2 diabetes mellitus(T2DM), as well as in the islet beta cells of normal pancreas It is a polypeptide hormone produced in islet beta cells and may lead to the insulin resistance and beta-cell dysfunction. In some studies, positive association was found between IAPP gene Ser20Gly mutation and inpaired glucose tolerance in Japanese population, but the frequencies of Ser20Gly mutation and its association with T2DM in YunNan Han population is unknown. On the other hand, IAPP plays a critical role in bone metabolism. It can stimulate the proliferation of osteoblastic and may acts as an inhibitor of bone reabsorption, In this study, we aim to investigate the relationships of serum IAPP levels and IAPP gene S20G mutation with bone mineral density of patients with T2DM.
Objective
1. To study the association between the serous IAPP levels and the bone mineral density of T2DM's patients.
2. To the evaluate the frequencies of the IAPP gene S20G mutation in Yunnan Han ethnic population.
3. To investigate the association between IAPP gene S20G mutation and bone mineral density of T2DM's patients.
Method In the first part of the study,266 unrelated YunNan Han individuals (T2DM 149, non-diabetes 119) with right dominant hand were included in this study. Height, weight, waist circumference, hip circumference, fasting IAPP, blood glucose, insulin, C-peptide, lipid, blood calcium, phosphate and the function of the liver and kidney were measured. Bone mineral density was measured with dual X-ray absorptiometry of the left fore arm. In the second part of this study,167 T2DM and 121 non-diabetes (ND) were enroled, all of them are unrelated Han race and resident in YunNan province. IAPP Ser20Gly mutation was examined by PCR-RFLP method.10% PCR products were randomly selected to perform direct DNA sequencing.
Result
1. The incidence rate of osteoporosis is 27.5% in T2DM and 3.4% in ND, that higher in T2DM than ND (P＜0.001).
2. In all subjects, T-score of the left forearm is association with age, sex, BMI, and IAPP. T-score is negatively associated with age, and positively associated with BMI, IAPP. In T2DM, after adjusting for sex, BMI, diabetes duration, hypertension, and cigrarette smoking, T-score was negatively associated with age(r=-0.062, P＜0.001) and positively with IAPP(r=0.027, P＜0.01). After adjusting for sex and GFR, T-score in ND was negatively significantly associated with age r=-0.035, P＜0.001),and positively associated with IAPP (r=0.018, P＜0.01) and BMI(r=0.099, P＜0.001).
3. In all subjects, logistic analysis indicates that every increment of 1μl/ml of IAPP may lead to 10.2% risk reduction of osteoporosis.
4. Only one Ser20Gly heterozygotic mutation was found in T2DM subjects, no Ser20Gly mutation was observed in ND group. The frequency of IAPP Ser20Gly mutation is 0.6% in T2DM group and no significant differences was found between T2DM and ND group. (Fisher two-tailed exact, P＞0.05).
Conclusions After correction for sex, BMI,GFR, diabetic duration, hypertension duration, and cigarette smoking, fasting serum IAPP level is positively associated with bone mineral density in T2DM patients, suggesting JAPP might be a protective factor for bone mass metabolism in T2DM. Low frequency of IAPP gene Ser20Gly
mutation was found in YunNan Han T2DM, but no positive association was observed
between this mutation and T2DM, as well as with bone mineral density.
引文
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