2型糖尿病患者血清SHBG水平及吡格列酮干预研究
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摘要
研究背景和目的
性激素结合球蛋白（SHBG）是肝脏产生的一种糖蛋白，可特异性地与性
激素结合并参与其转运，调控血液中生物活性的性激素的浓度。它与睾酮有
高度的结合力，与雌二醇有一定的亲和力，因而被认为是雄性性征的一个标
志。流行病学横断面研究资料发现，SHBG及性激素水平与2型糖尿病的许
多危险因素，如肥胖、中心性体脂分布、高胰岛素血症、高血糖等相关。少
部分研究用葡萄糖钳夹术直接测量胰岛素抵抗法进行研究后认为SHBG与
胰岛素敏感性相关。Nestler预期SHBG可能是高胰岛素血症性胰岛素抵抗
的一个标志。SHBG与2型糖尿病之间的相互联系尚不清，虽然己有一些研
究报导男性或女性2型糖尿病患者SHBG水平低于正常人，部分前瞻性研
究认为SHBG水平的降低能独立地预期2型糖尿病的发生，两者的因果关
系存在争论。毗格列酮属于噻唑烷二酮类，是一种胰岛素增敏剂，目前认为
它可激活过氧化物酶体增殖活化受体γ（PPARγ），抑制脂肪组织产生TNFα
及促进GLUT-4的表达而提高机体外周组织对胰岛素的敏感性。
本研究的目的是观察：（1）2型糖尿病患者血清SHBG及性激素与性别、
2001年浙江大学硕士学位论文
年龄、体重指数、血脂、血压相匹配的正常人比较的改变情况：（2）2型糖
尿病患者血清SHBG及性激素与其B、血糖、BMI等危险因素的相关性；
（3）通过唆陛烷二酮类干预治疗观察 SHBG及相关指标改变情况。
对象与方法
共有2型糖尿病患者85例（女性取绝经后为38例），均为毗格列酮二
期临床药物验证志愿者，按随机双盲的原则分为试验组（毗格列酮＋磺腮类
＋双肌类）和安慰剂组（安慰剂＋磺腺类＋双肌类），并收集相应清洗期后和
治疗3个月后患者血清标本。另有59例正常人对照血清来自浙医二院同期
健康体检人群（女性取绝经后27例），年龄、性别、体重指数、血压、胆固
醇。甘油三酯与患者组相匹配。用IRMA法测定血清SHBG，用AIA法测
定血清总 EZ。总 T、FINS，以 1／（FBG’FWS）为胰岛素敏感性指数。结果
用SPSS10刀进行统计分析。
结果
1、患者组空腹血糖。空腹胰岛素、胰岛素敏感性指数、B细胞功能指数较
对照组显著降低，而性别、年龄、体重指数。血压。胆固醇、甘油三酯
与对照组无显著性差异。
2。患者组血清S＊＊G水平较同性别对照组显著降低，女性（P＜0刀1）较男
性o＜0．05）更为显著；女性患者组血清总雌二醇较女性对照组增高，
但未达统计学意义（P。0063），男性无显著性差异；血清总睾酮水平患
者组与同性别对照组无显著性差异；总翠酮与SHBG的比值在女性患者
组显著高于对照组（P＜001），而男性无显著性差异。
3。女性患者组相关分析发现SHBG与空腹血糖、空腹胰岛素显著负相关（相
－2－
2001年浙江大学硕士学位论文
关系数分别为－0．372，P＜0刀5；－O．332，P＜0刀5），与胰岛素敏感性指
数显著正相关（相关系数为0．445，P＜0．01），而S＊＊G与体重指数无显
著相关。
4、男性患者组相关分析发现SHBG与体重指数显著负相关（相关系数为－
0．329，P＜0刀5）；总辜酮与体重指数显著负相关（相关系数为－0．424，
P＜0刀1），而删＊G与空腹血糖、空腹胰岛素及胰岛素敏感性指数无显
著相关性。
5、经毗格列酮干预治疗口周后，女性试验组FBG。HbA；C、CHO、TG、
HDL－C。LDL－C与自身治疗前相比显著改善，BMI显著增加；SHBG有
上升趋势，但未达统汁学意义；胰岛素敏感性指数与治疗前无显著差异。
6。经毗格列酮干预治疗门周后，男性试验组HbA；。、HDL－C、TG与自身
治疗前相比显著改善，BMI显著增加；SHBG和胰岛素敏感性指数与治
疗前无显著差异。
结论
1、2型糖尿病患者血清SHBG水平明显低于正常人，女性2型糖尿病患者
T／SHBG显著高于正常人。
2、女性2型糖尿病患者血清SHBG与胰岛素敏感性指数正相关，与空腹血
糖。空腹胰岛素负相关；男性患者血清SHBG及总翠酮与体重指数负相
关。
3、毗格列酮干预治疗12周的2型糖尿病患者血糖、血脂有显著改善，女
性患者血清SHBG有上升趋势，而胰岛素敏感性指数无显著性改变。
Backgrounds and Objectives
Sex hormone-binding globulin (SHBG), a kind of glycoprotein produced by liver, could conjugate and transfer sex hormones specifically, and thus control the levels of bioavailable sex hormones in blood. SHBG could bind testosterone with high affinity and estrogen with lower affinity, so it was thought to be a marker of androgenicity. Associations had been shown between sex hormone-binding globulin and several risk factors of type 2 diabetes mellitus, such as obesity, central fat distribution, increased blood glucose, hyperinsulinemia and insulin resistance. Nestler had proposed that SHBG might be a marker of hyperinsulinemic insulin resistance. The links between SHBG and type 2 diabetes have not been conclusive though in some studies an association between SHBG level and type 2 diabetes mellitus had been reported. In several prospective studies, the reduced SHBG could predict the development of type 2 diabetes mellitus independently. The causality between them is being debating. Pioglitazone is one of the insulin-sensitizing compounds,
2001 %-
thiazolidinediones. Thiazolidinediones were thought to improve insulin sensitivity through the activation of peroxisome proliferator-activated receptor y (PPARy), the suppression of lipogenic TNFa production and the facilitation of GLUT-4 expression.
The aims of the study were: 1) To examine the levels of serum SHBG and sex hormones in patients with type 2 diabetes compared with normal persons who were matched by sex, age, BMI, BP and blood lipids; 2) To observe the associations between serum concentration of SHBG and several risk factors such as ISI, FBG, BMI, etc in patients with type 2 diabetes; 3) To examine the levels of serum SHBG, etc after pioglitazone intervention.
Subjects and Methods
We recruited 85 cases with type 2 diabetes (38 women cases were postmenopausal) of participants in II phase clinical study of pioglitazone. They were randomized into two groups i treatment group (pioglitazone+SU+BD) and placebo group (placebo+SU+BD). A 12-week double-blind placebo controlled study was conducted in them. Serum samples were taken before and after 12-week study. The 59 control serum samples were collected from participants of physical examination matched by age, sex, BP, BMI, cholesterol and triglyceride. Serum SHBG were measured with IRMA, and serum total E2, total T, FINS were detected with RIA. I/ (FBG*FINS) was used to evaluate insulin sensitivity. All results were analyzed by SPSS 10.0.
Results
1) Compared with control groups, diabetic groups had lower fasting blood glucose, fasting blood insulin, insulin sensitivity index and Homa B cell index significantly; while their sex, age, BP, BMI, cholesterol, triglyceride were matched with control groups.
2) Diabetic groups had lower serum SHBG levels significantly compared with control groups of both sexes (women, P<0.01; men, P<0.05), especially in women. Serum total estradiol of women diabetic group was higher than that of women control group, but this difference was not significant (P=0.063). No significant difference was seen in serum total testosterone of both sexes, T/SHBG were significantly higher in diabetic women than that in normoglycemic women (P<0.01). While in men, this difference was not observed.
3) In women diabetic group, serum SHBG was negatively correlated with fasting blood glucose and fasting insulin (coefficients were -0.372, P0.05; -0.332, P<0.05), And there was a significant positive correlation between serum concentration of SHBG and insulin sensitivity index (coefficient was 0.445, P<0.01). While no significant correlation was seen between SHBG and BMI.
4) In men diabetic group, BMI was negatively correlated with seram SHBG and total testosterone (coefficients were - 0.329, P0.05 and - 0.424, P<0.01). Whlie no significant correlation was seen between serum SHBG and insulin, insulin sensitivity index and fasting blood glucose,
5) About treatment group of women, FBG, HbAiC and CHO, TG, HDL-C, LDL-C were significantly improved co
性激素结合球蛋白（SHBG）是肝脏产生的一种糖蛋白，可特异性地与性
激素结合并参与其转运，调控血液中生物活性的性激素的浓度。它与睾酮有
高度的结合力，与雌二醇有一定的亲和力，因而被认为是雄性性征的一个标
志。流行病学横断面研究资料发现，SHBG及性激素水平与2型糖尿病的许
多危险因素，如肥胖、中心性体脂分布、高胰岛素血症、高血糖等相关。少
部分研究用葡萄糖钳夹术直接测量胰岛素抵抗法进行研究后认为SHBG与
胰岛素敏感性相关。Nestler预期SHBG可能是高胰岛素血症性胰岛素抵抗
的一个标志。SHBG与2型糖尿病之间的相互联系尚不清，虽然己有一些研
究报导男性或女性2型糖尿病患者SHBG水平低于正常人，部分前瞻性研
究认为SHBG水平的降低能独立地预期2型糖尿病的发生，两者的因果关
系存在争论。毗格列酮属于噻唑烷二酮类，是一种胰岛素增敏剂，目前认为
它可激活过氧化物酶体增殖活化受体γ（PPARγ），抑制脂肪组织产生TNFα
及促进GLUT-4的表达而提高机体外周组织对胰岛素的敏感性。
本研究的目的是观察：（1）2型糖尿病患者血清SHBG及性激素与性别、
2001年浙江大学硕士学位论文
年龄、体重指数、血脂、血压相匹配的正常人比较的改变情况：（2）2型糖
尿病患者血清SHBG及性激素与其B、血糖、BMI等危险因素的相关性；
（3）通过唆陛烷二酮类干预治疗观察 SHBG及相关指标改变情况。
对象与方法
共有2型糖尿病患者85例（女性取绝经后为38例），均为毗格列酮二
期临床药物验证志愿者，按随机双盲的原则分为试验组（毗格列酮＋磺腮类
＋双肌类）和安慰剂组（安慰剂＋磺腺类＋双肌类），并收集相应清洗期后和
治疗3个月后患者血清标本。另有59例正常人对照血清来自浙医二院同期
健康体检人群（女性取绝经后27例），年龄、性别、体重指数、血压、胆固
醇。甘油三酯与患者组相匹配。用IRMA法测定血清SHBG，用AIA法测
定血清总 EZ。总 T、FINS，以 1／（FBG’FWS）为胰岛素敏感性指数。结果
用SPSS10刀进行统计分析。
结果
1、患者组空腹血糖。空腹胰岛素、胰岛素敏感性指数、B细胞功能指数较
对照组显著降低，而性别、年龄、体重指数。血压。胆固醇、甘油三酯
与对照组无显著性差异。
2。患者组血清S＊＊G水平较同性别对照组显著降低，女性（P＜0刀1）较男
性o＜0．05）更为显著；女性患者组血清总雌二醇较女性对照组增高，
但未达统计学意义（P。0063），男性无显著性差异；血清总睾酮水平患
者组与同性别对照组无显著性差异；总翠酮与SHBG的比值在女性患者
组显著高于对照组（P＜001），而男性无显著性差异。
3。女性患者组相关分析发现SHBG与空腹血糖、空腹胰岛素显著负相关（相
－2－
2001年浙江大学硕士学位论文
关系数分别为－0．372，P＜0刀5；－O．332，P＜0刀5），与胰岛素敏感性指
数显著正相关（相关系数为0．445，P＜0．01），而S＊＊G与体重指数无显
著相关。
4、男性患者组相关分析发现SHBG与体重指数显著负相关（相关系数为－
0．329，P＜0刀5）；总辜酮与体重指数显著负相关（相关系数为－0．424，
P＜0刀1），而删＊G与空腹血糖、空腹胰岛素及胰岛素敏感性指数无显
著相关性。
5、经毗格列酮干预治疗口周后，女性试验组FBG。HbA；C、CHO、TG、
HDL－C。LDL－C与自身治疗前相比显著改善，BMI显著增加；SHBG有
上升趋势，但未达统汁学意义；胰岛素敏感性指数与治疗前无显著差异。
6。经毗格列酮干预治疗门周后，男性试验组HbA；。、HDL－C、TG与自身
治疗前相比显著改善，BMI显著增加；SHBG和胰岛素敏感性指数与治
疗前无显著差异。
结论
1、2型糖尿病患者血清SHBG水平明显低于正常人，女性2型糖尿病患者
T／SHBG显著高于正常人。
2、女性2型糖尿病患者血清SHBG与胰岛素敏感性指数正相关，与空腹血
糖。空腹胰岛素负相关；男性患者血清SHBG及总翠酮与体重指数负相
关。
3、毗格列酮干预治疗12周的2型糖尿病患者血糖、血脂有显著改善，女
性患者血清SHBG有上升趋势，而胰岛素敏感性指数无显著性改变。
Backgrounds and Objectives
Sex hormone-binding globulin (SHBG), a kind of glycoprotein produced by liver, could conjugate and transfer sex hormones specifically, and thus control the levels of bioavailable sex hormones in blood. SHBG could bind testosterone with high affinity and estrogen with lower affinity, so it was thought to be a marker of androgenicity. Associations had been shown between sex hormone-binding globulin and several risk factors of type 2 diabetes mellitus, such as obesity, central fat distribution, increased blood glucose, hyperinsulinemia and insulin resistance. Nestler had proposed that SHBG might be a marker of hyperinsulinemic insulin resistance. The links between SHBG and type 2 diabetes have not been conclusive though in some studies an association between SHBG level and type 2 diabetes mellitus had been reported. In several prospective studies, the reduced SHBG could predict the development of type 2 diabetes mellitus independently. The causality between them is being debating. Pioglitazone is one of the insulin-sensitizing compounds,
2001 %-
thiazolidinediones. Thiazolidinediones were thought to improve insulin sensitivity through the activation of peroxisome proliferator-activated receptor y (PPARy), the suppression of lipogenic TNFa production and the facilitation of GLUT-4 expression.
The aims of the study were: 1) To examine the levels of serum SHBG and sex hormones in patients with type 2 diabetes compared with normal persons who were matched by sex, age, BMI, BP and blood lipids; 2) To observe the associations between serum concentration of SHBG and several risk factors such as ISI, FBG, BMI, etc in patients with type 2 diabetes; 3) To examine the levels of serum SHBG, etc after pioglitazone intervention.
Subjects and Methods
We recruited 85 cases with type 2 diabetes (38 women cases were postmenopausal) of participants in II phase clinical study of pioglitazone. They were randomized into two groups i treatment group (pioglitazone+SU+BD) and placebo group (placebo+SU+BD). A 12-week double-blind placebo controlled study was conducted in them. Serum samples were taken before and after 12-week study. The 59 control serum samples were collected from participants of physical examination matched by age, sex, BP, BMI, cholesterol and triglyceride. Serum SHBG were measured with IRMA, and serum total E2, total T, FINS were detected with RIA. I/ (FBG*FINS) was used to evaluate insulin sensitivity. All results were analyzed by SPSS 10.0.
Results
1) Compared with control groups, diabetic groups had lower fasting blood glucose, fasting blood insulin, insulin sensitivity index and Homa B cell index significantly; while their sex, age, BP, BMI, cholesterol, triglyceride were matched with control groups.
2) Diabetic groups had lower serum SHBG levels significantly compared with control groups of both sexes (women, P<0.01; men, P<0.05), especially in women. Serum total estradiol of women diabetic group was higher than that of women control group, but this difference was not significant (P=0.063). No significant difference was seen in serum total testosterone of both sexes, T/SHBG were significantly higher in diabetic women than that in normoglycemic women (P<0.01). While in men, this difference was not observed.
3) In women diabetic group, serum SHBG was negatively correlated with fasting blood glucose and fasting insulin (coefficients were -0.372, P0.05; -0.332, P<0.05), And there was a significant positive correlation between serum concentration of SHBG and insulin sensitivity index (coefficient was 0.445, P<0.01). While no significant correlation was seen between SHBG and BMI.
4) In men diabetic group, BMI was negatively correlated with seram SHBG and total testosterone (coefficients were - 0.329, P0.05 and - 0.424, P<0.01). Whlie no significant correlation was seen between serum SHBG and insulin, insulin sensitivity index and fasting blood glucose,
5) About treatment group of women, FBG, HbAiC and CHO, TG, HDL-C, LDL-C were significantly improved co
引文
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metabolic profile. Diabetes Care, 1999,22(11) : 1875-1881．
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