摘要
目的
探讨2型糖尿病患者早期皮质醇、ACTH水平改变与胰岛素抵抗(IR)的关系,并进一步讨论非腹型肥胖病人与腹型肥胖病人垂体—肾上腺轴功能紊乱情况是否有所差异。
方法
将一定数量2型糖尿病患者(T2DM)分为腹型肥胖组和非腹型肥胖组进行体格检查,测定腰围(WC),臀围(HC),计算腰臀比(WHR)、体重指数(BMI),测定血清皮质醇及ACTH(8am、4pm)水平,空腹状态下血糖、血脂、糖化血红蛋白(GHbAlc)(8Am)以及空腹血清胰岛素(FINS)和血糖水平;按HOMA模型计算胰岛素抵抗指数:HOMA—IR=FINS×FBG/22.5,以此反映2型糖尿病患者IR的情况,并分析血清皮质醇、ACTH水平在各组间的差异及其与胰岛素抵抗、血糖、体脂等因素的相关性。
结果
1.T2DM非腹型肥胖组晨血皮质醇高于正常对照组,ACTH高于正常对照组;晨血皮质醇水平与FPG、GHbAlc、FINS,HOMA-IR呈正相关。将与皮质醇相关的因素和晨血皮质醇水平进行多元逐步回归分析,结果显示HOMA-IR与高皮质醇水平密切相关。
2.T2DM腹型肥胖组晨血皮质醇、ACTH水平均高于正常对照组,ACTH水平高于非腹型肥胖组,晨血皮质醇水平与BMI、WHR、FPG、GHbAlc、FINS,HOMA-IR呈正相关,晨血ACTH水平与晨血皮质醇水平、BMI、FPG、FINS,HOMA-IR呈正相关,多元逐步回归分析表明T2DM腹型肥胖组的高皮质醇水平与高血糖关系最为密切,高ACTH水平与HOMA-IR密切相关。
3.T2DM非腹型肥胖组与T2DM腹型肥胖组均存在垂体-肾上腺轴昼夜分泌节律的紊乱。
结论
1.T2DM患者存在垂体-肾上腺轴功能的异常。
2.腹型肥胖与非腹型肥胖的2型糖尿病患者血清皮质醇、ACTH水平可能高于正常对照组,而且昼夜节律性消失。
3.T2DM腹型肥胖者的高皮质醇、高ACTH可能与高血糖及胰岛素抵抗状态密切相关。血清皮质醇、血糖和GHbAlC的联合检测对临床上伴有腹型肥胖的T2DM患者的评估和治疗具有指导意义,且可以考虑从糖皮质激素入手改善胰岛素的敏感性。
Objective
1.To evaluate the abnormalities of serum cortisol and ACTH in patients with Type 2 Diabetes Mellitus of different stature.
2.To evaluate the abnormalities of serum cortisol and ACTH in relation to development of insulin resistance.
Methods
Fifty T2DM subjects were grouped to patients with abdominal obesity and patients without abdominal obesity according to their Waist circumference(WC),Hip circumference(HC),waist-to-hip ratio(WHR),body mass index(BMI),serum cortisol and ACTH at 8am and 4pm,fasting plasma glucose(FPG),GHbA1c,insulin,and some other related index were measured in the subjects.HOMA-insulin resistance was calculated from the formula IR=fasting blood sugar×fasting insulin/22.5.To compare the difference of serum cortisol and ACTH among the groups and the abnormalities of serum cortisol and ACTH in relation to development of insulin resistance.
Results
1.Patients without abdominal obesity displayed higher plasma cortisol concentrations and higher plasma ACTH compared to normal control.The higher plasma cortisol concentrations was positively associated with FPG,GHbA1c、FINS and HOMA-IR.Further analysis revealed that HOMA-IR is the strongest factor associated with serum cortisol.
2.In patients with abdominal obesity,both cortisol and ACTH concentrations are higher than normal control,and the ACTH concentrations are higher than the ACTH concentrations in the patients without abdominal obesity.The high level of cortisol was positively associated with hyperglycemia,and the high level of ACTH was positively associated with insulin resistance.
3.All the patients of T2DM display abnormal circadian rhythms of cortisol and ACTH secretion.
Conclusions
All the patients of T2DM display abnormal circadian rhythms of cortisol and ACTH secretion.Patients with or without abdominal obesity displayed higher serum cortisol concentrations and higher serum ACTH compared to normal control,and the high level of cortisol and ACTH was closely associated with hyperglycemia and insulin resistance.
引文
[1]程志平.内分泌生理学[M].北京:人民卫生出版1998:284-293.
[2]桃兆耆.实用内科学[M].第7版.北京:人民卫生出版社,1998:932.
[3]Rosmond R.Stress induced disturbances of the HPA axis:a pathway to Type 2 diabetes[J].Med Sci Monit,2003;9(2):RA35-39.
[4]Jessop DA,Dallman MF,et al.Resistance to glucocorticoid feedback in obesity.J Clin Endocrinol Metab.2001,86:4109.
[5]Roy MS,Roy A,Brown S.Increased urinary-free cortisol outputs in diabetic patients.J Diabetes Complications.1998,12(1):24.
[6]Asensio C,Muzzin P,Rohner-Jeanrenaud F.Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance[J].Int J Obes Relat Metab Disord.2004 Dec;28 Suppl 4:s45-52.
[7]Phillips.DI,et al.Elevated plasma cortisol concentrations:a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab.1998,83:7578.
[8]Zoe S K Lee,et al.Plasma insulin,growth hormone and central obesity among young chinese type 2 diabetic patients Diabetes Care.1999.22(9):1450.
[9]Oppermann U,Type 1 11beta-hydroxysteroid dehydrogenase as universal drug target in metabolic diseases? Endocr Metab Immune Disord Drug Targets[J].2006 Sep,6(3):259-269.
[1] Grundv SM. Brewer HB, Cleeman,JI, et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute American Heart Association conference On scientific issues related todefinition[J]. Circulation,2004, 109(3): 433-438.
[2] Liu YJ, Nakagawa Y, Wang Y, et al. Increased glucocorticoid receptor and 11β-Hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes jn db/db mice[J]. Diabetes,2005; 54: 32-40.
[3] Friedman TC. Mastorakos G. Newman TD,et al. Carbohvdrate and lipid metabolism in endogenous hypercortisolism: shared features with metabolic syndrome X aid NIDDMl[J]. Endocr J, 1996;43: 645—655.
[4] Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome [J ]. Science, 2001; 294: 2166—2170.
[5] Reynolds RM. Chapman KE, Seckl JR. Skeletal muscle glucocorticoid receptor density and insulin resistance [J]. J Am Med Assoc,2002;287: 2505—2506.
[6] Rosmond R, Dallman MF, Bjormtorp P. Stress-related cortisol secretion in men relationships with abdominal obesity and endocrine , metabolic and haemodynamic abnormalities .J Clin Endocrinol Metab, 1998,83: 1853-1859.
[7] Levitt NS, Lambert EV, Woods D, et al.Impaired glucose tolerance and elevated blood pressure in low birth weight, nonobese, young south african adults: early programming of cortisol axis. J Clin Endocrinol Metab, 2000, 85: 4611-4618.
[8] Nyirenda MJ, Lindsay RS, Kenyon CJ, et al. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expresion and causes glucose intolerance in adult offspring. J Clin Invest, 1998, 101: 2174—2181.
[9] Whorwood CB. Donovan SJ. Flanagan D, et al. Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome[J].Diabetes,2002;51:1066-1075.
[10]Buren J,Liu HX,Jensen J,et al.Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1phosphatidylino-nositol 3-kinase and protein kinase B in primary cultured rat adipocytes.Eur J Endocrinol,2002,146:419-429.
[11]Lundgren M,Bure J,Ruge M,et al.Glucocorticoids down-regulateglucose uptake capacity and insulin-signaling proteins in omental but not subcutaneous human adipocytes.J Clin Endocfinol Metab.2004.89:2989-2997.
[12]Boullu-Ciocca S.Paulmyer-Lacroix O,Fina F,et al.Expression of the mRNAs coding for the glucocorticoid receptor isoforms jn obesity[J].Obes Res,2003;11:925-929.
[13]P.Black.The inflammatory consequences of psychologic stress:Relationship to insulin resistance,obesity,atherosclerosis and diabetes mellitus,type-Ⅱ[J].Med Hypotheses.2006,67(4):879-891.
[14]Petra Kok,Simon W.Kok,Madelon M,et al.Enhanced circadian ACTH release in obese premenopausal women:reversal by short-term acipimox treatment[J].Am J Physiol Endocrinol Metab.2004,287:848-856.
[15]Riddick F,Reisler D,Kipnis D.The sugar trasport system in striated muscle.Diabetes,1962,11:171-178.
[16]Cigolini M,Smith U.Human adipose tissue in culture.Studiesontheinsulin-Antagonistic effect of glucocorticoids.Metabolism,1979,20:502-510.
[17]Bonden G.Role of fatty acids in the pathogenesis of insulin resistance and NIDDM.Diabetes,1997,46:3-10.
[18]邵建华,高妍,袁振芳.游离脂肪酸对大鼠骨胳肌细胞胰岛素受体与胰岛素受体底物1的表达和酪氨酸磷酸化的影响.北京医科大学学报,1998,30:425-428.
[19]Fasshauer M,Kralisch S,Klier M,et al.Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes.Biochem Biophys Res Commun,2003, 301: 1045-1050.
[20] Land Rosmond, Claude Bouchard , Per Bj(o|¨)rntorp, 5-HT_(2A) Receptor Gene Promoter Polymorphism in Relation to Abdominal Obesity and Cortisol[J]. Obesity Research 2002, 10:585-589.
[21] Dagogo-Jack S,Tykodi G,Umamaheswaran I.Inhibition of Cortisol Biosynt hesis Decreases Circulating Leptin Levels in Obese Humans[J]. J Clin Endocrinol Metab.2005 Sep,90(9):5333-5335.
[22] Ahima RS , Qi Y, Singhal NS. Adipokines that link obesity and diabetes to the hypothalamus[J]. Prog Brain Res. 2006, 153:155-174.
[23] Jin L, Zhang S, Burguera BG, et al. Leptin and Leptin receptor expression in rat and mouse pituitary cells[J]. Endocrinology, 2000,141 (1): 333-339.
[24] Morash B ,Wilkinson D ,Ur E , et al . resistin expression and regulation in mouse pituitary[J].FEBS Lett ,2002 ,526(123) :26-30.
[25] Kresk M, Silha JV, Jezkova J, et al.Adipokine levels in Cushing's syndrome; elevated resistine levels in female patients with Cushing's syndrome Clinical Endocrinology[J], 2004, 60:350-357.
[26] Shojima N, Sakoda H, Ogihara T, et al. Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells. Diabetes, 2002, 51: 1737-1744.
[27] Fukuhara A , Matsuda M , Nishizawa M , et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science,2005,307: 426-430.
[28] Kralisch S,Klein J, Lossner U,et al. Hormonal regulation of the novel adipocytokine visfatin in 3T3-L1 adipocytes. J Endocrinol, 2005, 185: 1-8.
[29] O'Brien SM, Scott LV, Dinan TG. Cytokines: abnormalities in major depression and implications for pharmacological treatment[J]. Hum Psychopharmacol. 2004 Aug, 19(6):397-403.
[30] Seckl JR,Walker BR.Minireview:11β-hydroxysteroid dehydrogenase type 1: A tissue-specifi camplifier of glucocorticoid action[J].Endocrinology,2001, 142:1371-1376.
[31] Tomlinson JW,Moore J ,Cooper MS ,et al . Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue : tissue-specific induction by cytokines[J]. Endocrinology,2001,142:1982-1989.
[32] Morton NM, Holmes MC, Fievet C, et al. Improved lipid and lipoprotein profile , hepatic insulin sensitivity , and glucose tolerance in 11 beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem, 2001, 276:41293-41300.
[33] Weaver JU, Taylor NF, Monsen JP, et al. Sexual dimorphism in 11 beta hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity: a study in hypopituitary subjects. Clin Endocrinol, 1998,49: 13-20.
[34] Livingstone DE, Jones GC, Smith K, et al. Understanding the role of glucocorticoids in obesity : tissue-specific alterations of cortieosterone metabolism in obese Zueker rats. Endocrinology,2000, 141: 560-563.
[35] Rask E, Olsson T, Soderberg S, et al. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab,2001,86: 1418-1421.
[36] Whorwood CB, Donovan SJ, Flanagan D, et al. Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. Diabetes, 2002, 51: 1066-1075.
[37] Weaver JU, Hitman GA, KopelmanPG. 'An association between a BclI restriction fragment length polymorphism of the glucocorticoid receptor locus and hyperinsulinaemia in obese woman [J]. Mol Endocrinol, 1992, 9:295—300.
[38] Dobson MG,Redfern CP ,Unwin N ,et al. The N363S polymorphism of the glucocorticoid receptor : potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus[J]. J Clin Endocrinol Metab ,2001 ,86:2270-2274.
[39] Elisabeth FC,Van Rossum EF, Lamberts SW. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition[J]. Recent Prog Horm . Res ,2004 ,59 :333-357.
[40] Ullrich S. Berchtold S. Ranta F. et al. Serum-and glucocorticoid-inducible kinase 1(SGK1) mediates glucocorticoid induced inhibition of insulin secretion. Diabetes, 2005. 54: 1090-1099.
[41] Oppermann U, Type 1 11beta-hydroxysteroid dehydrogenase as universal drug target in metabolic diseases? Endocr Metab Immune Disord Drug Targets [J]. 2006 Sep,6(3):259-269.
