新诊断老年糖尿病患者的胰岛β细胞功能及与胰淀素和褪黑素的关系
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摘要
目的：通过观察新诊断的老年糖尿病患者胰岛素分泌的特点,测定血清中胰淀素、褪黑素含量,探讨胰淀素和褪黑素与老年糖尿病患者胰岛β细胞功能之间的关系,研究老年糖尿病发生的可能机制。
方法：收集初诊2型糖尿病(T2DM)患者70例,其中老年起病糖尿病组(EOD组；年龄≥60岁)37例,成年起病糖尿病组(AOD组；25岁≤年龄<60岁)33例,均行口服葡萄糖耐量试验(OGTT),根据OGTT试验各时点血糖、胰岛素值计算血糖曲线下面积(AUCg)、胰岛素曲线下面积(AUCi)、30min胰岛素增量与葡萄糖增量比值(△I30／△G30),胰岛β细胞功能指数(HOMA-p)及胰岛素抵抗指数(HOMA-IR)。采用酶联免疫(ELISA)法检测患者空腹血清胰淀素、褪黑素水平,与老年健康对照组(EHC组；30例)相比较。同时测定所有受试者的空腹血清甘油三脂(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C),测量血压、身高、体质量、腰围及臀围,计算体质指数(BMI)及腰臀比(WHR),并对结果进行统计分析。
结果：1.与AOD组相比,EOD组OGTT2 h血糖[(15.17±3.03)vs(13.59±2.76)mmol／L,P<0.05]、2 h胰岛素[(73.34±43.39)vs(64.22±29.75)uIU／ml,P<0.05]及HOMA-IR[(4.20±1.67)vs(3.49±1.83),P<0.05]明显升高,而HOMA-β[(58.20±24.89)vs(81.20±40.80),P<0.01]、△I30／／△G30(2.62±0.43)vs(3.37±0.58),P<0.01]明显降低。EOD组AUCg、AUCi均较AOD组略高,但差异无统计学意义(P>0.05)。
2.EOD组血清胰淀素水平显著高于AOD组[(21.57±15.88)Vs(19.8±13.18)ng/L,P<0.05]和EHC组[(21.57±15.88)vs(17.82±12.15)ng/L,P<0.01],AOD组与EHC组比较,血清胰淀素水平偏高,但无统计学意义(P>0.05)。EOD组血清褪黑素水平显著低于AOD组[(6.56±1.32)vs(8.17±1.23)pg/ml,P<0.05]和EHC组[(6.56±1.32)vs(7.65±1.39)pg／ml,P<0.01],EHC组与AOD组比较,血清褪黑素水平稍低,但无统计学意义(P>0.05)。
3.血清胰淀素与HOMA-IR(r=0.498,P=0.016)、空腹血清胰岛素(Fins)(r=0.517,P=0.031)、AUCi(r=0.516,P=0.021)呈正相关(P<0.05),与HOMA-β(r=-0.461,P=0.003)呈负相关,与空腹血糖(FBG)、血脂及AUCg、△I30／△G30、WHR、BMI均未见明显相关性。
4.血清褪黑素与与HOMA-p(r=0.403,P=0.016)、HDL-C(r=0.416,P=0.018)呈正相关；与HOMA-IR(r=0.549,P=0.019)、AUCi(r=-0.521,P=0.014)、WHR(r=-0.514,P=0.023)、FBG(r=-0.345,P=0.032)、LDL-C(r=0.479,P=0.012)呈负相关,与AUCg、BMI、△I30／／△G30均未见明显相关性。
结论：1、老年T2DM患者存在明显的胰岛β细胞功能下降及胰岛素早相分泌受损,同时存在一定程度的胰岛素抵抗及胰岛素释放高峰延迟,提示胰岛β细胞功能异常是老年糖尿病患者糖代谢紊乱的主要原因。
2、与健康老年人相比,老年起病糖尿病患者血清胰淀素水平明显增高,褪黑素水平明显降低,提示高胰淀素血症及低褪黑素血症可能与老年糖尿病的发病机制有关。
3、血清胰淀素水平与胰岛β细胞功能呈负相关关系,与肥胖、胰岛素抵抗呈正相关关系,提示血清胰淀素水平可作为评价胰岛β细胞功能的指标之一。
4、血清褪黑素水平与胰岛β细胞功能呈正相关关系,同时与血脂、胰岛素抵抗指数等存在负相关关系,推测其有可能成为评价胰岛β细胞功能的新指标之一。
Objective The present study was to explore the relationship between isletβ-cell function and the serum levels of amylin and melatonin by observing the feature of isletβ-cell function and measuring the serum levels of amylin and melatonin in newly diagnosed elderly diabetic patients, furtherly to explore the possible mechanism of senile diabetes.
Methods 70 newly diagnosed subjects with type 2 diabetes were divided into elderly-onset diabetes group (EOD, aged 60 to 94) and adult-onset diabetes group (AOD, aged 25 to 59 years), oral glucose tolerance test (OGTT) was detected and the area under the curve of glucose (AUCg)、the area under the curve of insulin (AUCi)、the function of pancreatic beta-cell(HOMA-β)、the ratio of the increment of insulin to that of serum glucose of the initial 30 minutes(△I30/△G30) and the homeostasis model assessment of insulin resistance (HOMA-IR) after OGTT was calculated. The levels of serum amylin and melatonin of all patients were determined with ELISA, compared with that of 30 healthy aged subjects(elderly healthy control group, EHC). For all of the subjects, fasting serum triglycerid (TG)、total cholesterol(TC)、high density lipoprotein cholesterol (HDL-C)、low density lipoprotein cholesterol (LDL-C) and blood pressure were measured and body mass index (BMI), waist/hip ratio(WHR) were calculated.
Results 1. Compared with AOD group, EOD group had lower value of HOMA-β[(58.20±24.89) vs (81.20±40.80), P＜0.01] and△I30/△G30[(2.62±0.43) vs (3.37±0.58), P＜0.01], but had higher values of OGTT 2 h serum glucose[(15.17±3.03) vs (13.59±2.76) mmol/L, P＜0.05], serum insulin[(73.34±43.39) vs (64.22±29.75) uIU/ml, P＜0.05] and HOMA-IR[(4.20±1.67) vs (3.49±1.83), P＜0.05], though the values of AUCg and AUCi were higher in EOD group than that in AOD group, no significant difference was found.
2. The serum amylin level in EOD group was obviously higher than that in AOD group[(21.57±15.88) vs (19.8±13.18) ng/L, P＜0.05] and EHC group[(21.57±15.88) vs (17.82±12.15) ng/L, P＜0.01].There wasn't obvious difference between AOD group and EHC group on serum amylin level(P＞0.05).The serum melatonin level in EOD group was obviously lower than that in AOD group[(6.56±1.32) vs (8.17±1.23) pg/ml, P＜0.05] and EHC group[(6.56±1.32) vs (7.65±1.39) pg/ml, P＜0.01]; There wasn't obvious difference between AOD group and EHC group on serum melatonin level(P＞0.05).
3. The correlation analysis results showed that:serum amylin level had positive correlation with HOMA-IR(r= 0.498, P= 0.016), fasting serum insulin(r= 0.517, P= 0.031), AUCi(r= 0.516, P= 0.021) and had negative correlation with HAMA-β(r=-0.461, P= 0.003). The serum amylin had no significant correlation with AUCg, FBG, blood lipids,△I30/△G30, WHR and BMI(P＞0.05).
4. The level of serum melatonin had positive correlation with HAMA-β(r= 0.403, P= 0.016) and HDL-C(r= 0.416, P= 0.018) and had negative correlation with HOMA-IR(r=-0.549, P= 0.019), AUCi(r=-0.521, P= 0.014), WHR(r=-0.514, P = 0.023), fasting blood glucose(r=-0.345, P= 0.032) and LDL-C(r=-0.479, P= 0.012), the serum melatonin had no significant correlation with AUCg,△I30/△G30 and BMI(P＞0.05).
Conclusion 1. Newly diagnosed elderly diabetic patients have obviousβ-cell deterioration and impaired early-phase insulin secretion, at the same time have a certain degree of insulin resistance and delayed peak of insulin release, suggesting that isletβ-cell dysfunction is the main reason of glucose metabolism disorder in elderly diabetic patients.
2. Compared with the healthy elderly, the elderly-onset diabetic patients had significantly higher level of amylin and lower level of melatonin, suggesting that the increased serum amylin and decreased serum melatonin may be related to the pathogenesis of senile diabetes.
3. The serum amylin level had significant negative correlation relationship with islets beta-cell function and had positive correlation relationship with obesity and insulin resistance, it is one of useful markers which estimate the function of pancreaticβ-cells.
4. The serum melatonin level had positive correlation with pancreatic beta-cell function and had negative correlation relationship with blood lipids and insulin resistance index, speculating that it may become a new index of evaluation of isletβ-cell function.
方法：收集初诊2型糖尿病(T2DM)患者70例,其中老年起病糖尿病组(EOD组；年龄≥60岁)37例,成年起病糖尿病组(AOD组；25岁≤年龄<60岁)33例,均行口服葡萄糖耐量试验(OGTT),根据OGTT试验各时点血糖、胰岛素值计算血糖曲线下面积(AUCg)、胰岛素曲线下面积(AUCi)、30min胰岛素增量与葡萄糖增量比值(△I30／△G30),胰岛β细胞功能指数(HOMA-p)及胰岛素抵抗指数(HOMA-IR)。采用酶联免疫(ELISA)法检测患者空腹血清胰淀素、褪黑素水平,与老年健康对照组(EHC组；30例)相比较。同时测定所有受试者的空腹血清甘油三脂(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C),测量血压、身高、体质量、腰围及臀围,计算体质指数(BMI)及腰臀比(WHR),并对结果进行统计分析。
结果：1.与AOD组相比,EOD组OGTT2 h血糖[(15.17±3.03)vs(13.59±2.76)mmol／L,P<0.05]、2 h胰岛素[(73.34±43.39)vs(64.22±29.75)uIU／ml,P<0.05]及HOMA-IR[(4.20±1.67)vs(3.49±1.83),P<0.05]明显升高,而HOMA-β[(58.20±24.89)vs(81.20±40.80),P<0.01]、△I30／／△G30(2.62±0.43)vs(3.37±0.58),P<0.01]明显降低。EOD组AUCg、AUCi均较AOD组略高,但差异无统计学意义(P>0.05)。
2.EOD组血清胰淀素水平显著高于AOD组[(21.57±15.88)Vs(19.8±13.18)ng/L,P<0.05]和EHC组[(21.57±15.88)vs(17.82±12.15)ng/L,P<0.01],AOD组与EHC组比较,血清胰淀素水平偏高,但无统计学意义(P>0.05)。EOD组血清褪黑素水平显著低于AOD组[(6.56±1.32)vs(8.17±1.23)pg/ml,P<0.05]和EHC组[(6.56±1.32)vs(7.65±1.39)pg／ml,P<0.01],EHC组与AOD组比较,血清褪黑素水平稍低,但无统计学意义(P>0.05)。
3.血清胰淀素与HOMA-IR(r=0.498,P=0.016)、空腹血清胰岛素(Fins)(r=0.517,P=0.031)、AUCi(r=0.516,P=0.021)呈正相关(P<0.05),与HOMA-β(r=-0.461,P=0.003)呈负相关,与空腹血糖(FBG)、血脂及AUCg、△I30／△G30、WHR、BMI均未见明显相关性。
4.血清褪黑素与与HOMA-p(r=0.403,P=0.016)、HDL-C(r=0.416,P=0.018)呈正相关；与HOMA-IR(r=0.549,P=0.019)、AUCi(r=-0.521,P=0.014)、WHR(r=-0.514,P=0.023)、FBG(r=-0.345,P=0.032)、LDL-C(r=0.479,P=0.012)呈负相关,与AUCg、BMI、△I30／／△G30均未见明显相关性。
结论：1、老年T2DM患者存在明显的胰岛β细胞功能下降及胰岛素早相分泌受损,同时存在一定程度的胰岛素抵抗及胰岛素释放高峰延迟,提示胰岛β细胞功能异常是老年糖尿病患者糖代谢紊乱的主要原因。
2、与健康老年人相比,老年起病糖尿病患者血清胰淀素水平明显增高,褪黑素水平明显降低,提示高胰淀素血症及低褪黑素血症可能与老年糖尿病的发病机制有关。
3、血清胰淀素水平与胰岛β细胞功能呈负相关关系,与肥胖、胰岛素抵抗呈正相关关系,提示血清胰淀素水平可作为评价胰岛β细胞功能的指标之一。
4、血清褪黑素水平与胰岛β细胞功能呈正相关关系,同时与血脂、胰岛素抵抗指数等存在负相关关系,推测其有可能成为评价胰岛β细胞功能的新指标之一。
Objective The present study was to explore the relationship between isletβ-cell function and the serum levels of amylin and melatonin by observing the feature of isletβ-cell function and measuring the serum levels of amylin and melatonin in newly diagnosed elderly diabetic patients, furtherly to explore the possible mechanism of senile diabetes.
Methods 70 newly diagnosed subjects with type 2 diabetes were divided into elderly-onset diabetes group (EOD, aged 60 to 94) and adult-onset diabetes group (AOD, aged 25 to 59 years), oral glucose tolerance test (OGTT) was detected and the area under the curve of glucose (AUCg)、the area under the curve of insulin (AUCi)、the function of pancreatic beta-cell(HOMA-β)、the ratio of the increment of insulin to that of serum glucose of the initial 30 minutes(△I30/△G30) and the homeostasis model assessment of insulin resistance (HOMA-IR) after OGTT was calculated. The levels of serum amylin and melatonin of all patients were determined with ELISA, compared with that of 30 healthy aged subjects(elderly healthy control group, EHC). For all of the subjects, fasting serum triglycerid (TG)、total cholesterol(TC)、high density lipoprotein cholesterol (HDL-C)、low density lipoprotein cholesterol (LDL-C) and blood pressure were measured and body mass index (BMI), waist/hip ratio(WHR) were calculated.
Results 1. Compared with AOD group, EOD group had lower value of HOMA-β[(58.20±24.89) vs (81.20±40.80), P＜0.01] and△I30/△G30[(2.62±0.43) vs (3.37±0.58), P＜0.01], but had higher values of OGTT 2 h serum glucose[(15.17±3.03) vs (13.59±2.76) mmol/L, P＜0.05], serum insulin[(73.34±43.39) vs (64.22±29.75) uIU/ml, P＜0.05] and HOMA-IR[(4.20±1.67) vs (3.49±1.83), P＜0.05], though the values of AUCg and AUCi were higher in EOD group than that in AOD group, no significant difference was found.
2. The serum amylin level in EOD group was obviously higher than that in AOD group[(21.57±15.88) vs (19.8±13.18) ng/L, P＜0.05] and EHC group[(21.57±15.88) vs (17.82±12.15) ng/L, P＜0.01].There wasn't obvious difference between AOD group and EHC group on serum amylin level(P＞0.05).The serum melatonin level in EOD group was obviously lower than that in AOD group[(6.56±1.32) vs (8.17±1.23) pg/ml, P＜0.05] and EHC group[(6.56±1.32) vs (7.65±1.39) pg/ml, P＜0.01]; There wasn't obvious difference between AOD group and EHC group on serum melatonin level(P＞0.05).
3. The correlation analysis results showed that:serum amylin level had positive correlation with HOMA-IR(r= 0.498, P= 0.016), fasting serum insulin(r= 0.517, P= 0.031), AUCi(r= 0.516, P= 0.021) and had negative correlation with HAMA-β(r=-0.461, P= 0.003). The serum amylin had no significant correlation with AUCg, FBG, blood lipids,△I30/△G30, WHR and BMI(P＞0.05).
4. The level of serum melatonin had positive correlation with HAMA-β(r= 0.403, P= 0.016) and HDL-C(r= 0.416, P= 0.018) and had negative correlation with HOMA-IR(r=-0.549, P= 0.019), AUCi(r=-0.521, P= 0.014), WHR(r=-0.514, P = 0.023), fasting blood glucose(r=-0.345, P= 0.032) and LDL-C(r=-0.479, P= 0.012), the serum melatonin had no significant correlation with AUCg,△I30/△G30 and BMI(P＞0.05).
Conclusion 1. Newly diagnosed elderly diabetic patients have obviousβ-cell deterioration and impaired early-phase insulin secretion, at the same time have a certain degree of insulin resistance and delayed peak of insulin release, suggesting that isletβ-cell dysfunction is the main reason of glucose metabolism disorder in elderly diabetic patients.
2. Compared with the healthy elderly, the elderly-onset diabetic patients had significantly higher level of amylin and lower level of melatonin, suggesting that the increased serum amylin and decreased serum melatonin may be related to the pathogenesis of senile diabetes.
3. The serum amylin level had significant negative correlation relationship with islets beta-cell function and had positive correlation relationship with obesity and insulin resistance, it is one of useful markers which estimate the function of pancreaticβ-cells.
4. The serum melatonin level had positive correlation with pancreatic beta-cell function and had negative correlation relationship with blood lipids and insulin resistance index, speculating that it may become a new index of evaluation of isletβ-cell function.
引文
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[31]Kanter M, Uysal H, Karaca T, et al. Depression of glucose levels and partial restoration of pancreatic β-cell damage by melatonin in Streptozotocin-induced diabetic rats[J]. Arch Toxicol,2006,80(6):362-9.
[32]Robeva R, Kirilov G, Tomova A, et al. Melatonin-insulin interactions in patients with metabolic syndrome[J]. Pineal Res.2008,44(1):52-6.
[33]Meihua She, Xiaojian Deng, Zhenyu Guo, et al. NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulinsensitivity in high-fat/high-sucrose-fed rats[J]. Pharmacological Research,2009,59(4):248-253.
[34]Peschke E, Wolgast S, Bazwinsky I, et al. Increased melatonin synthesis in pineal glands of rats in streptozotocin induced type 1 diabetes. J Pineal Res.2008, 45(4):439-48.
[1]Muthusamy K, Arvidsson PI, Govender P, et al.Design and study of peptide-based inhibitors of amylin cytotoxicity[J]. Bioorg Med Chem Lett.2010, 20(4):1360-2.
[2]Guardado-Mendoza R, Davalli AM, Chavez AO,et al.Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons[J]. Proc Natl Acad Sci USA. 2009,106(33):13992-7.
[3]Shaker ME, Houssen ME, Abo-Hashem EM, et-al. Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress[J].J Physiol Biochem.2009,65(3):225-33.
[4]Sartori C, Dessen P, Mathieu C, et al.Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice[J].Endocrinology.2009,150(12):5311-7
[5]Hoppener JW, Nieuwenhuis MG, Vroom TM, et al. Islet amyloid and diabetes mellitus type 2 [J]. Ned Tijdschr Geneeskd.2000,144(42):1995-2000.
[6]Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes[J]. Diabetes,2003,52(1):102 110.
[7]Akesson B, Panagiotidis G, Westermark P, et al. Islet amyloid polypep tide inhibits glucagon release and exerts adual action on insulin release from isolated islets[J]. Regul Pept,2003,111 (1-3):55-60.
[8]Dunican KC, Adams NM, Desilets AR. The role of pramlintide for weight loss[J]. Ann Pharmacother.2010,44(3):538-45.
[9]Zraika S, Hull RL, Udayasankar J, et al. Glucose-and time-dependence of islet amyloid formation in vitro[J]. Bioehem Biophys Res Commun,2007,354(1):234-239.
[10]Ritzel RA, Butler PC. Replication increases beta-cell vulnerability to human islet amyloid polypeptide-induced apoptosis[J]. Diabetes,2003,52(7):1701-8.
[11]Butler AE, Jang J,Gurlo T, et al. Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat):a new model for type 2 diabetes[J]. Diabetes,2004,53(6):1509-16.
[12]Ritzel RA, Meier JJ, Lin CY, et al. Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets[J]. Diabetes,2007,56(1):65-71.
[13]Butler AE, Janson J, Soeller WC, et al. Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes evidence for role of islet amyloid formation rather than direct action of amyloid[J]. Diabetes,2003,52(9):2304-14.
[14]Chandra J, Zhivotovsky B, Zaitsev S, et al. Role of apoptosis in pancreatic beta-cell death in diabetes[J]. Diabetes,2001(50):S44-7.
[15]Janson J, Ashley RH, Harrison D, et al. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles[J]. Diabetes,1999,48(3):491-498.
[16]Zraika S, Hull RL, Udayasankar J, et al. Identification of the amyloid-degrading enzyme neprilysin in mouse islets and potential role in islet amyloidogenesis[J]. Diabetes,2007,56(2):304-10.
[17]Henson MS, Buman BL Jordank, et al. An in vitro model of early islet amyloid polypeptide(IAPP) Fibrillogenesis using human IAPP-transgenic mouse islets[J], Amyloid,2006,13(4):250-9.
[18]Konarkowska B, Aitken JF, Kistler J, et al. Thiol reducing compounds prevent human amylin-evoked cytotoxicity[J].FEBS J,2005,272(19):4949-59.
[19]Hayden MR, Tyagi SC. Islet redox stress:the manifold toxicities of insulin resistance,metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus[J]. JOP,2002,3(4):86-108.
[20]Hayden MR. Islet amyloid,metabolic syndrome, and the natural progressive history of type 2 diabetes mellitus[J]. JOP,2002,3(5):126-138.
[21]Sakuraba H, Mizukami H, Yagihashi N, et al. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type 2 diabetic patients[J]. Diabetologia,2002,45(1):85-96.
[22]Cao P, Meng F, Abedini A, et al.The ability of rodent islet amyloid polypeptide to inhibit amyloid formation by human islet amyloid polypeptide has important implications for the mechanism of amyloid formation and the design of inhibitors[J].Biochemistry.2010,49(5):872-81.
[23]Ye JM, Lim-Fraser M, Cooney GJ, et al. Evidence that amylin stimulates lipolysis in vivo:a possible mediator of induced insulin resistance[J]. Am J Physiol Endocrinol Metab,2001,280(4):E562-E569.
[24]王静,卞茸文,娄青林,等.胰淀素对胰岛素刺激的人脂肪细胞糖摄取的影响[J].中国糖尿病杂志,2007,15(2)：112-113.
[25]Steinberg HO, Baron AD. Vascular function,insulin resistance and fatty acids[J]. Diabetologia,2002,45(5):623-34.
[26]Qi D, Cai K, Wang O, Li Z, Fatty acids induce amylin expression and secretion by pancreatic{beta}-cells[J].Am J Physiol Endocrinol Metab.2010; 298: E99-E107.
[27]Eitel K, Staiger H, Rieger J, et al. Protein kinase C delta activation and translocation to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells[J]. Diabetes,2003,52(4):991-7.
[28]Hayden MR, Tyagi SC. "A" is for amylin and amyloid in type 2 diabetes mellitus[J]. JOP,2001,2(4):124-39.
[29]Ryan G, Briscoe TA, Jobe L. Review of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes[J]. Drug Des Devel Ther.2009(2):203-14.
[30]赵子彦,路方红,栾杨,等.老年人血清褪黑素水平变化的探讨[J].中华老年心脑血管病杂志,2003,5(3)：156-8.
[31]Frese T, Bach AG, Muhlbauer E, et al.Pineal melatonin synthesis is decreased in type 2 diabetic Goto-Kakizaki rats[J].Life Sci.2009,85(13-14):526-33.
[32]Andersson AK, Sandler S. Melatonin protects against streptozotocin, but noy interleukin-1 beta-induced damage of rodent pancreatic beta-cells[J]. J Pineal Res, 2001,30(3):157-165.
[33]Meigs JB, Larson MG, Fox CS, et al. Association of oxidative stress, insulin resistance, and diabetes risk phenotypes:the Framingham offspring study. Diabetes Care,2007,30(10):2529-35.
[34]Kedziora-Kornatowska K, Szewczyk-Golec K, Czuczejko J, et al. Effect of melatonin on the oxidative stress in erythrocytes of healthy young and elderly subjects[J]. J Pineal Res,2007,42(2):153-8.
[35]Tomas-Zapico C, Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes[J].J Pineal Res,2005,39(2): 99-104.
[36]Escames G, Lopez LC, Tapias V, et al. Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice[J]. J Pineal Res,2006,40(1):71-78.
[37]Klepac N, Rudes z, Klepac R. Effect of melatonin on plasma oxidative stress in rats with streptozotocin-induced Diabetes[J]. Biomed Pharmacother,2006,60(1):32-35.
[38]Oktem F, Ozguner F, Yilmaz HR, et al. Melatonin reduces urinary excretion of N-acetyl-beta-D-glucosaminidase, albumin and renal oxidative markers in diabetic rats[J]. Clin Exp Pharmacol Physiol,2006,33(1-2):95-101.
[39]Korkmaz A, Topal T, Oter S, et al. Hyperglycemia-related pathophysiologic mechanisms and potential beneficial actions of melatonin[J]. Mini Rev Med Chem, 2008,8(11):1144-53.
[40]Nishida S, Sato R, Murai I, et al. Effect of pinealectomy on plasma levels of insulin and leptin and on hepatic lipids in type 2 diabetic rats[J]. Pineal Res,2003, 35(4):251-6.
[41]Zanquetta MM, Seraphim PM, Sumida DH et al. Calorie restriction reduces pinealectomy-induced insulin resistance by improving GLUT4 gene expression and its translocation to the plasma membrane[J]. Pineal Res,2003,35(3):141-8.
[42]Robeva R, Kirilov G, Tomova A, et al. Melatonin-insulin interactions in patients with metabolic syndrome[J]. Pineal Res,2008,44(1):52-6.
[43]Meihua She, Xiaojian Deng, Zhenyu Guo, et al. NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats[J]. Pharmacological Research,2009,59(4):248-253.
[44]Kadhim HM, Ismail SH, Hussein KI et al. Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin[J]. J Pineal Res 2006,41 (2):189-193.
[45]Cano P, Jimenez-Ortega V, Larrad A, et al. Effect of a high-fat diet on 24-h pattern of circulating levels of prolactin, luteinizing hormone, testosterone, corticosterone, thyroid-stimulating hormone and glucose, and pineal melatonin content, in rats[J]. Endocrine 2008,33(2):118-25.
[46]Rodriguez-Rodriguez E, Perea JM, Lopez-Sobaler AM,et al.Obesity, insulin resistance and increase in adipokines levels:importance of the diet and physical activity[J]. Nutr Hosp.2009,24(4):415-21.
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[10]Muzumdar R, Ma X, Atzmon G,et al. Decrease in glucose-stimulated insulin secretion with aging is independent of insulin action[J]. Diabetes 2004,53(2): 441-446.
[11]Wang X, Li H, De Leo D,et al. Gene and protein kinase expression profiling of reactive oxygen species-associated lipotoxicity in the pancreatic beta-cell line MIN6[J].Diabetes,2004,53(1):129-140.
[12]Sesti G. Searching for type 2 diabetes genes:prospects in pharmacotherapy. [J] Pharmacogenomics J,2002,2(1):25-29.
[13]Zraika S, Hull RL, Udayasankar J, et al. Glucose-and time-dependence of islet amyloid formation in vitro[J]. Bioehem Biophys Res Commun,2007,354(1):234-9.
[14]Peschke E. Melatonin, endocrine pancreas and diabetes[J]. J Pineal Res, 2008,44(1):26-40.
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[18]Winiarska K, Fraczyk T, Malinska D, et al. Melatonin attenuates diabetes-induced oxidative stress in rabbits[J].J Pineal Res,2006,40(2):168-176
[19]Nishida S. Metabolic effects of melatonin on oxidative stress and diabetes mellitus[J]. Endocrine,2005,27(2):131-136.
[20]钟历勇,杨志红,王 惠,等.褪黑素对糖尿病患者氧化应激抑制作用和糖脂代谢影响的观察[J].中国实用内科杂志,2005,25(6)：507-9.
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[22]Chang AM, Smith MJ, Galecki AT, et al. Impaired beta-cell function in human aging:response to nicotinic acid-induced insulin resistance [J]. Clin Endocrinol Metab, 2006,91(9):3303-9.
[23]Hull RL, Westermark GT, Westermark P, et al. Islet amyloid:a critical entity in the pathogenesis of type 2 diabetes[J]. J Clin Endocrinol Metab,2004,89(8):3629-43.
[24]Lopes DH, Colin C, Degaki TL, et al. Amyloidogenicity and cytotoxicity of recombinant mature human islet amyloid polypeptide(rhIAPP)[J]. J Biol Chem,2004, 279(41):42803-10.
[25]Hoppener JW, Nieuwenhuis MG, Vroom TM, et al. Islet amyloid and diabetes mellitus type 2[J].Ned Tijdschr Geneeskd,2000,144(42):1995-2000.
[26]Butler AE, Jang J, Gurlo T, et al. Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat):a new model for type 2 diabetes[J]. Diabetes,2004,53(6):1509-16.
[27]Andersson AK, Sandler S. Melatonin protects against streptozotocin, but not interleukin-1 beta-induced damage of rodent pancreatic beta-cells[J]. J Pineal Res, 2001,30(3):1571-65.
[28]Kurcer Z, Parlakpinar H, Vardi N, et al. Protective effects of chronic melatonin treatment against renal ischemia/reperfusion injury in streptozotocin-induced diabetic rats[J]. Exp Clin Endocrinol Diabetes,2007,115(6):365-71.
[29]Ha E, Yim SV, Chung JH. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells[J]. J Pineal Res,2006,41(1):67-72.
[30]Peschke E, Frese T,Chankiewitz E,et al.Diabetic Goto Kakizaki rats as well as type 2 diabetic patients show a decreased diurnal serum melatonin level and an increased pancreatic melatonin-receptor status[J]. J Pineal Res.2006,40(2):135-43.
[31]Kanter M, Uysal H, Karaca T, et al. Depression of glucose levels and partial restoration of pancreatic β-cell damage by melatonin in Streptozotocin-induced diabetic rats[J]. Arch Toxicol,2006,80(6):362-9.
[32]Robeva R, Kirilov G, Tomova A, et al. Melatonin-insulin interactions in patients with metabolic syndrome[J]. Pineal Res.2008,44(1):52-6.
[33]Meihua She, Xiaojian Deng, Zhenyu Guo, et al. NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulinsensitivity in high-fat/high-sucrose-fed rats[J]. Pharmacological Research,2009,59(4):248-253.
[34]Peschke E, Wolgast S, Bazwinsky I, et al. Increased melatonin synthesis in pineal glands of rats in streptozotocin induced type 1 diabetes. J Pineal Res.2008, 45(4):439-48.
[1]Muthusamy K, Arvidsson PI, Govender P, et al.Design and study of peptide-based inhibitors of amylin cytotoxicity[J]. Bioorg Med Chem Lett.2010, 20(4):1360-2.
[2]Guardado-Mendoza R, Davalli AM, Chavez AO,et al.Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons[J]. Proc Natl Acad Sci USA. 2009,106(33):13992-7.
[3]Shaker ME, Houssen ME, Abo-Hashem EM, et-al. Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress[J].J Physiol Biochem.2009,65(3):225-33.
[4]Sartori C, Dessen P, Mathieu C, et al.Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice[J].Endocrinology.2009,150(12):5311-7
[5]Hoppener JW, Nieuwenhuis MG, Vroom TM, et al. Islet amyloid and diabetes mellitus type 2 [J]. Ned Tijdschr Geneeskd.2000,144(42):1995-2000.
[6]Butler AE, Janson J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes[J]. Diabetes,2003,52(1):102 110.
[7]Akesson B, Panagiotidis G, Westermark P, et al. Islet amyloid polypep tide inhibits glucagon release and exerts adual action on insulin release from isolated islets[J]. Regul Pept,2003,111 (1-3):55-60.
[8]Dunican KC, Adams NM, Desilets AR. The role of pramlintide for weight loss[J]. Ann Pharmacother.2010,44(3):538-45.
[9]Zraika S, Hull RL, Udayasankar J, et al. Glucose-and time-dependence of islet amyloid formation in vitro[J]. Bioehem Biophys Res Commun,2007,354(1):234-239.
[10]Ritzel RA, Butler PC. Replication increases beta-cell vulnerability to human islet amyloid polypeptide-induced apoptosis[J]. Diabetes,2003,52(7):1701-8.
[11]Butler AE, Jang J,Gurlo T, et al. Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat):a new model for type 2 diabetes[J]. Diabetes,2004,53(6):1509-16.
[12]Ritzel RA, Meier JJ, Lin CY, et al. Human islet amyloid polypeptide oligomers disrupt cell coupling, induce apoptosis, and impair insulin secretion in isolated human islets[J]. Diabetes,2007,56(1):65-71.
[13]Butler AE, Janson J, Soeller WC, et al. Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes evidence for role of islet amyloid formation rather than direct action of amyloid[J]. Diabetes,2003,52(9):2304-14.
[14]Chandra J, Zhivotovsky B, Zaitsev S, et al. Role of apoptosis in pancreatic beta-cell death in diabetes[J]. Diabetes,2001(50):S44-7.
[15]Janson J, Ashley RH, Harrison D, et al. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles[J]. Diabetes,1999,48(3):491-498.
[16]Zraika S, Hull RL, Udayasankar J, et al. Identification of the amyloid-degrading enzyme neprilysin in mouse islets and potential role in islet amyloidogenesis[J]. Diabetes,2007,56(2):304-10.
[17]Henson MS, Buman BL Jordank, et al. An in vitro model of early islet amyloid polypeptide(IAPP) Fibrillogenesis using human IAPP-transgenic mouse islets[J], Amyloid,2006,13(4):250-9.
[18]Konarkowska B, Aitken JF, Kistler J, et al. Thiol reducing compounds prevent human amylin-evoked cytotoxicity[J].FEBS J,2005,272(19):4949-59.
[19]Hayden MR, Tyagi SC. Islet redox stress:the manifold toxicities of insulin resistance,metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus[J]. JOP,2002,3(4):86-108.
[20]Hayden MR. Islet amyloid,metabolic syndrome, and the natural progressive history of type 2 diabetes mellitus[J]. JOP,2002,3(5):126-138.
[21]Sakuraba H, Mizukami H, Yagihashi N, et al. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type 2 diabetic patients[J]. Diabetologia,2002,45(1):85-96.
[22]Cao P, Meng F, Abedini A, et al.The ability of rodent islet amyloid polypeptide to inhibit amyloid formation by human islet amyloid polypeptide has important implications for the mechanism of amyloid formation and the design of inhibitors[J].Biochemistry.2010,49(5):872-81.
[23]Ye JM, Lim-Fraser M, Cooney GJ, et al. Evidence that amylin stimulates lipolysis in vivo:a possible mediator of induced insulin resistance[J]. Am J Physiol Endocrinol Metab,2001,280(4):E562-E569.
[24]王静,卞茸文,娄青林,等.胰淀素对胰岛素刺激的人脂肪细胞糖摄取的影响[J].中国糖尿病杂志,2007,15(2)：112-113.
[25]Steinberg HO, Baron AD. Vascular function,insulin resistance and fatty acids[J]. Diabetologia,2002,45(5):623-34.
[26]Qi D, Cai K, Wang O, Li Z, Fatty acids induce amylin expression and secretion by pancreatic{beta}-cells[J].Am J Physiol Endocrinol Metab.2010; 298: E99-E107.
[27]Eitel K, Staiger H, Rieger J, et al. Protein kinase C delta activation and translocation to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells[J]. Diabetes,2003,52(4):991-7.
[28]Hayden MR, Tyagi SC. "A" is for amylin and amyloid in type 2 diabetes mellitus[J]. JOP,2001,2(4):124-39.
[29]Ryan G, Briscoe TA, Jobe L. Review of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes[J]. Drug Des Devel Ther.2009(2):203-14.
[30]赵子彦,路方红,栾杨,等.老年人血清褪黑素水平变化的探讨[J].中华老年心脑血管病杂志,2003,5(3)：156-8.
[31]Frese T, Bach AG, Muhlbauer E, et al.Pineal melatonin synthesis is decreased in type 2 diabetic Goto-Kakizaki rats[J].Life Sci.2009,85(13-14):526-33.
[32]Andersson AK, Sandler S. Melatonin protects against streptozotocin, but noy interleukin-1 beta-induced damage of rodent pancreatic beta-cells[J]. J Pineal Res, 2001,30(3):157-165.
[33]Meigs JB, Larson MG, Fox CS, et al. Association of oxidative stress, insulin resistance, and diabetes risk phenotypes:the Framingham offspring study. Diabetes Care,2007,30(10):2529-35.
[34]Kedziora-Kornatowska K, Szewczyk-Golec K, Czuczejko J, et al. Effect of melatonin on the oxidative stress in erythrocytes of healthy young and elderly subjects[J]. J Pineal Res,2007,42(2):153-8.
[35]Tomas-Zapico C, Coto-Montes A. A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes[J].J Pineal Res,2005,39(2): 99-104.
[36]Escames G, Lopez LC, Tapias V, et al. Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice[J]. J Pineal Res,2006,40(1):71-78.
[37]Klepac N, Rudes z, Klepac R. Effect of melatonin on plasma oxidative stress in rats with streptozotocin-induced Diabetes[J]. Biomed Pharmacother,2006,60(1):32-35.
[38]Oktem F, Ozguner F, Yilmaz HR, et al. Melatonin reduces urinary excretion of N-acetyl-beta-D-glucosaminidase, albumin and renal oxidative markers in diabetic rats[J]. Clin Exp Pharmacol Physiol,2006,33(1-2):95-101.
[39]Korkmaz A, Topal T, Oter S, et al. Hyperglycemia-related pathophysiologic mechanisms and potential beneficial actions of melatonin[J]. Mini Rev Med Chem, 2008,8(11):1144-53.
[40]Nishida S, Sato R, Murai I, et al. Effect of pinealectomy on plasma levels of insulin and leptin and on hepatic lipids in type 2 diabetic rats[J]. Pineal Res,2003, 35(4):251-6.
[41]Zanquetta MM, Seraphim PM, Sumida DH et al. Calorie restriction reduces pinealectomy-induced insulin resistance by improving GLUT4 gene expression and its translocation to the plasma membrane[J]. Pineal Res,2003,35(3):141-8.
[42]Robeva R, Kirilov G, Tomova A, et al. Melatonin-insulin interactions in patients with metabolic syndrome[J]. Pineal Res,2008,44(1):52-6.
[43]Meihua She, Xiaojian Deng, Zhenyu Guo, et al. NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats[J]. Pharmacological Research,2009,59(4):248-253.
[44]Kadhim HM, Ismail SH, Hussein KI et al. Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin[J]. J Pineal Res 2006,41 (2):189-193.
[45]Cano P, Jimenez-Ortega V, Larrad A, et al. Effect of a high-fat diet on 24-h pattern of circulating levels of prolactin, luteinizing hormone, testosterone, corticosterone, thyroid-stimulating hormone and glucose, and pineal melatonin content, in rats[J]. Endocrine 2008,33(2):118-25.
[46]Rodriguez-Rodriguez E, Perea JM, Lopez-Sobaler AM,et al.Obesity, insulin resistance and increase in adipokines levels:importance of the diet and physical activity[J]. Nutr Hosp.2009,24(4):415-21.