二甲双胍在新诊断2型糖尿病患者中的应用
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摘要
目的：
观察新诊断2型糖尿病患者短期给予生活方式联合二甲双胍治疗后,其血糖、血糖波动、胰岛素敏感性和胰岛功能的改变,分析可能的影响因素,为更合理用药提供参考。
方法：
新诊断2型糖尿病患者21例,同年龄段糖代谢正常的志愿者5例作为对照。2型糖尿病患者给予生活方式加二甲双胍(0.5g口服3／日)治疗12周。前3周每周对患者进行一次门诊随访,从第4周开始每月进行一次门诊随访。治疗前后均进行如下检查：
(1)收集患者一般情况；
(2)动态血糖监测系统(CGMS)检查：计算各时间段平均血糖指标、血糖变异度指标；
(3)高胰岛素-正常葡萄糖钳夹试验(正糖钳夹)：计算M值及评估胰岛素抵抗的各简易指标；
(4)静脉葡萄糖耐量试验(IVGTT)：计算第一时相胰岛素分泌(AIR)及评估胰岛功能的各简易指标。
比较以上指标在2型糖尿病患者治疗前、后和糖代谢正常者之间的差异。
结果：
(1)一般情况：治疗后患者的体重、BMI、腰围和腰臀比与治疗前有较明显下降(P<0.05或P<0.01),但血脂改变不明显。
(2)血糖及其变异度：①治疗后患者的平均血糖、SD和CV均有明显下降(P<0.01)。②CV-PBG和CV-night是最重要的血糖变异指标。③相关分析：各变异度指标均与HbAlc和AIR有关。逐步回归显示：MBG、PBG、CV-night是影响HbAlc的血糖因素；M值、2hINS和Alb/Cr与HbAlc成正相关,2hCP与HbAlc成负相关。
(3)胰岛素敏感性：①新诊断2型糖尿病患者的M值约为糖代谢正常者的71.8%,治疗后M值明显增高,与糖代谢正常者无明显差异(P>0.05)。②对钳夹过程的比较：胰岛素敏感性与钳夹30-60min的血糖水平有关。胰岛素抵抗对葡萄糖输注率的影响主要表现在3个方面：达平台期时间延迟,变异率增加和钳夹后1h的葡萄糖摄取率明显下降。③逐步回归显示：M-PBG、M-FBG、MBG是与M值有关的血糖因素；年龄、腰臀比、TG、LDL与M值有关；M值与2hINS成负相关,与FINS成负相关。
(4)胰岛功能：①新诊断2型糖尿病患者的AIR较糖耐量正常者明显下降,治疗后AIR明显增加,但与糖耐量正常者仍存在显著差异(P<0.01)。②对IVGTT曲线的比较：新诊断糖尿病患者的各点血糖均增高；基础胰岛素分泌增高,而糖负荷后胰岛素分泌反而不足,峰值降低,分泌延迟；治疗后患者的胰岛素和血糖曲线均有所改善,但仍与糖耐量正常者有较大的差距。③逐步回归显示：MBG、PBG、M-night、FINS、TC、SD和M值与AIR有关；h-duration、AIR、MBG、FBG和M值与DI相关。
结论：
(1)血糖及其波动：新诊断2型糖尿病患者,应用生活方式加二甲双胍治疗后血糖水平明显下降,变异度减小。MBG和PBG是影响HbAlc最主要的指标,血糖波动是独立于血糖水平影响HbAlc的因素之一。胰岛素抵抗和胰岛β细胞功能的改善对HbAlc的下降也具有重要的作用。HbAlc的下降有助于延缓糖尿病微血管病变的发生。
(2)胰岛素敏感性：新诊断2型糖尿病患者的胰岛素抵抗较重,治疗后的胰岛素敏感性明显改善,主要是增加了患者肝脏和骨骼肌的胰岛素敏感性。胰岛素敏感性的改善与平均餐后血糖水平的关系最为密切。胰岛素敏感性与年龄、腹型肥胖有关,血脂水平也有一定的影响。
(3)胰岛功能：中国新诊断2型糖尿病患者的胰岛β细胞功能差,生活方式加二甲双胍治疗可有限的改善患者的胰岛分泌数量和质量。AIR与餐后血糖的相关性要大于空腹血糖；AIR的改善可以降低全天平均血糖和血糖的波动。对于新诊断的2型糖尿病患者的血糖处置能力,胰岛β细胞作用大于胰岛素敏感性。
(4)治疗建议：对于新诊断2型糖尿病患者,二甲双胍是有效、安全的治疗方案。强化血糖控制和血脂达标,有助于改善胰岛素敏感性、保护胰岛β细胞的功能和延缓糖尿病血管并发症的发生。
Objective:
To investigate the changes of the glucose levels, glucose variations, insulin sensitivity and islet function in newly diagnosed type 2 diabetes mellitus after short period of metformin treatment, analyses the possible influence elements, in order to provide reference of more rational treatment.
Methods:
21 newly diagnosed type 2 diabetes were given life style intervene and metformin (0.5g tid) treatment for 12 weeks. Flow-up once a week was taken at first 3 weeks, then flow-up once a month. All the follow exams were executed before and after the treatment.5 normal 75g glucose tolerance volunteers were taken as control.
(1) Collection of general conditions;
(2) Continuous glucose monitoring system (CGMS):calculate mean glucose levels and glucose variation coefficients;
(3) Hyperinsulinemic euglycemic clamp test (HECT):calculate M value and other simple indices of insulin sensitivity.
(4) Intravenous glucose tolerance test (IVGTT):Calculate AIR and other simple indices of islet function.
Result:
(1) General condition:weight, BMI, waist and waist/hip were decreased after treatment (P<0.05orP<0.01), plasma lipid only partly improved
(2) glucose levels and variations:①Mean glucose levels, SD and CV dropped obviously after treatment (P<0.01).②CV-PBG and CV-night occupied the most important place in daily variation.③All glucose variation indices were related with HbAlc and AIR. Step-wise regression showed that MBG、PBG and CV-night were the glucose elements that effected HbAlc. HbAlc had positive relation with M value、2hINS and Alb/Cr, and negative relation with 2hCP.
(3) Insulin sensitivity:①M value of the newly diagnosed type 2 diabetes was 71.8% of the normal glucose tolerance control (P<0.01), which increased significantly after treatment (P<0.01) and no longer had difference with the control.②Compared of the clamp showed that 30-60min glucose level had relation with insulin sensitivity. The main effect of insulin resistance on GIR included 3 aspects:delaying the time of reaching platform, elevating variation, and decreasing the GIR of the last hour.③Step-wise regression showed that M-PBG、M-FBG、MBG were the glucose elements that related with M value; Age、waist/hip、TG and LDL were related with M value; M value had positive relation with FINS and negative relation with 2hCP.
(4) Islet function:①AIR was significantly decreased in newly diagnosed diabetes mellitus, which was elevated after treatment and still lower obviously than control (P<0.01).②Comparing of the IVGTT curves showed that:insulin level of newly diagnosed diabetes elevated in base line when compared with control, while insufficiently after intravenous glucose burden with lower insulin level of curve peak; insulin curves and glucose curves ameliorated after treatment though still far from control.③Step-wise regression showed that MBG、PBG、M-night、FINS、TC、SD and M value were related with AIR; h-duration、AIR、MBG、FBG and M value were relation with glucose disposition index (DI).
Conclusion:
(1) Glucose levels and variations:Mean glucose levels and variations decrease sharply. MBG and PBG are the mainly causes that influenced HbAlc, glucose variation is an independent element that effected HbAlc, as well as insulin sensitivity and islet function. Lowering HbAlc will be helpful in putting off the microvascular complications.
(2) Insulin sensitivity:Heavy insulin resistance exists in newly diagnosed type 2 diabetes mellitus, which improves obviously after treatment mainly by ameliorating hepatic and skeleton muscle insulin sensitivities. PBS has close relation with insulin sensitivity. Insulin sensitivity is also influenced by lipid level, as well as age and abdomen fat.
(3) Islet function:Isletβcell function of china newly diagnosed type 2 diabetes mellitus is bad, life style and metformin treatment could ameliorate islet function to some content. AIR relates more with PBG than FBG; the increase of AIR could decrease the mean glucose level and glucose variation of whole day. Islet function plays more important role than insulin sensitivity in glucose disposition.
(4) Treatment proposal:Metformin is a efficient and safe treatment protocol for newly diagnosed type 2 diabetes. Intensive control of glucose and lipid will do help to ameliorating insulin sensitivity, protecting islet function and preventing diabetes vascular complications.
观察新诊断2型糖尿病患者短期给予生活方式联合二甲双胍治疗后,其血糖、血糖波动、胰岛素敏感性和胰岛功能的改变,分析可能的影响因素,为更合理用药提供参考。
方法：
新诊断2型糖尿病患者21例,同年龄段糖代谢正常的志愿者5例作为对照。2型糖尿病患者给予生活方式加二甲双胍(0.5g口服3／日)治疗12周。前3周每周对患者进行一次门诊随访,从第4周开始每月进行一次门诊随访。治疗前后均进行如下检查：
(1)收集患者一般情况；
(2)动态血糖监测系统(CGMS)检查：计算各时间段平均血糖指标、血糖变异度指标；
(3)高胰岛素-正常葡萄糖钳夹试验(正糖钳夹)：计算M值及评估胰岛素抵抗的各简易指标；
(4)静脉葡萄糖耐量试验(IVGTT)：计算第一时相胰岛素分泌(AIR)及评估胰岛功能的各简易指标。
比较以上指标在2型糖尿病患者治疗前、后和糖代谢正常者之间的差异。
结果：
(1)一般情况：治疗后患者的体重、BMI、腰围和腰臀比与治疗前有较明显下降(P<0.05或P<0.01),但血脂改变不明显。
(2)血糖及其变异度：①治疗后患者的平均血糖、SD和CV均有明显下降(P<0.01)。②CV-PBG和CV-night是最重要的血糖变异指标。③相关分析：各变异度指标均与HbAlc和AIR有关。逐步回归显示：MBG、PBG、CV-night是影响HbAlc的血糖因素；M值、2hINS和Alb/Cr与HbAlc成正相关,2hCP与HbAlc成负相关。
(3)胰岛素敏感性：①新诊断2型糖尿病患者的M值约为糖代谢正常者的71.8%,治疗后M值明显增高,与糖代谢正常者无明显差异(P>0.05)。②对钳夹过程的比较：胰岛素敏感性与钳夹30-60min的血糖水平有关。胰岛素抵抗对葡萄糖输注率的影响主要表现在3个方面：达平台期时间延迟,变异率增加和钳夹后1h的葡萄糖摄取率明显下降。③逐步回归显示：M-PBG、M-FBG、MBG是与M值有关的血糖因素；年龄、腰臀比、TG、LDL与M值有关；M值与2hINS成负相关,与FINS成负相关。
(4)胰岛功能：①新诊断2型糖尿病患者的AIR较糖耐量正常者明显下降,治疗后AIR明显增加,但与糖耐量正常者仍存在显著差异(P<0.01)。②对IVGTT曲线的比较：新诊断糖尿病患者的各点血糖均增高；基础胰岛素分泌增高,而糖负荷后胰岛素分泌反而不足,峰值降低,分泌延迟；治疗后患者的胰岛素和血糖曲线均有所改善,但仍与糖耐量正常者有较大的差距。③逐步回归显示：MBG、PBG、M-night、FINS、TC、SD和M值与AIR有关；h-duration、AIR、MBG、FBG和M值与DI相关。
结论：
(1)血糖及其波动：新诊断2型糖尿病患者,应用生活方式加二甲双胍治疗后血糖水平明显下降,变异度减小。MBG和PBG是影响HbAlc最主要的指标,血糖波动是独立于血糖水平影响HbAlc的因素之一。胰岛素抵抗和胰岛β细胞功能的改善对HbAlc的下降也具有重要的作用。HbAlc的下降有助于延缓糖尿病微血管病变的发生。
(2)胰岛素敏感性：新诊断2型糖尿病患者的胰岛素抵抗较重,治疗后的胰岛素敏感性明显改善,主要是增加了患者肝脏和骨骼肌的胰岛素敏感性。胰岛素敏感性的改善与平均餐后血糖水平的关系最为密切。胰岛素敏感性与年龄、腹型肥胖有关,血脂水平也有一定的影响。
(3)胰岛功能：中国新诊断2型糖尿病患者的胰岛β细胞功能差,生活方式加二甲双胍治疗可有限的改善患者的胰岛分泌数量和质量。AIR与餐后血糖的相关性要大于空腹血糖；AIR的改善可以降低全天平均血糖和血糖的波动。对于新诊断的2型糖尿病患者的血糖处置能力,胰岛β细胞作用大于胰岛素敏感性。
(4)治疗建议：对于新诊断2型糖尿病患者,二甲双胍是有效、安全的治疗方案。强化血糖控制和血脂达标,有助于改善胰岛素敏感性、保护胰岛β细胞的功能和延缓糖尿病血管并发症的发生。
Objective:
To investigate the changes of the glucose levels, glucose variations, insulin sensitivity and islet function in newly diagnosed type 2 diabetes mellitus after short period of metformin treatment, analyses the possible influence elements, in order to provide reference of more rational treatment.
Methods:
21 newly diagnosed type 2 diabetes were given life style intervene and metformin (0.5g tid) treatment for 12 weeks. Flow-up once a week was taken at first 3 weeks, then flow-up once a month. All the follow exams were executed before and after the treatment.5 normal 75g glucose tolerance volunteers were taken as control.
(1) Collection of general conditions;
(2) Continuous glucose monitoring system (CGMS):calculate mean glucose levels and glucose variation coefficients;
(3) Hyperinsulinemic euglycemic clamp test (HECT):calculate M value and other simple indices of insulin sensitivity.
(4) Intravenous glucose tolerance test (IVGTT):Calculate AIR and other simple indices of islet function.
Result:
(1) General condition:weight, BMI, waist and waist/hip were decreased after treatment (P<0.05orP<0.01), plasma lipid only partly improved
(2) glucose levels and variations:①Mean glucose levels, SD and CV dropped obviously after treatment (P<0.01).②CV-PBG and CV-night occupied the most important place in daily variation.③All glucose variation indices were related with HbAlc and AIR. Step-wise regression showed that MBG、PBG and CV-night were the glucose elements that effected HbAlc. HbAlc had positive relation with M value、2hINS and Alb/Cr, and negative relation with 2hCP.
(3) Insulin sensitivity:①M value of the newly diagnosed type 2 diabetes was 71.8% of the normal glucose tolerance control (P<0.01), which increased significantly after treatment (P<0.01) and no longer had difference with the control.②Compared of the clamp showed that 30-60min glucose level had relation with insulin sensitivity. The main effect of insulin resistance on GIR included 3 aspects:delaying the time of reaching platform, elevating variation, and decreasing the GIR of the last hour.③Step-wise regression showed that M-PBG、M-FBG、MBG were the glucose elements that related with M value; Age、waist/hip、TG and LDL were related with M value; M value had positive relation with FINS and negative relation with 2hCP.
(4) Islet function:①AIR was significantly decreased in newly diagnosed diabetes mellitus, which was elevated after treatment and still lower obviously than control (P<0.01).②Comparing of the IVGTT curves showed that:insulin level of newly diagnosed diabetes elevated in base line when compared with control, while insufficiently after intravenous glucose burden with lower insulin level of curve peak; insulin curves and glucose curves ameliorated after treatment though still far from control.③Step-wise regression showed that MBG、PBG、M-night、FINS、TC、SD and M value were related with AIR; h-duration、AIR、MBG、FBG and M value were relation with glucose disposition index (DI).
Conclusion:
(1) Glucose levels and variations:Mean glucose levels and variations decrease sharply. MBG and PBG are the mainly causes that influenced HbAlc, glucose variation is an independent element that effected HbAlc, as well as insulin sensitivity and islet function. Lowering HbAlc will be helpful in putting off the microvascular complications.
(2) Insulin sensitivity:Heavy insulin resistance exists in newly diagnosed type 2 diabetes mellitus, which improves obviously after treatment mainly by ameliorating hepatic and skeleton muscle insulin sensitivities. PBS has close relation with insulin sensitivity. Insulin sensitivity is also influenced by lipid level, as well as age and abdomen fat.
(3) Islet function:Isletβcell function of china newly diagnosed type 2 diabetes mellitus is bad, life style and metformin treatment could ameliorate islet function to some content. AIR relates more with PBG than FBG; the increase of AIR could decrease the mean glucose level and glucose variation of whole day. Islet function plays more important role than insulin sensitivity in glucose disposition.
(4) Treatment proposal:Metformin is a efficient and safe treatment protocol for newly diagnosed type 2 diabetes. Intensive control of glucose and lipid will do help to ameliorating insulin sensitivity, protecting islet function and preventing diabetes vascular complications.
引文
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3、程时武,陆菊明,杨国庆等.高胰岛素一正常葡糖钳夹技术的建立.第四军医大学学报2007,28(22)：2082-2084.
4、 Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment insulin resistance and beta cell function from fasting Plasma glucose and insulin concentrations in man. Diabetologia,1985,28:412-419.
5、李剑,徐岩,李春霖等.甘精胰岛素联合瑞格列奈治疗老年2型糖尿病患者的有效性和安全性分析.中国医刊.2008,7(5)：45-46
6、 American Diabetes Association. Consensus development conference on insulin resistance. Diabetes Care,1998,21:310-314.
7、 Fery F., Plat L., Batasse, E.O. Effects of metformin on the pathways of glucose utilization after oral glucose in non-insulin-dependent diabetes mellitus patents. Metabofism,1997,46:227-233.
8、 Thiebaud D, Jacot E, DeFronzo RA, et al. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 1982; 31:957-963
9、 DeFronzo RA, Jacot E, Jequier E, et al. The effect of insulin on the disposal of intravenous glucose:results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981; 30:1000-1007
10、 AD Karelis, JF Henry, F Malita, et al. Comparison of insulin sensitivity values using the hyperinsulinemic euglycemic clamp:2 vs 3 hours. Diabetes Metab2004,30,413-414
11、 Spiegelman BM. PPAR-γ:An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med,1997,102:99-110.
12、 Ralph A. DeFronzo, Devjit Tripathy. Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes. Diabetes care,2005,30,213-224.
1、 Yanbing Li, Wen Xu, Zhihong Liao, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of β-cell function. Diabetes Care,2004 vol.27 no.112597-2602
2、 Pimenta W, Korytkowski M, Mitrakou A, et al. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA 1995;273:1855-1861.
3、 Gorden P, Hendricks CM, Roth J:Circulating proinsulin-like component in man:increased proportion in hypoinsulinemia state. Diabetologia, 1974,10:469-474.
4、 Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England journal of medicine.2002(346):393-403.
5、 Turner, R,C, (1998)The U.K. Prospective Diabetes Study. A review. Diabetes Care,21(Suppl 3):C35-C38.
6、 Claudio Cobelli, Gianna Maria Toffolo, Chiara Dalla Man, et al. Assessment of-cell function in humans,simultaneously with insulin sensitivity and hepatic extraction,from intravenous and oral glucose tests. Am J Physiol Endocrinol Metab,2007(293):E1-E15,.
7、 Ryan, Imes, Wallace, et al. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 27:1028-1032,2004
8、 Anny H. Xiang, Miwa Kawakubo, Enrique Trigo, et al. Declining P-Cell Compensation for Insulin Resistance in Hispanic Women With Recent Gestational Diabetes Mellitus Association with changes in weight, adiponectin, and C-reactive protein.
9、 Weyer C, Tataranni PA, Bogardus C, et al. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 2001; 24:89-94
10、 Festa A, Williams K, D'Agostino R Jr, et al. The natural course of β-cell function in nondiabetic and diabetic individuals. Diabetes 2006; 55:1114-1120
11、 Xiang AH, Wang C, Peters RK, et al. Coordinate changes in plasma glucose and pancreatic β-cell function in Latino women at high risk for type 2 diabetes. Diabetes 2006; 55:1074-1079 12 、 Joy C. Bunt, Jonathan Krakoff, Emilio Ortega, et al. Acute insulin response is an independent predictor of type 2 diabetes mellitus in individuals with both normal fasting and 2-h plasma glucose concentrations. Diabetes Metab Res Rev.2007,23(4):304-310.
1、 Alberti, K.G.M., Zimmet P, Shaw J, et al. The metabolic syndrome-a new worldwide definition. Lancet,2005,366,1059-1062.
2、杨文英,陆菊明,翁建平,等.Prevalenceof diabetes among men and wemen in China. N Engl J Med.2010,25;362(12):1090-101.
3、 UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet 1998;352:837-853.
4、程时武,陆菊明,杨国庆等.高胰岛素一正常葡糖钳夹技术的建立.第四军医大学学报2007,28(22)：2082—2084.
5、 Laakso M. How good a marker is insulin level for insulin resistance? Am J Epidemiol,1992,137:959-965.
6、 American Diabetes Association. Consensus development conference on insulin resistance. Diabetes Care,1998,21:310-314.
7、 Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia,1985,28:412-419.
8、 Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely minors the of insulin sensitivity. Diabetes Care,2000,23:57-63.
9、 Hanson RL, Pratley RE, Bogardus C, et al. Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol,2000,1 S 1:190-198.
10、 Balion CM, Raina PS, Gerstein HC, et al.Reproducibility of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) classification:a systematic review. Clin Chem Lab Med,2007,45:1180-1185.
11、 Hosker JP, Matthews DR, Rudenski AS, et al. Continuous infusion of glucose with model assessment:measurement of insulin resistance and beta cell function in man. Diabetologia,1985,28:401-411.
12、 李玲,历平,王贵新,等.糖耐量受损者胰岛素敏感性及胰岛β细胞功能的研究.中华糖尿病杂志,2005,13：87-89.
13、 Johnson A.B., Webster].M., Sum C, et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type 2 diabetic patients. Metabolism,1993,42:1217-1222.
14、 Hundal R.S., Krssak M., Dufour S., et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes,2000,49: 2063-2069.
15、 Nagi O.K., Yudkin D.S. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care,1993,16: 621-629.
16、 Metformin monotherapy for type 2 diabetes mellitus. Cochrane database of systematic review,2005, CD002966.
17、 Haffner SM, Stern MP. Miettinen H.et al. Higher proinsulin and specific insulin are both associated with a parental history of diabetes in non diabetic Mexican-American subjects. Diabetes,1995,44:1156-1160.
18、 Breda E, Cavaghan MK, Toffolo G, et al. Oral glucose tolerance test minimal model indexes of p-cell function and insulin sensitivity. Diabetes 2001, 50:150-158.
19、 Festa A, Williams K, D'Agostino R Jr, et al. The natural course of P-cell function in nondiabetic and diabetic individuals. Diabetes 2006; 55:1114-1120
20 、 Christian Weyer, Antonio Tataranni, Clifton Bogardus, et al. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care,2001,24:89-94.
2、 Yanbing Li, Wen Xu, Zhihong Liao, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of β-cell function. Diabetes Care,2004 vol.27 no.112597-2602
3、 The relationship of glycemic exposure (HbAlc) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 1995;44:968-983.
4、 UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet 1998;352:837-853.
5、 Shichiri M, Kishikawa H, Ohkubo Y, et al. Long-term results of the Kumamoto Study on optional diabetes control in type 2 diabetic patients. Diabetes Care 2000;23(Suppl 2):B21-B29.
6、 Clinical guidelines task force. International diabetes federation.2005 global guideline for type 2 diabetes.
7、 Esposito K, Giugliano D, Nappo F, et al. Companion Postprandial Hyperglycemia Study Group. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation,2004 (110): 214-219.
8、 Saenz A, Fernandez E, Mataix A, et al. Diabetes Control and Complications Trial Research Group:The effect of intensive treatment of diabetes on the development and progression of long-terms complications in insulin-dependent diabetes mellitus. N Engl J Med,1993,329:977-986.
9、 Muggeo M, Verlato G, Bonora E, et al. Long-term instability of fasting plasma glucose, a novel predictor of cardiovascular mortality in elderly patients with non-insulin-dependent diabetes mellitus. Verona Diabetes Study. Circulation, 1997,961:1750-1754.
10、 程时武,陆菊明,杨国庆等.高胰岛素-正常葡糖钳夹技术的建立.第四军医大学学报2007,28(22)：2082-2084.
11、 熊红霞.2型糖尿病胰岛β细胞功能缺陷的研究进展.中国医学创新,2009,7(6)：195-196.
12、 白晓苏,张素华,丘彦等.罗格列酮对多囊卵巢综合征患者胰岛素敏感性和β细胞功能之改善.第三军医大学学报,2006,28(18)：1894-1896.
13、 American diabetes association. Standard of medical care in diabetes-2007. Diabetes care,30(Supply 1):S4-S41.
1、 Turner, R,C. The U.K. Prospective Diabetes Study. A review. Diabetes Care,1998,21(Suppl 3):C35-C38
2、 王先令,陆菊明,潘长玉.动态血糖监测系统的临床应用.军医进修学院学报,2005,26：63-65.
3、 Jian Zhou, Hong Li, Xingwu Ran, et al. Reference Values for Continuous Glucose Monitoring in Chinese Subjects. Diabetes Care,2009,32(7):1188-1193
4、 孙敬芳,王先令,李春霖等.动态血糖监测系统-CGMS的临床回顾及展望.解放军医学杂志,2006,31(4)：65-66
5、 Mooy JM, Grootenhuis PA, de Vries H,et al. Intra-individual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose. the Hoorn Study. Diabetologia,1996,39:298-305.
6、 Murata GH, Duckworth WC,et al. Sources of glucose variability in insulin-treated type 2 diabetes:the Diabetes Outcomes in Veterans Study. (DOVES). Clin Endocrinol (Oxl),2004,60:451-456.
7、 徐岩,李春霖,田慧.两种动态血糖监测系统的比较分析.人民军医杂志.2008,51(4)：207-209.
8、 Saenz A, Fernandez E, Mataix A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane database of systematic review,2005, CD002966.
9、 Esposito K,Giugliano D,Nappo F, et al. Companion Postprandial Hyperglycemia Study Group. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus.Circulation 2004; 110: 214-219.
10、 Muggeo M, Zoppini G, Bonora E, et al. Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients. Diabetes Care,2000,23:50-54.
11、 Mcintrre H. D., Ma A., Bird D. M., et al. Metformin increases insulin sensitivity and basal glucose clearance in type 2 diabetes mellitus. Australian and new Zealand journal of medicine,21,714-719.
12 、 Shichiri M, Kishikawa H, Ohkubo Y, et al. Long-term results of the Kumamoto Study on optional diabetes control in type 2 diabetic patients. Diabetes Care 2000;23(Suppl 2):B21-B29.
13、徐岩,李春霖,李剑等.盐酸二甲双胍对老年糖尿病患者黎明现象的影响.中华保健医学杂志.2009,11(5)：339-341.
1、 Umberto Picchini, Andrea De Gaetano, Simona Panunzi, et al. A mathematical model of the euglycemic hyperinsulinemic clamp. Theoretical Biology and Medical Modelling,2005,2:44-50
2、 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique:a method for quantifying insulin secretion and resistance. Am J Physiol,1979,23 7:E214-E223.
3、程时武,陆菊明,杨国庆等.高胰岛素一正常葡糖钳夹技术的建立.第四军医大学学报2007,28(22)：2082-2084.
4、 Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment insulin resistance and beta cell function from fasting Plasma glucose and insulin concentrations in man. Diabetologia,1985,28:412-419.
5、李剑,徐岩,李春霖等.甘精胰岛素联合瑞格列奈治疗老年2型糖尿病患者的有效性和安全性分析.中国医刊.2008,7(5)：45-46
6、 American Diabetes Association. Consensus development conference on insulin resistance. Diabetes Care,1998,21:310-314.
7、 Fery F., Plat L., Batasse, E.O. Effects of metformin on the pathways of glucose utilization after oral glucose in non-insulin-dependent diabetes mellitus patents. Metabofism,1997,46:227-233.
8、 Thiebaud D, Jacot E, DeFronzo RA, et al. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 1982; 31:957-963
9、 DeFronzo RA, Jacot E, Jequier E, et al. The effect of insulin on the disposal of intravenous glucose:results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981; 30:1000-1007
10、 AD Karelis, JF Henry, F Malita, et al. Comparison of insulin sensitivity values using the hyperinsulinemic euglycemic clamp:2 vs 3 hours. Diabetes Metab2004,30,413-414
11、 Spiegelman BM. PPAR-γ:An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med,1997,102:99-110.
12、 Ralph A. DeFronzo, Devjit Tripathy. Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes. Diabetes care,2005,30,213-224.
1、 Yanbing Li, Wen Xu, Zhihong Liao, et al. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of β-cell function. Diabetes Care,2004 vol.27 no.112597-2602
2、 Pimenta W, Korytkowski M, Mitrakou A, et al. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA 1995;273:1855-1861.
3、 Gorden P, Hendricks CM, Roth J:Circulating proinsulin-like component in man:increased proportion in hypoinsulinemia state. Diabetologia, 1974,10:469-474.
4、 Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England journal of medicine.2002(346):393-403.
5、 Turner, R,C, (1998)The U.K. Prospective Diabetes Study. A review. Diabetes Care,21(Suppl 3):C35-C38.
6、 Claudio Cobelli, Gianna Maria Toffolo, Chiara Dalla Man, et al. Assessment of-cell function in humans,simultaneously with insulin sensitivity and hepatic extraction,from intravenous and oral glucose tests. Am J Physiol Endocrinol Metab,2007(293):E1-E15,.
7、 Ryan, Imes, Wallace, et al. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care 27:1028-1032,2004
8、 Anny H. Xiang, Miwa Kawakubo, Enrique Trigo, et al. Declining P-Cell Compensation for Insulin Resistance in Hispanic Women With Recent Gestational Diabetes Mellitus Association with changes in weight, adiponectin, and C-reactive protein.
9、 Weyer C, Tataranni PA, Bogardus C, et al. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 2001; 24:89-94
10、 Festa A, Williams K, D'Agostino R Jr, et al. The natural course of β-cell function in nondiabetic and diabetic individuals. Diabetes 2006; 55:1114-1120
11、 Xiang AH, Wang C, Peters RK, et al. Coordinate changes in plasma glucose and pancreatic β-cell function in Latino women at high risk for type 2 diabetes. Diabetes 2006; 55:1074-1079 12 、 Joy C. Bunt, Jonathan Krakoff, Emilio Ortega, et al. Acute insulin response is an independent predictor of type 2 diabetes mellitus in individuals with both normal fasting and 2-h plasma glucose concentrations. Diabetes Metab Res Rev.2007,23(4):304-310.
1、 Alberti, K.G.M., Zimmet P, Shaw J, et al. The metabolic syndrome-a new worldwide definition. Lancet,2005,366,1059-1062.
2、杨文英,陆菊明,翁建平,等.Prevalenceof diabetes among men and wemen in China. N Engl J Med.2010,25;362(12):1090-101.
3、 UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet 1998;352:837-853.
4、程时武,陆菊明,杨国庆等.高胰岛素一正常葡糖钳夹技术的建立.第四军医大学学报2007,28(22)：2082—2084.
5、 Laakso M. How good a marker is insulin level for insulin resistance? Am J Epidemiol,1992,137:959-965.
6、 American Diabetes Association. Consensus development conference on insulin resistance. Diabetes Care,1998,21:310-314.
7、 Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia,1985,28:412-419.
8、 Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely minors the of insulin sensitivity. Diabetes Care,2000,23:57-63.
9、 Hanson RL, Pratley RE, Bogardus C, et al. Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol,2000,1 S 1:190-198.
10、 Balion CM, Raina PS, Gerstein HC, et al.Reproducibility of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) classification:a systematic review. Clin Chem Lab Med,2007,45:1180-1185.
11、 Hosker JP, Matthews DR, Rudenski AS, et al. Continuous infusion of glucose with model assessment:measurement of insulin resistance and beta cell function in man. Diabetologia,1985,28:401-411.
12、 李玲,历平,王贵新,等.糖耐量受损者胰岛素敏感性及胰岛β细胞功能的研究.中华糖尿病杂志,2005,13：87-89.
13、 Johnson A.B., Webster].M., Sum C, et al. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type 2 diabetic patients. Metabolism,1993,42:1217-1222.
14、 Hundal R.S., Krssak M., Dufour S., et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes,2000,49: 2063-2069.
15、 Nagi O.K., Yudkin D.S. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care,1993,16: 621-629.
16、 Metformin monotherapy for type 2 diabetes mellitus. Cochrane database of systematic review,2005, CD002966.
17、 Haffner SM, Stern MP. Miettinen H.et al. Higher proinsulin and specific insulin are both associated with a parental history of diabetes in non diabetic Mexican-American subjects. Diabetes,1995,44:1156-1160.
18、 Breda E, Cavaghan MK, Toffolo G, et al. Oral glucose tolerance test minimal model indexes of p-cell function and insulin sensitivity. Diabetes 2001, 50:150-158.
19、 Festa A, Williams K, D'Agostino R Jr, et al. The natural course of P-cell function in nondiabetic and diabetic individuals. Diabetes 2006; 55:1114-1120
20 、 Christian Weyer, Antonio Tataranni, Clifton Bogardus, et al. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care,2001,24:89-94.