胰岛素类似物: 设计和临床应用1型糖尿病发病胰岛素缺乏2型糖尿病发病胰岛素分泌减少+ 胰岛素作用异常2型糖尿病发病胰岛素分泌减少+ 胰岛素作用异常肝糖输出增加2型糖尿病发病胰岛素分泌减少+ 胰岛素作用异常外周组织对葡萄糖异常2 型糖尿病的病理生理学: 餐时胰岛素分泌不足早期胰岛素释放不足造成餐后高血糖12-小时血糖状态餐后血糖与心血管病变风险提示餐后血糖与心血管疾病相关的研究Whitehall Study Helsinki Policemen Study Paris Prospective Survey Tecumseh Study Honolulu Heart Program 研究结果表明与空腹血糖及HbA1c 相比，餐后血糖对于心血管疾病的风险预测有更好的相关性糖尿病干预研究( DIS) DECODE DECODE: 在未诊断糖尿病的人群中多变量校正的总体死亡危险度胰岛素治疗的里程碑动物胰岛素单组分动物胰岛素人胰岛素胰岛素类似物人胰岛素应用的局限性皮下注射后胰岛素的扩散天门冬胰岛素类似物1型糖尿病患者实验餐后胰岛素状态1型糖尿病患者实验餐后葡萄糖状态1 型糖尿病－餐后血糖餐后血糖控制—1型糖尿病（儿童）24小时胰岛素模式—1型糖尿病24 小时控制—1型糖尿病治疗12个月后HbA1c 状态2型糖尿病实验餐后的胰岛素状态2 型糖尿病实验餐后的血糖状态2型糖尿病- 餐后血糖控制低血糖—主要的问题DCCT 证实在不增加低血糖风险的情况下，对血糖进行良好控制是非常困难的有30% 以上的1型糖尿病患者曾经历过需第三者帮助的严重夜间低血糖严重夜间低血糖的风险NovoRapid 改善长期血糖控制减少严重夜间低血糖风险改善用药便利性和灵活性双时效Insulin aspart 30NovoMix 30 30% insulin aspart 70% 鱼精蛋白insulin aspart NovoMix 30 与BHI 30 交叉对照: 吸收更快，胰岛素峰值水平更高于2 型糖尿病，用药后改善餐后血糖控制用药后使餐时血糖波动显著降低总结NovoMix 30 vs. BHI 30: 起效快速，降血糖作用更强餐后血糖的变化较小更少发生严重低血糖事件长期血糖控制及安全性相当NovoRapid vs SHI，临床疗效比较起效迅速，并迅速回复至正常ANA/DCD/046/NL,UK 时间0 80 100 40 20 18:00 60 22:00 08:00 18:00 血清胰岛素(mU/l) 13:00 NovoMix 30 BHI 30 dinner breakfast lunch * p < 0.05 * * Jacobsen L et al. Diabetes 2000 49(Suppl 1):A112 ANA/DCD/046/NL,UK 时间dinner breakfast lunch 0 17 11 8 18:00 14 22:00 08:00 18:00 血清葡萄糖(mmol/l) 13:00 NovoMix 30 BHI 30 * p < 0.05 (favours NovoMix 30) * p < 0.05 (favours BHI 30) * * * Jacobsen L et al. Diabetes 2000 49(Suppl 1):A112 ANA/DCD/046/NL,UK NovoMix 30 0 5 10 15 20 25 晚餐后早餐后BHI 30 餐后4小时内平均血糖浓度(www.book118.com-1) 44%* * p = 0.001 34%** ** p = 0.037 Jacobsen L et al. Diabetes 2000 49(Suppl 1):A112 有效降低餐后血糖水平维持平稳的24-小时血糖控制显著降低严重夜间低血糖的风险在不增加低血糖风险的情况下，显著改善长期血糖控制可在餐前即刻注射速度控制方便性Slide 14: 24 hour insulin profiles in type 1 diabetes In patients with type 1 diabetes, NovoRapid is absorbed more rapidly and has a higher peak concentration after all three meals than soluble human insulin1. Reference 1. Home PD, Lindholm A, Hylleberg B, et al. Improved glycemic control with insulin aspart: a multicenter randomized double-blind crossover trial in type 1 diabetic patients. Diabetes Care 1998; 21: 1904–1909. Slide 15: 24 hour insulin profiles in type 1 diabetes NovoRapid improves post-prandial glucose control compared with human insulin, therefore effecting smoother 24 hour glycaemic control. Plasma glucose concentrations with NovoRapid were significantly lower after breakfast (p<0.0001) and lunch (p<0.0001), but higher at night (p<0.01) than with soluble human insulin. This demonstrates that NovoRapid is effective in controlling glucose peaks following a meal, and treatment with NovoRapid leads to smoother 24 hour glycaemic control, compared to soluble human insulin1. Reference 1. Home PD, Lindholm A, Hylleberg B, et al. Improved glycemic control with insulin aspart: a multicenter randomized double-blind crossover trial in type 1 diabetic patients. Diabetes Care 1998; 21: 1904–1909. The natural history of Type 2 diabetes is inevitable deterioration in beta-cell function, often in association with insulin resistance, rendering it a relentlessly progressive disorder. Early phase insulin secretion becomes progressively reduced in amplitude as beta-cell function declines, and the late phase is both blunted and delayed in onset. In contrast to the physiological insulin response in which insulin peaks just 30 minutes after food, the insulin peak in Type 2 diabetes is not reached until 90-120 minutes after the meal. In individuals with fasting glucose levels > 18 mmol/l, the prandial insulin response is negligible. Loss of the early phase insulin response results in excessive exposure to postprandial glucose. This has been shown to have toxic effects with both short and long-term consequences. 20 If reducing the postprandial glucose peak by appropriate insulin replacement is the key to recreating the physiological profile and reducing cardiovascular risk, it is important to clarify the optimal timing for meal-time insulin replacement. Bruce and colleagues have shown that the most effective way to limit the postprandial glucose peak is to provide insulin within the first half hour after a meal. When replacement is delayed until 30-60 minutes after the meal or prolonged for up-to 3 hours after the meal, the postprandial glucose excursion is suboptimally controlled. Slide 13: Post-prandial glucose control in type 1 diabetic children NovoRapid demonstrates superior post-prandial glucose control compared with soluble human insulin injected just before breakfast in children (6–17 years) with type 1 diabetes. The maximum glucose concentration was significantly lower with NovoRapid compared with soluble human insulin ( p<0.05)1. Reference 1. Data on file, Novo Nordisk (Study ANA/DCD/043). Slide 24: Type 2 diabetes This study showed that glucose excursion, 0 –360 minutes after a test meal, was significantly lower for NovoRapid than for soluble human insulin dosed at meal-time (p=0.01) and was comparable with soluble human insulin dosed 30 minutes before the meal1. Reference 1. Rosenfalck AM, Thorsby P, Kjems L, et al. Effects of the rapid-acting analogue insulin aspart on post-prandial glycaemic excursions compared to human soluble insulin Actrapid given immediately or 30 minutes before a meal in insulin treated type 2 diabetes patients. Diabetes 1999; 48: (Suppl 1): A116. Slide 7: NovoRapid –a new flexible and convenient insulin NovoRapid is a new rapid-acting insulin analogue, that can help meet the major challenge of achieving effective glycaemic control without increasing the risk of hypoglycaemia, whilst also improving patient flexibility and convenience. The greater importance of acute prandial glucose peaks compared with fasting hyperglycaemia as a determinate of risk was particularly well illustrated by the recent DECODE study (Diabetes Epidemiology: Collaborative analysis Of Diagnostic Criteria in Europe). A retrospective meta-analysis of data from more than 25,000 individuals found that when stratified by level of fasting blood glucose, patients’mortality risk increased with increasing blood glucose levels 2-hours after an oral glucose challenge. Conversely, when patients were stratified by 2-hour blood glucose levels there was no trend for increasing mortality risk with increasing fasting blood glucose levels. Thus, the major determinate of risk was post-challenge blood glucose level and not fasting blood glucose. This was true for non-diabetic individuals, those with impaired glucose tolerance and patients with diabetes. Slide 9: Dissociation of insulin after s.c. injection Following subcutaneous injection NovoRapid is rapidly absorbed through the capillary wall and into the systemic circulation. In physiological concentrations insulin circulates and exerts its effects on tissues as a monomer. However, in higher concentrations, soluble insulin associates into hexamers. In NovoRapid the replacement of a proline amino acid residue by aspartic acid disrupts an important structural interaction, which reduces the strength of binding between insulin monomers1, 2. This therefore enables the fast dissociation of hexamers and dimers into monomers and allows ease of transfer through the capillary wall and hence speeds up the rate of absorption into the circulation. References 1. Brange J, Owens DR, Kang S, et al. Monomeric insulins and their experimental and clinical implications. Diabetes Care 1990; 13: 923–954. 2. Brange J, V lund A. Insulin analogs with improved