27 Recommended therapy for T1DM 1) use multiple dose insulin injections (3–4 injections per day basal and prandial insulin) or CSII therapy;2) matching prandial insulin to carbohydrate intake, premeal blood glucose, and anticipated activity;3) for many patients (especially if hypoglycemia is a problem), use insulin analogs.
41 2型糖尿病胰岛素治疗的第1阶段 白天OHA ＋ 睡前胰岛素 Slide 6-39 Starting With Basal Insulin INSULIN TACTICSStarting With Basal InsulinCombination Oral Agents + Evening Basal InsulinThe next group of slides explores the synergistic or complementary effects of this type of combination. Different strategies for combining oral agents with basal insulin are discussed.
42 OHA与胰岛素联合治疗的协同或补充作用 磺脲类及苯甲酸衍生物（胰岛素分泌激动剂）： 二甲双胍（Metformin）： 增加肝脏内源性胰岛素水平并且增强饮食介导的胰岛素释放二甲双胍（Metformin）：在肝脏增加胰岛素的敏感性并且减少肝糖输出噻唑烷二酮（胰岛素增敏剂）：在外周组织增强胰岛素的作用并且增加外周组织对葡萄糖的摄取-糖苷酶抑制剂 ：延缓餐后葡萄糖的吸收Slide 6-40INSULIN TACTICSCombination Oral Agents + InsulinSynergistic or Complementary EffectsThe oral agents can be divided into two general categories: those augmenting the supply of insulin by increasing the secretion of insulin into the portal circulation and those enhancing the effectiveness of insulin. Injected insulin, in turn, increases insulin in the systemic circulation. Because the mechanisms of action for these classes of oral agents differ, they may have complementary or additive effects and can help meet the individualized needs of patients. The sulfonylureas are oral agents that augment the supply of portal insulin. They increase hepatic levels of endogenous insulin and enhance meal-mediated insulin release. Metformin and the glitazones are oral agents that enhance the effectiveness of insulin. Metformin improves insulin sensitivity at the liver and reduces hepatic glucose production. The glitazones improve insulin action in peripheral tissues and enhance glucose uptake. The a-glucosidase inhibitors have a different mechanism of action, decreasing postprandial glucose absorption by inhibiting digestion of complex carbohydrates and disaccharides, thereby retarding gastrointestinal glucose absorption.
47 每天二次胰岛素方案 胰岛素的作用 Regular NPH B L S HS B Slide 6-23 INSULIN TACTICSTwice-daily Split-mixed RegimensTwice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split- mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times.Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care. 1999;22(suppl 3):C71-C75; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews ;3:BLSHSB
48 每天二次胰岛素治疗方案 单独饮食控制 每天二次胰岛素治疗6个月 血浆葡萄糖 血胰岛素水平 70/30预混胰岛素 70/30预混胰岛素 100070/30预混胰岛素70/30预混胰岛素400800300600pmol/Lmg/dL200400Slide 6-49INSULIN TACTICSAdvancing With Multiple Daily InjectionsNPH + Regular, Twice DailyHenry et al studied a group of 14 patients with type 2 diabetes to determine whether tight glycemic control can be obtained using conventional split-dose insulin therapy in an outpatient setting by aggressively titrating insulin therapy. Patients received conventional subcutaneous NPH and regular insulin before breakfast and supper for 6 months, with dose adjustments based on an algorithm built on frequent blood glucose measurements (4-6 times a day). The total dose of required exogenous insulin was 86 ± 13 U at 1 month and 100 ± 24 U at 6 months. Hypoglycemic events at 1 month were infrequent, with mean 4.1 ± 0.3 events/patient/month. These events were mild in nature and progressively decreased to 1.3 ± 0.5 events/patient/month by 6 months. At study completion, the average weight gain was >9% (8.7 ± 1.9 kg) of the pretreatment body weight. Weight gain was inversely related to the rate of pretreatment glucose disposal and was directly correlated with mean day-long serum insulin level and total exogenous insulin dose. One month after initiating intensive insulin therapy, day-long glycemia had improved to within normal range and remained at this level through month 6 of therapy. The HbA1c, which was 7.7% ± 0.3% at baseline, decreased to 5.1% ± 0.2% at 6 months. All postprandial glucose excursions before treatment were similar and virtually identical before and after insulin treatment. These glycemic peaks indicate that the primary contributor to improved overall glycemia is the reduction in FPG levels.Henry RR, Gumbiner B, Ditzler T, Wallace P, Lyon R, Glauber HS. Intensive conventional insulin therapy for type II diabetes. Diabetes Care. 1993;16:21-31.1002000600120018002400060006001200180024000600BLSBLSHenry, et al. Diabetes Care. 1993;16:21-31.
50 每天多次胰岛素治疗方案 (MDI) 二短二中 三短一中 短效 短效 NPH NPH 胰岛素的作用 胰岛素的作用 B L S HS B B L Slide 6-24INSULIN TACTICSMultiple Daily Injections (MDI)NPH + RegularAnother strategy, shown in this slide, consists of two injections of NPH (or lente) insulin daily plus two or three injections of regular insulin with meals. The second injection of NPH is given at bedtime, to confer less risk of nocturnal hypoglycemia while providing enough insulin to control overnight fasting glucose levels. This is often called a multiple daily injection (MDI) regimen. It is widely used for type 1 diabetes patients but is also appropriate for type 2 diabetes patients whose endogenous levels are declining. The match of insulin levels to endogenous needs is better with this approach than with twice-daily NPH and regular, but still not very good.BLSHSBBLSHSB
51 每天多次胰岛素治疗方案（三短一中） 正常对照 OHA治疗 三短一中胰岛素治疗8周 血浆葡萄糖 血胰岛素水平 RRRNRRRN300300250200200pmol/Lmg/dL150Slide 6-50INSULIN TACTICSAdvancing With Multiple Daily InjectionsBedtime NPH + Mealtime RegularIn a randomized crossover study of 8 weeks of oral hypoglycemic agents followed by 8 weeks of 2- or 4-dose insulin regimens, blood glucose and free insulin were measured in 10 type 2 diabetes patients and 10 nondiabetic control subjects. During the first 8 weeks, diabetic patients received oral hypoglycemic agents and then were randomized to receive either 2 or 4 daily insulin injections for the next 8 weeks. Twenty-four hour glycemic profiles were obtained during both treatment periods. The patients were instructed on diet and encouraged to maintain normal physical activities during the course of the study. Mean blood glucose and free-insulin profiles show that patients taking the oral agents had higher blood glucose and lower postprandial insulin concentrations than those receiving insulin. When patients received the daily 4-dose regimen of preprandial regular insulin and intermediate-acting NPH insulin at 10:00 PM, glycemic control improved. The mean HbA1c was 8.8% during treatment with oral therapy compared with 5.6% on the 4-dose insulin regimen.Lindström TH, Arnqvist HJ, von Schenck HH. Effect of conventional and intensified insulin therapy on free-insulin profiles and glycemic control in NIDDM. Diabetes Care ;15:27-34.1001005008001200160020002400040008000800120016002000240004000800BLSHSBLSHSLindström, et al. Diabetes Care. 1992;15:27-34.
52 当前在2型糖尿病 患者中进行胰岛素治疗的 指南 Slide 6-57Practical Guidelines for Insulin Therapy in Type 2 Diabetes Today!For physicians managing patients with type 2 diabetes, practical guidelines for pharmacologic interventions are particularly important in view of the fact that there have been major changes in the pharmacotherapy of type 2 diabetes over the past 5 years. In addition, a number of new classes of antidiabetic drugs have recently been approved for use in the United States, and there is a move to start pharmacotherapy earlier in the course of the disease in order to address the dual defect of type 2 diabetes: insulin deficiency and insulin resistance. There is also an emerging paradigm shift, with increasing use of combination therapy involving lower doses of insulin secretagogues plus an insulin sensitizer, doing so almost from the outset of a patient’s treatment regimen. This concept of treatment is embraced by the community of diabetes experts, who also view insulin therapy as an early strategy to supplement the oral therapy in reaching their glycemic target.ADA：Clinical Practice Recommendations 2001,Diabetes Care 2001;24(suppl 1)
54 联合治疗方案 适用一般2型糖尿病患者 适用明显胰岛素抵抗的2型糖尿病患者 假如仍然无法达到HbA1c < 7％的血糖控制目标 早期联合应用胰岛素分泌激动剂及胰岛素增敏剂可根据简便及效价比原则制订临床治疗方案小剂量联合应用磺脲类及双胍类口服降糖药亚最大剂量磺脲类联合双胍类口服降糖药（双胍逐渐加量）适用明显胰岛素抵抗的2型糖尿病患者联合应用双胍类及胰岛素增敏剂假如仍然无法达到HbA1c < 7％的血糖控制目标尝试进行三种OHA联合治疗方案: No或者增加睡前胰岛素治疗Slide 6-58PRACTICAL GUIDELINESCombination Therapy RegimensFor the usual patient with type 2 diabetes, the recommendation is for early use of combination therapy involving an insulin secretagogue and an insulin sensitizer. The simplest and most cost-effective approach consists of either a once-daily, low-dose or eventually full-dose sulfonylurea in combination with increasing doses of metformin. For patients with type 2 diabetes who show marked insulin resistance, a combination of metformin + glitazone can be recommended. If the target HbA1c < 7% is not achieved, triple oral therapy can be attempted, or basal insulin can be added while continuing oral therapy.
55 继续保持原有OHA剂量（或最终适当减量），同时增加睡前胰岛素（6－10U） < 130%标准体重,NPH (睡前)> 130%标准体重,70/30 预混胰岛素 (晚餐)每周根据血糖情况逐渐增加胰岛素剂量假如 FBG >180 mg/dL，则增加 4 U假如 FBG >140 mg/dL，则增加 2 U争取达到血糖控制目标（FBG <120 mg/dL，HbA1c <7％) ，假如仍然无法达标，则停用OHA开始每天二次直至每天多次胰岛素治疗Slide 6-59PRACTICAL GUIDELINESStarting Basal InsulinThe most critical approach to the management of type 2 diabetes patients with persistent hyperglycemia despite combination oral therapy is to use a simple, straightforward strategy that will facilitate initiation of insulin therapy. The increasing use of insulin pens will certainly simplify the administration of insulin, and its use can be demonstrated to patients in “real time” during their visit to the physician’s office. It is very important that patients continue the oral agents at the same dosage and eventually reduce this dose when appropriate. Conservatively, a single insulin dose of around 10 U of NPH given at bedtime or 70/30 insulin given at the evening meal is a standard initial approach to treatment. Basal insulin glargine has the potential to facilitate and extend the use of this insulin strategy because of its long duration of action, peakless flat profile, more predictable response, and reduced risk of hypoglycemia. Insulin glargine is given once daily at bedtime, but based on its insulin kinetics, it could theoretically be given at any time. The insulin dose should be adjusted according to the fasting SMBG level. The insulin dose can be increased on a weekly basis as needed. It should be increased by 4 U if the fasting blood glucose (FBG) is greater than 140 mg/dL, and by 2 U if the FBG is 120 to 140 mg/dL. The treat- to-target level is usually an FBG < 120 mg/dL.