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【进展】内分泌进展瞭望窗口(2008-5-26罗格列酮与匹格列酮：怎么使用？) [精华]

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New Guidelines Issued on Optimal Hemoglobin A1C Targets for Type 2 Diabetes
2型糖尿病糖化血红蛋白最佳目标值新指南

The American College of Physicians (ACP) has issued a guidance statement on the optimal hemoglobin A1c targets for patients with type 2 diabetes. The statement is published in the September 18 issue of the Annals of Internal Medicine.
美国医师学院最近发表了一篇关于2性糖尿病最佳血红蛋白目标值的指导论据。论据发表在国内医学年会杂志九月刊18页上。

"This guidance statement is derived from other organizations' guidelines and is based on an evaluation of the strengths and weaknesses of the available guidelines," write Amir Qaseem, MD, PhD, MHA, from the ACP in Philadelphia, and colleagues from the Clinical Efficacy Assessment Subcommittee of the ACP. "We used the Appraisal of Guidelines, Research and Evaluation in Europe (AGREE) appraisal instrument to evaluate the guidelines from various organizations."
”指导方针来源于其它组织的指南并以对这些有用的指南的深度和弱点的综合评估为基础“ ......“我们运用了欧洲指南、研究和评估的指导性的方针来评估各种指南的价值.”

The reviewed guidelines differed in whether they recommended a specific hemoglobin A1c target, as well as in their choice of a specific target hemoglobin A1c level. Except for the American Academy of Family Physicians guidelines, all guidelines specified hemoglobin A1c target levels. Although most guidelines recommend a target hemoglobin A1c level of approximately 7%, several guidelines recommend tailoring the target hemoglobin A1c based on individual patient factors, including risk for microvascular and macrovascular complications, life expectancy, and comorbid conditions. All the reviewed guidelines agreed that target hemoglobin A1c levels should be individualized for specific patients.
这些回顾性指南的差别在于，他们是否推荐了一个特定的血红蛋白目标范围，和在他们选择范围下血红蛋白水平。除去美国家庭医生学院的指南，所有的指南都特定了一个血红蛋白目标水平。尽管大部分指南都推荐糖化血红蛋白目标范围水平近似7%，还有一些指南推荐他们的目标血红蛋白要以个体患者的影响因子为参考，包括微血管病变和微血管并发症的危险、预计的生存期、和其它系统患病情况。所有这些指南都同意糖化血红蛋白目标范围应该针对特定的患者个体化。

After reviewing the available guidelines, the ACP committee issued 3 summary statements:
通过回顾这些适宜的指南，ACP协会发表了3条简要建议：

Statement 1: The goal for glycemic control should be set as low as is feasible to prevent microvascular complications of diabetes, while avoiding undue risk for adverse events or placing an unacceptable burden on patients. Discussing with the patient the risks and benefits of specific levels of glycemic control should precede setting treatment goals.
建议1：血糖控制的目标应该设定在尽可能低的阻止糖尿病患者微血管并发症可行性上，同时应避免各种不良反应的过度危险和增加患者不必要的负担。讨论患者血糖控制特定水平的风险和收益应在设定治疗目标之前进行。

Based on individualized assessment, a hemoglobin A1c level less than 7% is a reasonable target for many patients, but not for all. Hemoglobin A1c goals higher than 7% may be indicated for patients who are elderly or frail, who are at higher risk for adverse events from tight control, or who have substantially lowered life expectancy from comorbid conditions. More stringent targets may be indicated in patients who are at increased risk for microvascular complications.
以个体化评估为基础，不超过7%的糖化血红蛋白水平对多数患者来说是一个合理的范围，不过并非对所有患者如此。超过7%的糖化血红蛋白水平可以考虑某些患者如年长、虚弱，他们对于血糖的严格控制有着更大的不良反应风险，或者他们本质上因为合并症有较短的预生存期。更严格的目标范围可以考虑那些有微血管并发症的高危患者。

Statement 2: Individualized evaluation of risk for complications from diabetes, comorbidity, life expectancy, and patient preferences should determine the specific goal for hemoglobin A1c level.
建议2：综合患者糖尿病病情、合并症、预生存期和患者的个人选择等情况对并发症危险的个体化评估决定了血红蛋白水平的特定目标。

Statement 3: The ACP committee recommends additional research to evaluate the optimal level of glycemic control, particularly in patients who have significant comorbid conditions.
建议3： ACP协会建议需要有更多的研究来评估合理的血糖控制水平，特别是那些有明显合并症的患者。

"Understanding the benefits and harms of various levels of glycemic control remains challenging, particularly in patients with other comorbid conditions," the authors conclude. "In addition to the importance of glycemic control, management of blood pressure and lipid levels is also essential to prevent complications of diabetes. Further research that elucidates optimal level of glycemic control in patients of different ages, in patients with comorbid conditions, and in patient populations representative of those seen in practice would provide important additional guidance for management of diabetes."
“理解不同水平下血糖控制的收益和危害还是有挑战的，特别是那些有合并症患者，”作者推断，“除去血糖控制的重要性，血压的管理和血脂的水平在阻止糖尿病并发症方面都是很重要的。那些阐明在不同年龄、不同合并症，和那些现实中患者代表人群的不同患者的合理血糖控制水平的更深入的研究，将会提供其它更重要的血糖管理指南。

The ACP supported creation of this statement. Some of the authors have disclosed various financial relationships with the Centers for Disease Control and Prevention, Novo Nordisk, Bristol-Myers Squibb, Pfizer Inc., and/or Merck Pharmaceuticals.
ACP支持这个论断的创建。一些作者也揭露了同糖尿病控制与预防、Novo Nordisk, Bristol-Myers Squibb, Pfizer Inc., and/or Merck Pharmaceuticals等各种经济上的关系。

Clinical Context
临床语义

Diabetes is a leading cause of morbidity and mortality in the United States, with approximately 20.8 million affected (7% of the population) and more than 90% with type 2 diabetes, and hemoglobin A1c, known as glycosylated or glycated hemoglobin, is used as a measure of control of diabetes. Glycemic control for patients with diabetes was a priority area identified by the Institute of Medicine in the quality chasm report.
糖尿病是美国致残率和致死率的最主要原因，有越2千8百万患病（7%人口），超过90%为2型糖尿病。糖化血红蛋白，为糖基化或糖化的血红蛋白，作为一种方法用于糖尿病的控制。

This is a synthesis of recommendations from guidelines developed by organizations, as assessed by the ACP Efficacy Assessment Subcommittee using the AGREE criteria, with 23 questions in 6 domains of scope and purpose, stakeholder involvement, rigor, clarity, applicability, and editorial independence.
这是从不同组织不同指南推荐的综合，ACP协会运用了AGREE标准评估，有23个问题在6个主要领域：范围和目的，介入的利益相关者，严密性，透明度，适用性和独立性。

Study Highlights
研究亮点

A MEDLINE search was conducted that identified 416 articles of which primary research articles and duplicate and outdated references were excluded.
MEDLINE 研究管理了相关的416篇文章，其中排除了初始研究的文章和复制及过时的文献。

2 independent reviewers scored the articles and ranked them using quantitative and qualitative criteria.
2位独立的研究者给这些文章打分并用质和量的标准给做了排名：

A group of 9 guidelines were identified for this review.
一组9个指南出现在此回顾上。

Individual guidelines were summarized as follows:
以下是各个指南的摘要：

The American Association of Clinical Endocrinologists (2002) recommended normalization of glucose levels with suggested hemoglobin A1c levels of 6.5% or less, based on consensus but not systematic literature review.
2002年AACE推荐的血糖控制建议糖化血红蛋白正常水平在6.5%或以下,专家共识非系统回顾.

The American Academy of Family Physicians (1999-2005) did not set a uniform target for hemoglobin A1c but recommended individual customized goals, and the guideline has not been updated since 1999.
1999-2005AAFP没有给出一个具体的糖化血红蛋白目标值,不过建议个体化治疗,这个指南自1999年以来没有更新.

The American Diabetes Association (2006) recommended a stringent level of less than 6% for hemoglobin A1c with less stringent levels for those with shorter life expectancy and for the elderly, but there is no reference to a systematic review.
2006年ADA推荐了一个更严格的糖化血红蛋白控制水平,不超过6%,但对那些预生存期短,老年患者建议不这么严格.但是没有相关资料显示有系统回顾.

The American Geriatrics Society (2003) recommended hemoglobin A1c levels of 7% or lower for healthy adults and less stringent levels of less than 8% for those with life expectancy of less than 5 years, based on a comprehensive review.
2003年AGS推荐糖化血红蛋白水平7%,健康成年人更低,预生存期不超过5年的患者不超过8%.基于系统回顾.

The Canadian Diabetes Association (2003) recommended a level of 7% or lower to reduce risk for microvascular and macrovascular complications with even lower levels of less than 6% if it could be achieved without risk.
2003年CDA推荐7%或更低的血红蛋白水平来降低危险,如果可以安全达到,微血管和微血管并发症患者可以低于6%.

The Institute for Clinical Systems Improvement (2004) recommended individualizing the target hemoglobin A1c level and having a target of less than 7% except for those with advanced age, those at risk of hypoglycemia, or those with limited life expectancy.
2004年ICSI推荐个体化糖化血红蛋白治疗,建议目标小于7%,除外高龄,有低血糖危险的及预生存期短的患者.

The National Institute of Health and Clinical Excellence (2002) recommended a level between 6.5% and 7.5% based on comprehensive evidence.
2002年NIHCE推荐水平,6.5%-7.5%,基于系统回顾.

The Scottish Intercollegiate Guidelines Network (2001) and the Veterans Health Administration (2003) both recommend a level below 7%.
2001年SIGN和2003年VHA都推荐小于7%.

Summary statements for review:
简要回顾

All guidelines recommended setting individual goal levels, and most recommended targets of around 7%.
所有指南都推荐个体化治疗,大部分推荐目标7%左右.

Some guidelines recommended less stringent levels for older or frail patients and those with short life expectancy.
一些指南推荐老年,虚弱及预生存期短的患者放宽要求.

The goal for glycemic control should be a hemoglobin A1c level that is as low as possible without undue risk for adverse events or an unacceptable burden on patients.
血糖控制的目标应该将糖化血红蛋白水平控制在一个尽可能低的水平,同事没有严重的不良反应,并避免额外给患者增加负担.

Individual assessment of risk for complications, comorbidity, life expectancy, and patient preference should be taken into account in setting individual goals.
在设定个体化目标时,应考虑患者的个体化危险评估,包括并发症,合并症,预生存期,和患者的个人偏好.

Further research should be conducted on the optimal hemoglobin A1c level, particularly in the presence of comorbidities.
应该有更多关于最佳糖化血红蛋白的研究,特别是有合并症的情况下.

Pearls for Practice
临床精要
A target of around 7% and below for hemoglobin A1c level is recommended by most guidelines on diabetes glycemic control except for those by the American Academy of Family Physicians, which provides no target level.
大部分指南推荐糖尿病患者的血糖控制使的糖化血红蛋白在7%或更低,除了AAFP,他们没有给出具体数值.

Individualized goal-setting for hemoglobin A1c level should take into account risk for complications, comorbidities, risk for hypoglycemia, age, life expectancy, and patient preference.
设定个体化目标时,应考虑患者的个体化危险评估,包括并发症,合并症,预生存期,和患者的个人偏好.

2007-10-09 15:55

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Insulin Therapy of Diabetes: Pathophysiology and Indications

Patients With Diabetes Are Not Reaching Treatment Goals
We have a fairly generous toolbox of therapies for the treatment of patients with diabetes, and I will discuss the ways we can apply these therapeutic tools.

We have all heard about the explosion in the prevalence of diabetes; and frequently the term "epidemic" is used in this context. Currently, about 10% of adults in the United States have diabetes; that is, about 20 million people. Nearly a third do not know they have diabetes; that is a lot of people, but it is better than it was about 10 years ago when it was 50%.

In addition, and perhaps a little bit more alarmingly, is the fact that there are 2 to 3 times that number of people who have what is now called prediabetes; they either have impaired fasting glucose or impaired glucose tolerance. This category is very important because these individuals have a 40-fold likelihood of making the transition from prediabetes to actual type 2 diabetes. Although their vascular risk is not quite as high as in DM2, the increase in macrovascular disease in these individuals is substantial.

In addition, not all of those with prediabetes actually make the move to DM2, so attention is being drawn to this category as a legitimate treatment target. Consequently, about 1 out of every 3 adults in the US has either diabetes or prediabetes, which is a substantial number of people--70 or 80 million.

Slide 1. Glucose Tolerance Categories
When talking about the prediabetic state, make sure you are familiar with these glucose criteria: Normal (normoglycemia) is fasting blood glucose of less than 100 mg/dL, and diabetes is diagnosed at levels of 126 mg/dL or above. Two-hour postprandial glucose of 140 mg/dL or less is normal and a postprandial glucose of 200 mg/dL or over constitutes diabetes. Between these parameters are the categories of either impaired fasting glucose or impaired glucose tolerance. Prediabetes is no longer a descriptive term; it actually applies to a category of individuals who have blood glucose levels that fall within certain clearly defined parameters.

Slide 2. 63% of Patients With Diabetes Are Not at ADA A1C Goal <7%
Given the fact that we know all of this, it is surprising that we have not been able to make better penetration in terms of control of diabetes. This is information from the National Health and Nutrition Examination Survey (NHANES), which is a large, government-sponsored, population-based epidemiologic study that examined many conditions, including diabetes. This study tells us that only 37% of individuals with diabetes in the study population had hemoglobin A1C levels of less than 7%, which means that the other two thirds are above that fairly conservative American Diabetes Association (ADA) goal.

If you include other macrovascular risk factors that we are supposed to be controlling, only about 7% of adults with diabetes have an A1C less than 7%, blood pressure less than 130/80 mm Hg, and total cholesterol less than 200 mg/dL. This represents a substantial opportunity for improvement.

Pathogenesis and Etiology of Type 1 and 2 Diabetes

Slide 3. Pathogenesis of Type 1 Diabetes
The vast majority of diabetes is type 2 diabetes, but about 5% to 10% of individuals have type 1 diabetes. This is a complex condition of absolute insulin deficiency focused around immune dysregulation, immune disorders, in which autoantibodies are directed at various surface components of the beta cell, leading to diabetes. We used to think of it as childhood diabetes and as an explosive condition. But we know now, based on our ability to track autoantibodies and various circulating chemical markers, that there is a preamble to type 1 diabetes. Perhaps in the future we will be able to intervene before the beta-cell mass is decreased to the point where there is no insulin being produced.

The hallmark of type 1 diabetes from a clinical point of view is that these individuals cannot make any insulin, and therefore are dependent on external insulin for survival.

Of the 95% of people with type 2 diabetes, a substantial number will eventually need insulin therapy to control their blood glucose. However, they are not absolutely insulin-deficient, meaning they do make insulin, in some cases a substantial amount. But it is not enough to overcome their insulin resistance. Although they may require insulin, they are not dependent on insulin for survival; that is a critical differential between the pathogenesis of those two conditions.

Slide 4. Natural Development of Type 2 Diabetes and CV Risk
In type 2 diabetes, the underpinning of its pathophysiology, insulin resistance, present in almost every individual with type 2 diabetes, starts early. By the time we diagnose diabetes, insulin resistance is essentially at or almost at a peak, and stays at that level for the rest of that patient's life unless we include a strategy in our therapy to reduce insulin resistance.

If you are a person with insulin resistance, meaning you are one of 70 to 80 million people, your response should be to make more insulin, to mount a compensatory hyperinsulinemia. And if you are an individual who has insulin resistance and you can make unlimited amounts of insulin, your blood glucose will remain normal. But if you are in that approximately 25% of insulin-resistant individuals who cannot continue to make insulin in unlimited amounts, your beta cells die, and as they fail, insulin levels will go down, followed by rises in postprandial and then fasting blood glucose. At that point, we will diagnose prediabetes or type 2 diabetes.

You can extract a number of things from diagrams such as this. One is that if you were able to raise the insulin level -- for example, you gave an insulin secretagogue, (e.g., a sulfonylurea) or insulin itself -- you might be able to lower or even normalize the blood glucose, but you still would not have done very much to reduce the insulin resistance. That is important, because the general feeling is that most of the macrovascular risk factors that we see clustered in these individuals are related to the insulin resistance and not necessarily to the hyperglycemia, per se.

Secondly, there is a lot going on before the diagnosis of DM2 is made. Insulin resistance has increased, and parallel to this increase is the development of macrovascular disease, which may start well before a patient is diagnosed with type 2 diabetes. The goal, then, is to intervene in the natural history of these patients much earlier, when their beta-cell mass is more substantial, because it is always easier to prevent things from happening than it is to try to reverse them after they have happened.

Slide 5. Beta-Cell Function in Type 2 Diabetes
Beta-cell function is the discriminating feature of people with diabetes; it is what determines blood glucose levels, because insulin resistance is at or near maximal by the time we diagnose diabetes. Consequently, the degree of dysglycemia is predominantly related to beta-cell function, and this starts to decline well before we diagnosis type 2 diabetes, possibly as long as 10 years prior to diagnosis. This is another good argument for getting involved earlier in the natural history of this condition.

The beta cell, the insulin producer, is subject to a number of factors that can lead to progressive malfunction. Hyperglycemia itself creates glucose toxicity: If blood glucose is high, this elevation in and of itself will impair insulin production and secretion, and also will increase insulin resistance. Conversely, when you lower blood glucose by any means, you may overcome some of the associated glucose toxicity and improve beta-cell function.

There also is a lipotoxicity. Insulin is an antilipolytic hormone; it keeps fatty acids in fat cells. But when you do not produce enough insulin or when there is insulin resistance, there is less insulin action. Free fatty acids, as well as other chemical products, flow from adipose tissue, accumulating in and affecting the function of the beta cell. We are even beginning to think of the beta cell as possibly being an insulin-sensitive tissue; at the very least, it seems to be a victim of the systemic chemical environment that accompanies insulin resistance. Therefore, strategies that lower insulin resistance may also improve beta-cell function. This is a very complex set of events, but it also presents multiple treatment targets as well.

Slide 6. Glucose Toxicity: Improvement of Insulin Secretion
These data demonstrate glucose toxicity. If one tracks plasma glucose and plasma insulin, if you lower blood glucose (for example by giving insulin), you can improve insulin release. For example, if you have a patient who presents with a blood glucose level of 400 or 500 mg/dL, and you give that patient insulin at the beginning of their therapy and lower his or her blood glucose to normal, you may actually improve insulin production. Therefore, in some patients, the early administration of insulin may prevent the use of more complex regimens, or insulin altogether, at a later time.

Slide 7. Etiology of Type 2 Diabetes: Insulin Resistance and Diminished Insulin Secretion
Insulin resistance occurs partially because of genetic predisposition (represented by double helix icon). Additionally, there are lifestyle issues -- eating too much, weighing too much, and not getting enough exercise -- represented by the fast food burger and fries. In that situation, if you can produce unlimited amounts of insulin, blood glucose will remain normal, but you may still have the metabolic syndrome, a cluster of risk factors related to insulin resistance. If you are in the 25% of people who cannot make enough insulin, your blood glucose will go up and you will be somebody with type 2 diabetes as part of your metabolic syndrome.

Slide 8. Elevated FFAs May Play a Key Role in Insulin Resistance
I would like to underscore the importance of free fatty acids. When released from adipose tissue, they end up in a number of tissues critical to the insulin resistant and dysglycemic state. In the liver, the net effect is to antagonize insulin action. We see less glucose staying in the liver and more gluconeogenesis and glycogenolysis, contributing to both fasting and postprandial hyperglycemia. But a large contribution to hyperglycemia comes from free fatty acids being deposited in muscle, since over 80% of glucose is taken up in muscle tissue. Free fatty acids can end up in the beta cell as well, where again there are structural and functional impairments of insulin synthesis and insulin release due to the lipotoxic part of beta-cell dysfunction.

Insulin Physiology: Normal and Diabetic States

Slide 9. Physiologic Insulin Secretion: 24-hour Profile
The objective of insulin therapy is to recreate normal physiology. In the basal fasting state, blood glucose stays fairly constant. The level of insulin is low, but a basal amount is always present. Superimposed on the basal level will be bursts or spikes (sometimes referred to as a bolus) of insulin being released periodically into the circulatory system, to assimilate the carbohydrates that we have ingested. This concept of basal and bolus insulin as found in normal physiology is the platform upon which our insulin strategies are based.

Slide 10. Fasting Plasma Glucose and the Acute Insulin Response
When people develop diabetes, they always produce insufficient amounts of insulin relative to the level of blood glucose and insulin resistance that exists. Type 1 diabetes patients have no insulin at all and type 2 diabetes patients have some insulin, but less than they need to keep their blood glucose levels normal. Shown here on the y-axis is insulin response as a percentage increase from baseline for groups of patients who have varying degrees of impaired glucose tolerance and a varying severity of diabetes.

What you see is more than an overall decrease in insulin production. The first thing to disappear is the "first-phase" or acute insulin response, during which nondiabetic individuals may have as much as an 8-fold increase in insulin production over the basal level. By the time you reach a fasting blood glucose in the highest range, there is practically no acute insulin response. When we construct insulin therapies, short-acting insulins best mimic this phase of insulin release.

Understanding A1C

Slide 11. Glucose Factors Contributing to A1C
Hemoglobin A1C, which is the surrogate for mean integrated average blood glucose over a period of roughly 8 to 12 weeks, may represent many factors. Glucose is released by the liver to prevent hypoglycemia when not eating overnight. When there is decreased insulin activity, this process is dysregulated and you release too much blood glucose.

We also have a number of factors that not only contribute to fasting glucose, but also contribute to postprandial glucose, including insulin secretory capacity, how much glucose is ingested, and the sensitivity of the tissues to insulin. It is, then, a complex set of factors and regulators that contribute to the overall glycemic burden.

Slide 12. Lower A1C Reduces Incidence of Complications
We know that lowering A1C reduces complications. This is particularly true for microvascular complications, such as retinopathy or nephropathy, but also true, to perhaps a less robust degree, for macrovascular disease.

A number of studies have demonstrated this protection. The sentinel study for type 1 diabetes is the Diabetes Control and Complications Trial (DCCT), which included type 1 patients who were getting either conventional insulin therapy or an intensified insulin regimen of multiple doses per day, with A1C targets that were more aggressive.

In that study there were substantial reductions in all of the vascular parameters that were followed.

This same intensive insulin strategy was applied to type 2 patients in the Kumamoto study, and similar results were seen.

In another study of type 2 patients receiving not only insulin but also metformin (the United Kingdom Prospective Diabetes Study or UKPDS), diet and exercise, or a sulfonylurea, the same principle was reinforced; lowering A1C reduces the incidence of complications. To whatever degree that you can reduce A1C, whether it is 1% or 2%, or taking a patient from 10% to 9%, or 9% to 8%, you will convey a protective effect to their tissues.

Slide 13. DCCT: Relationship of A1C to Risk of Microvascular Complications
This is another analysis of data from the DCCT, which examines individual complications: retinopathy, nephropathy, neuropathy, and microalbuminuria. All of these would be considered microvascular complications, which are very tightly linked to blood glucose. Macrovascular disease is more complex because we have many other risk factors such as lipids and hypertension that are contributing to the macrovascular disease.

As shown, no matter what the complication, there is a significant relationship between A1C and the relative risk of developing that complication. The higher the A1C, the more the complications or, conversely, the lower the A1C, the less the complications.

Slide 14. Schematic Course of DCCT/EDIC: Intensive and Conventional Groups
The DCCT investigators did something that was interesting. The original trial duration was 7 years. Patients were either given a conventional type of insulin regimen, perhaps 2 shots per day, or an intensive regimen where patients might get multiple subcutaneous injections and received very intensive management with a high ratio of healthcare personnel to patients. This intensive group had lower A1Cs during the study period.

After these DCCT results were published, the investigators followed patients for another several years. Not surprisingly, when the intensity of management was relaxed, A1Cs rose. In addition, during this period of time, the notion of being more aggressive about insulin therapy took hold in the medical community, and those patients who had initially received "conventional" therapy were actually getting a little bit better therapy than previously, and the two groups met in the middle in terms of A1Cs.

The investigators also tracked complications during this extended observation period. Patients who received conventional therapy at the beginning had a progressive increase in microvascular complications, whereas patients who had the initial intensive care were able to maintain their advantage in terms of reduced rates of retinopathy, nephropathy, and neuropathy. Note that the rate of complications between groups is not parallel; complications increased as A1C went up, but not as much in the intensive therapy group during this extended period of time, as in the conventional therapy group. So it appeared that there was some memory from the period of intensive control. These same trends were also shown for macrovascular disease.

Slide 15. UKPDS Epidemiologic Data in Type 2 Diabetes
Data from the UKPDS for type 2 diabetes showed that a 1% reduction in mean A1C could result in the substantial percentage reduction shown for all of these various complication endpoints.

Slide 16. Aggressive Control of Diabetes: Goals of Treatment
There is no single agreed-upon A1C target, but most people would agree that the goal is to get A1C to normal without exposing the patient to undue risks of hypoglycemia. Organizational goals are always consensus statements; for the ADA, the A1C goal is less than 7% and for the American College of Endocrinology, it is less than/equal to 6.5%. But both groups acknowledge the fact that if you can get patients to normal, you should do so.

Patient Education and Monitoring

Slide 17. Education at Diabetes Diagnosis
We have a lot of therapeutic tools to offer patients. We have education. The role of Certified Diabetes Educators is inestimably important in terms of the breadth and depth of education they give in a number of areas, not only in disease education but education regarding various therapeutic modalities, explaining the nature of these therapies and getting patients involved in self-monitoring. Educators are able to devote the time and the skills necessary in terms of teaching patients about their diabetes

Slide 18. Principles of Medical Nutrition Therapy
Medical nutrition therapy forms a large part of this education, and there are a number of goals. Weight loss does not have to be overwhelming to reduce hyperglycemia or other macrovascular risk factors. A reduction of about 5% to 10% of body weight has substantial metabolic benefits. Patients are not always happy with a 5% weight loss; their goals are sometimes more cosmetic or social. But metabolically, even that amount of weight loss will be very beneficial.

h[img]ttp://images.medscape.com/pi/editorial/cmecircle/2007/7838/images/weissman/slide19.jpg[/img]
Slide 19. SMBG and Glycemic Control: The Northern California Kaiser Permanente Diabetes Registry
Self-monitoring of blood glucose is equally important. Not many studies have looked at this, but this was a very good study from Kaiser Permanente Health System of roughly 24,000 patients. Patients who monitored blood glucose at home had better A1Cs; in type 1 patients, it was about 1% lower and in type 2 patients, it was about 0.6% lower. Individuals who practiced self-monitoring of blood glucose with any frequency had some statistically significant lowering of A1C. Working with patients to impart the meaning of their blood glucose can make this is a very useful technique.

Slide 20. Glucose Monitoring Patterns for Insulin-Treated Patients
There are many different patterns for testing blood glucose. Patients can do "block testing" once or twice daily. If they do it once daily, sometimes we will tell them to do fasting glucose one day and postprandial the next day. Or we may rotate postprandial blood glucose in combination with fasting; a patient will be testing fasting glucose one day, 2 hours after breakfast the next day, 2 hours after lunch on the next day; and 2 hours after dinner on the next. Over a period of time you can develop a grid that yields good information while testing only once a day.

There are more intensive ways of approaching this, such as having patients check their blood glucose 4 or more times daily. This can be used to determine patterns that will help adjust patient insulin programs.

Slide 21. Monitoring: Patient Issues
There are issues with self-monitoring. It causes pain in some patients more than others. Some patients do not have the manual or visual skills to be able to accomplish self-monitoring. There may be issues with cognitive function. We have to work with those patients, and the educators do a great job. There are also a number of different meters, which tend to work better for one type of patient than the other.

Then we have the excuses that patients give us as to why they do not want to do testing, which do not have anything to do with physical issues. But they are, nonetheless, real-life issues, particularly the expense.

Oral Agents for Diabetes Treatment

Slide 22. Oral Antidiabetes Medication Monotherapy: Maximum Therapeutic Effect on A1C
In terms of oral therapy, we have a number of tools. The medications we tend to use the most are the ones capable of conveying a 1% to 2% reduction in A1C, either as monotherapies or as add-on therapies. Remember that the degree of reduction in A1C is going to be conditioned by the A1C at which the patient starts treatment; the lower the A1C at baseline, the smaller the decrease in A1C that is likely to occur with the addition of a therapy. All of these medications are good as monotherapies or in combination, with the obvious exception of using 2 insulin secretagogues together or 2 thiazolidinediones (TZDs) together. But each class of drugs is effective as a mono- or combination therapy.

Slide 23. Most Current Therapies Do Not Control Glucose Long-term
During the early years of the UKPDS, all study arms were effective in lowering A1C, whether insulin, metformin, or a sulfonylurea was the treatment modality. But as time went on, there was a decline in glycemic control. Not surprisingly, this was associated with a decrease in beta-cell function. The implication is that most patients end up using combination therapy, similar to the way in which hypertension and dyslipidemia are treated.

Numerically, the rise in A1C was about 0.2% to 0.3% per year despite being on a given monotherapy, and is much the same whether the result of diet failure, sulfonylurea failure, or metformin failure. All treatment groups experienced failure at more or less the same rate, and the decline in beta-cell function was also approximately the same for all of them. As such, combination therapy is routinely needed.

In addition, if your patient has been on combination therapy (2 agents) that is inadequate, you could add a third oral agent, exenatide or insulin. A number of insulins are available: long-acting basal insulin; premixed insulin (70/30, 75/25); and prandial insulin coverage, the latter being short- or extremely short-acting insulins that target postprandial blood glucose.

Insulin Therapy for Diabetes

Slide 24. Insulin Therapy of Type 2 Diabetes
Insulin therapy is not the course of last resort. Many patients view it as the end of the road for their diabetes. Of course it is not that, it is just a tool for controlling blood glucose. But many patients have heard that their parents or their grandparents got insulin just before they died, their kidneys failed, or they had an amputation. Insulin is an appropriate therapy for any patients who have not reached targets by other means.

I used to think that people did not like the idea of injections. But then I realized that injecting insulin is not as uncomfortable as self-glucose monitoring. Exenatide, which is an injectable administered twice a day, comes with the promise of weight loss, and suddenly it becomes very acceptable. Although there are occasional patients who are truly phobic, the fear of injections is not as widespread as we once thought it was.

Slide 25. Estimated Pharmacokinetics of Current Insulin Preparations
What types of insulin are available? There are rapid-acting insulins that begin to work in about 15 minutes, and peak somewhere between 1 and 2 hours. Examples of such rapidly acting insulins are insulin lispro, insulin aspart, or insulin glulisine. These are very appealing insulin choices because they have a quick onset of action, and their peak action tends to coincide with the time that postprandial glucose levels are at their peak.

In addition, we have inhaled insulin, which is also quick-acting. Regular insulin pharmacokinetics are similar to the rapid-acting insulins, but with some significant time course differences. There are also intermediate-acting insulins, such as neutral protamine Hagedorn (NPH), which has a peak 7 to 8 hours after you take it. The longer-acting analogs, such as insulin glargine or insulin detemir, are "24-hour" insulins.

Slide 26. Action Profiles of Injectable Insulins
This schematic gives you the profiles for injectable insulin. The longer-acting insulins, such as glargine or detemir, are theoretically 24-hour insulins; they have a duration of action of about 24 hours, and they tend to mimic basal insulin levels.

In terms of shorter-acting insulins, we have the rapid-acting ones, aspart, glulisine, or lispro, which have a fairly rapid peak of onset, but their effect is dissipated fairly quickly, in a few hours. The rapid dissipation of these insulins results in less hypoglycemia but also can leave a void in insulin activity in some patients between meals. NPH has a significantly longer profile.

Slide 27. Comparison of Insulin Formulations in Controlling Postprandial Glucose Levels
If one examines the glucose profiles over a period of 4 hours in nondiabetic controls and in individuals given either glucose and NPH, a mixture of 70% NPH/30% regular, or 75%/25%, (a mixture of an NPH-type insulin with a short-acting insulin, either lispro or aspart), the insulins that have a quicker onset tend to suppress the rise in postprandial glucose to a greater degree.

Slide 28. Inhaled Insulin: A Rapid-Acting Insulin With Unique Pharmacodynamic Profile
Inhaled insulin fits in between the more rapid-acting insulins, in this case lispro or regular. In terms of the onset of action, it is rapid, close to the more rapid-acting insulin, but it is not gone quite as quickly, which is more like regular. So, to a certain extent, you get some of both when using the inhaled insulin.

Slide 29. Time to Peak Effect (Tmax)
This is a more quantitative bar graph of the time to peak effect of these 3 insulins. And you can see, when viewed in this format, the inhaled insulin is more like the rapid-acting insulin, lispro, than it is like the regular insulin.

Insulin Effects on A1C

Slide 30. Type 1 Diabetes: Conventional Therapy
Many studies have compared the effect of inhaled insulin to subcutaneous insulin. This is a 6-month study in which type 1 diabetes patients either receive subcutaneous insulin or inhaled insulin as part of their program. As shown, there was essentially no difference in A1C at the end of 6 months between the two groups.

Slide 31. Type 2 DM: Conventional Insulin Therapy
This is a study of type 2 diabetes patients being treated either with subcutaneous insulin or inhaled insulin. Again, at the end of 6 months, there is essentially no difference in A1Cs.

Slide 32. Type 2 DM: Conventional Insulin Therapy
If you compare inhaled insulin with subcutaneous insulin in terms of percentage of patients who reached some predetermined A1C goal, more of the patients on inhaled insulin got to a target of less than 7% than those on subcutaneous insulin.

Slide 33. Mealtime Inhaled Insulin in Patients With Type 2 Diabetes: Decrease in A1C
These data show decreases in A1C in patients who are being treated with combinations of oral agents, with inhaled insulin, or both. These patients all qualified for the study because they had been on combinations of an insulin sensitizer, either metformin or a TZD, plus a secretagogue such as a sulfonylurea. In those in whom no therapy change was made, there was no further decrease in A1C. In patients taken off the combination and started on inhaled insulin, an A1C decrease of 1.4% was seen. If left on oral agents and adding inhaled insulin, the largest decrease of 1.9% occurred.

Slide 34. Mealtime Inhaled Insulin in Patients With Type 2 Diabetes: Target A1C
This study involved stratification according to the achievement of predetermined targets for A1C in that same group of patients, i.e., patients maintained on oral agents, switched to inhaled insulin, or combining the two. A larger percentage of patients reached a target of either less than 8% or less than 7% with the combination of inhaled insulin and oral agents.

Safety With Inhaled Insulin: Adverse Events and Pulmonary Safety

Slide 35. Incidence of Hypoglycemia With Inhaled Insulin: Type 1 and Type 2 Diabetes
There are adverse effects with every drug and inhaled insulin is no exception. The most commonly reported side effects in clinical trials were hypoglycemia, a type of chest discomfort, cough, and dyspnea.

As with every type of insulin, hypoglycemia is the most frequent adverse event that is reported in trials. The incidence of hypoglycemia in trials was comparable in the inhaled and subcutaneous insulin groups. When compared with oral agents, some of which do not even cause hypoglycemia, obviously hypoglycemia was more common in the patients who took inhaled insulin.

In a numerical comparison of the incidence of hypoglycemia in patients with type 1 diabetes receiving either inhaled or subcutaneous insulin, there is roughly the same incidence in both groups; in patients with type 2 diabetes, similar results were seen. The biggest differential was in patients who were taking inhaled insulin plus oral agents vs the oral agents alone. Remember, these patients had failed on oral agents, were therefore not as close to hypoglycemic levels, and received no additional intervention.

Slide 36. Inhaled Insulin Safety Profile: Chest Discomfort
Chest discomfort is a vaguely described group of symptoms that patients often report when they have taken inhaled insulin, with about 5% incidence in the trials. Most of the patients classified it as either mild or moderate. There were few patients who discontinued therapy because of this particular sensation, and there was not any increase in reported ischemic cardiac adverse events in the inhaled insulin group.

Slide 37. Inhaled Insulin Safety Profile: Cough
Cough was another symptom that occurred with enough frequency to draw attention. It tends to occur early, soon after the insulin is inhaled, is characterized as relatively mild, and is associated with some but relatively modest sputum production. There was a tendency for patients to develop some tolerance to this symptom. Overall, in the clinical trials, slightly over 1% of patients discontinued specifically because of the cough.

Slide 38. Pulmonary Studies Summary
The reasons for paying attention to pulmonary safety with an inhaled drug are obvious. It will be chronically administered, is a growth-promoting factor, and can stimulate immune responses, systemically and locally. Therefore, it is important to pay attention to patients receiving inhaled insulin and to symptoms that may develop.

Pulmonary studies generally have shown a small decline in some aspects of pulmonary function. It is usually recommended to do a pulmonary function test both before and 6 months after you start the inhaled insulin. If a decline from baseline of over 20% in any pulmonary function test is seen, the dose of inhaled insulin should be decreased or the drug discontinued altogether. No anatomic findings were noted on computed tomography scanning.

Slide 39. Type 1 DM: Intensive Insulin Therapy
These data represent pulmonary function tests in patients on inhaled vs subcutaneous insulin. In this study of these specific parameters of pulmonary function over a 6-month period, no major change was noted.

Slide 40. Acceptance of Insulin Therapy: Inhaled Insulin vs Injected Insulin
Patient acceptance of inhaled insulin is very good, since most patients who gravitate towards this modality do so because they do not like self-administered injection. It has been well received in those studies that have addressed this issue.

2007-10-09 20:06

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• 浙一咋了？？爆炸了？？？

shaoyxu

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Hard to deny,it's a long passage,but I'm prond of finining translating it,although I admit I'm nearly in the peak of endurance.

Insulin Therapy of Diabetes: Pathophysiology and Indications
糖尿病的胰岛素治疗：病理生理学和适应症

Patients With Diabetes Are Not Reaching Treatment Goals
糖尿病患者治疗还没有达标
We have a fairly generous toolbox of therapies for the treatment of patients with diabetes, and I will discuss the ways we can apply these therapeutic tools.
我们有大量的方法来治疗糖尿病患者，我将来讨论这些我们能运用的治疗工具。

We have all heard about the explosion in the prevalence of diabetes; and frequently the term "epidemic" is used in this context. Currently, about 10% of adults in the United States have diabetes; that is, about 20 million people. Nearly a third do not know they have diabetes; that is a lot of people, but it is better than it was about 10 years ago when it was 50%.
我们都已听说糖尿病患者流行的情况，在这个方面我们运用更多的是“流行病”这个词。当前，美国约10%的成年人都有糖尿病，也就是说大概有2千万的糖尿病患者。且将近有三分之一的患者并不知道他们有糖尿病，这是其中的一部分患者，不过现在这种情况总比10年前要好，因为那时将近有50%的患者不知道。

In addition, and perhaps a little bit more alarmingly, is the fact that there are 2 to 3 times that number of people who have what is now called prediabetes; they either have impaired fasting glucose or impaired glucose tolerance. This category is very important because these individuals have a 40-fold likelihood of making the transition from prediabetes to actual type 2 diabetes. Although their vascular risk is not quite as high as in DM2, the increase in macrovascular disease in these individuals is substantial.
此外，或许要有更多提醒的是，有2-3倍那种数量的人患有现在我们称之为的疾病“糖尿病前期”，他们为空腹血糖受损或糖耐量受损。这个分类非常重要，因为这些患者有40%的可能从“糖尿病前期”转变为实际的“2型糖尿病”。尽管他们的心血管危险并没有2型糖尿病那么高，但本质上有微血管病变的危险。

In addition, not all of those with prediabetes actually make the move to DM2, so attention is being drawn to this category as a legitimate treatment target. Consequently, about 1 out of every 3 adults in the US has either diabetes or prediabetes, which is a substantial number of people--70 or 80 million.
此外，并非所有糖尿病前期患者以后都会转为2型糖尿病，故要关注这种分类，给予正确的治疗。所以，每3个美国人就会有一个人是糖尿病或者糖尿病前期，这是个很大的人群，约有七八千万。

Slide 1. Glucose Tolerance Categories
幻灯1.糖耐量分类

When talking about the prediabetic state, make sure you are familiar with these glucose criteria: Normal (normoglycemia) is fasting blood glucose of less than 100 mg/dL, and diabetes is diagnosed at levels of 126 mg/dL or above. Two-hour postprandial glucose of 140 mg/dL or less is normal and a postprandial glucose of 200 mg/dL or over constitutes diabetes. Between these parameters are the categories of either impaired fasting glucose or impaired glucose tolerance. Prediabetes is no longer a descriptive term; it actually applies to a category of individuals who have blood glucose levels that fall within certain clearly defined parameters.
谈及糖尿病前期状态，相信你肯定会对那些血糖标准很熟悉：正常空腹血糖不超过100mg/dL,超过126mg/dL即诊断糖尿病。正常餐后2h血糖不超过140mg/dL,餐后血糖超过200mg/dL诊断糖尿病。血糖在这些参数间时诊断空腹血糖受损或糖耐量受损。糖尿病前期不再是个描述性的名词，它实际上是指患者的一种分类，即那些血糖水平在明确诊断的参数之间的一个状态。

Slide 2. 63% of Patients With Diabetes Are Not at ADA A1C Goal <7%
幻灯2：63%的糖尿病患者糖化血红蛋白都没有控制到7%以下

Given the fact that we know all of this, it is surprising that we have not been able to make better penetration in terms of control of diabetes. This is information from the National Health and Nutrition Examination Survey (NHANES), which is a large, government-sponsored, population-based epidemiologic study that examined many conditions, including diabetes. This study tells us that only 37% of individuals with diabetes in the study population had hemoglobin A1C levels of less than 7%, which means that the other two thirds are above that fairly conservative American Diabetes Association (ADA) goal.
根据已知的情况，很吃惊我们还不能更好的研究糖尿病的控制。这个消息来源于国际健康和营养研究调查，这是个巨大的、由政府发起的、基于大样本的关于许多情况包括糖尿病的流行病学研究。研究告诉我们，样本中只有37%的糖尿病个体糖化血红蛋白水平在7%以下，这意味着其它近2/3的人群血糖控制高于美国糖尿病协会建议的这个保守的目标。

If you include other macrovascular risk factors that we are supposed to be controlling, only about 7% of adults with diabetes have an A1C less than 7%, blood pressure less than 130/80 mm Hg, and total cholesterol less than 200 mg/dL. This represents a substantial opportunity for improvement.
如果你考虑了其它我们要控制的微血管危险因素，那只有7%的糖尿病成年人糖化血红蛋白水平低于7%、血压低于130/80mm Hg,同时胆固醇低于200mg/dL。这本质上也反映了治疗有提升的可能。

Pathogenesis and Etiology of Type 1 and 2 Diabetes
1型和2型糖尿病的发病原因和病因学

Slide 3. Pathogenesis of Type 1 Diabetes
幻灯3：1型糖尿病的发病原因

The vast majority of diabetes is type 2 diabetes, but about 5% to 10% of individuals have type 1 diabetes. This is a complex condition of absolute insulin deficiency focused around immune dysregulation, immune disorders, in which autoantibodies are directed at various surface components of the beta cell, leading to diabetes. We used to think of it as childhood diabetes and as an explosive condition. But we know now, based on our ability to track autoantibodies and various circulating chemical markers, that there is a preamble to type 1 diabetes. Perhaps in the future we will be able to intervene before the beta-cell mass is decreased to the point where there is no insulin being produced.
绝大部分糖尿病为2型，而只有大概5%到10%的患者为1型糖尿病。1型糖尿病是胰岛素绝对缺乏的一个复杂的情况，涉及到免疫缺陷和免疫紊乱，1型糖尿病的患者自身抗体直接在β细胞各组分的表面，从而导致了糖尿病的产生。我们过去认为它是种儿童型和爆发性糖尿病，现在通过对自身抗体的追踪及各种化学标志物的应用，我们知道1型糖尿病前有一个前期过程。或许在将来我们就能在β细胞量减少到不能产生胰岛素之前去干预。

The hallmark of type 1 diabetes from a clinical point of view is that these individuals cannot make any insulin, and therefore are wdependent on external insulin for survival.
从临床观点来看，1型糖尿病的特性就是，患者不能产生胰岛素，从而依赖于外源性胰岛素替代。

Of the 95% of people with type 2 diabetes, a substantial number will eventually need insulin therapy to control their blood glucose. However, they are not absolutely insulin-deficient, meaning they do make insulin, in some cases a substantial amount. But it is not enough to overcome their insulin resistance. Although they may require insulin, they are not dependent on insulin for survival; that is a critical differential between the pathogenesis of those two conditions.
约95%的很大数量的2型糖尿病患者会逐渐需要胰岛素治疗来控制血糖。然而，他们并不是完全的胰岛素缺陷，这意味着他们能产生胰岛素，某些情况下还能产生大量的胰岛素。不过这并不足以克服胰岛素抵抗现象。尽管他们可能需要胰岛素，但并不完全依赖。这是这两种状态病因学的关键不同之处。

Slide 4. Natural Development of Type 2 Diabetes and CV Risk
幻灯4：2型糖尿病的自然病程和心血管危险

In type 2 diabetes, the underpinning of its pathophysiology, insulin resistance, present in almost every individual with type 2 diabetes, starts early. By the time we diagnose diabetes, insulin resistance is essentially at or almost at a peak, and stays at that level for the rest of that patient's life unless we include a strategy in our therapy to reduce insulin resistance.
2型糖尿病的病理生理支柱，即胰岛素抵抗，存在于几乎所有的患者身上，而且很早就开始。到我们诊断糖尿病时，胰岛素抵抗本质上已经在或接近于顶峰了，并且会以后一直维持在此水平，除非我们采取一些措施来减少胰岛素抵抗。

If you are a person with insulin resistance, meaning you are one of 70 to 80 million people, your response should be to make more insulin, to mount a compensatory hyperinsulinemia. And if you are an individual who has insulin resistance and you can make unlimited amounts of insulin, your blood glucose will remain normal. But if you are in that approximately 25% of insulin-resistant individuals who cannot continue to make insulin in unlimited amounts, your beta cells die, and as they fail, insulin levels will go down, followed by rises in postprandial and then fasting blood glucose. At that point, we will diagnose prediabetes or type 2 diabetes.
如果你是位胰岛素抵抗患者，也就是七千万到八千万患者中的一个，你就会需要更多的胰岛素，从而造成代偿性的高胰岛素血症。如果你是位胰岛素抵抗患者但能由机体产生不限量的胰岛素，那么你的血糖就能维持在正常水平。不过如果你是那近25%的胰岛素抵抗但机体并不能产生足够量胰岛素的患者中的一个，你的β细胞衰竭，伴随着胰岛素水平的下降，餐后和空腹血糖升高。那种情况下，我们诊断为“糖尿病前期”或“2型糖尿病”。

You can extract a number of things from diagrams such as this. One is that if you were able to raise the insulin level -- for example, you gave an insulin secretagogue, (e.g., a sulfonylurea) or insulin itself -- you might be able to lower or even normalize the blood glucose, but you still would not have done very much to reduce the insulin resistance. That is important, because the general feeling is that most of the macrovascular risk factors that we see clustered in these individuals are related to the insulin resistance and not necessarily to the hyperglycemia, per se.
你能从这个图表中提取很多东西。一是如果你能提高胰岛素水平，比如给予促分泌素（如磺脲类）或者直接给胰岛素，你就能使血糖降低或正常，不过这还是不能减少胰岛素抵抗现象。这点很重要，因为一般的感觉是我们认为的大部分心血管疾病危险因素都跟胰岛素抵抗有关，而跟高血糖症没有必要关系。

Secondly, there is a lot going on before the diagnosis of DM2 is made. Insulin resistance has increased, and parallel to this increase is the development of macrovascular disease, which may start well before a patient is diagnosed with type 2 diabetes. The goal, then, is to intervene in the natural history of these patients much earlier, when their beta-cell mass is more substantial, because it is always easier to prevent things from happening than it is to try to reverse them after they have happened.
第二，在诊断2型糖尿病之前还有很多事要做。胰岛素抵抗增加，伴行的是心血管疾病的增加，而这种情况在患者诊断2型糖尿病之前就已经发生。然后我们的目标就是在这些患者还有大量β细胞更早之前就去干预自然病程，因为这比胰岛素抵抗发生后才来逆转更容易阻止其发生。

Slide 5. Beta-Cell Function in Type 2 Diabetes
幻灯5：2型糖尿病β细胞的功能

Beta-cell function is the discriminating feature of people with diabetes; it is what determines blood glucose levels, because insulin resistance is at or near maximal by the time we diagnose diabetes. Consequently, the degree of dysglycemia is predominantly related to beta-cell function, and this starts to decline well before we diagnosis type 2 diabetes, possibly as long as 10 years prior to diagnosis. This is another good argument for getting involved earlier in the natural history of this condition.
β细胞功能是糖尿病患者特征性的特点，它决定了血糖的水平，因为胰岛素抵抗是在或接近我们诊断糖尿病时最大化。结果是高血糖的水平主要还是跟β细胞功能有关，这种联系在我们诊断2型糖尿病之前就开始变小，可能在诊断10年之前。这是另一个关于更早的介入糖尿病自然病程的争论点。

The beta cell, the insulin producer, is subject to a number of factors that can lead to progressive malfunction. Hyperglycemia itself creates glucose toxicity: If blood glucose is high, this elevation in and of itself will impair insulin production and secretion, and also will increase insulin resistance. Conversely, when you lower blood glucose by any means, you may overcome some of the associated glucose toxicity and improve beta-cell function.
β细胞作为产生胰岛素的组织跟导致机体故障的各种因素都有关。高血糖症本身会产生高血糖毒性。如果血糖高，这种升高介入的或其本身就会损伤胰岛素的产生和分泌，同样会产生胰岛素抵抗。相反地，通过各种方式降低血糖就会克服许多相关的血糖毒性和提高β细胞功能。

There also is a lipotoxicity. Insulin is an antilipolytic hormone; it keeps fatty acids in fat cells. But when you do not produce enough insulin or when there is insulin resistance, there is less insulin action. Free fatty acids, as well as other chemical products, flow from adipose tissue, accumulating in and affecting the function of the beta cell. We are even beginning to think of the beta cell as possibly being an insulin-sensitive tissue; at the very least, it seems to be a victim of the systemic chemical environment that accompanies insulin resistance. Therefore, strategies that lower insulin resistance may also improve beta-cell function. This is a very complex set of events, but it also presents multiple treatment targets as well.
这里同样有个亲脂性的问题，胰岛素是一个亲脂激素，维持脂肪细胞中的脂肪酸。不过当不能产生足够的胰岛素或当有胰岛素抵抗，就不会有足够的胰岛素效应。同其它化学产物一样，游离脂肪酸流动在脂肪组织种，聚集并影响β细胞功能。我们甚至开始思考β细胞有可能是一种胰岛素敏感组织，至少它看起来是伴随胰岛素抵抗的机体化学环境的受害者。因此，减少胰岛素抵抗的策略同样也能提高β细胞功能。这是一系列非常复杂的事件，同样也能给我们提供多样的治疗目标。

Slide 6. Glucose Toxicity: Improvement of Insulin Secretion
幻灯6：高血糖的毒性作用：刺激胰岛素分泌

These data demonstrate glucose toxicity. If one tracks plasma glucose and plasma insulin, if you lower blood glucose (for example by giving insulin), you can improve insulin release. For example, if you have a patient who presents with a blood glucose level of 400 or 500 mg/dL, and you give that patient insulin at the beginning of their therapy and lower his or her blood glucose to normal, you may actually improve insulin production. Therefore, in some patients, the early administration of insulin may prevent the use of more complex regimens, or insulin altogether, at a later time.
这些资料阐明了高血糖的毒性作用。如果追踪血糖和血胰岛素水平，如果降低了血糖（例如给予胰岛素注射），就会发现胰岛素释放增加。举例说明，如果如果一位血糖水平在400-500mg/dL的患者一开始就给予胰岛素治疗来降低血糖至正常，会发现实际上他/她的胰岛素生成会增加。因此，某些患者的早期胰岛素管理会在以后阻止更多复杂生活方式的建议或者联合胰岛素治疗的使用。

Slide 7. Etiology of Type 2 Diabetes: Insulin Resistance and Diminished Insulin Secretion
幻灯7：2型糖尿病病因学：胰岛素抵抗和胰岛素分泌减少

Insulin resistance occurs partially because of genetic predisposition (represented by double helix icon). Additionally, there are lifestyle issues -- eating too much, weighing too much, and not getting enough exercise -- represented by the fast food burger and fries. In that situation, if you can produce unlimited amounts of insulin, blood glucose will remain normal, but you may still have the metabolic syndrome, a cluster of risk factors related to insulin resistance. If you are in the 25% of people who cannot make enough insulin, your blood glucose will go up and you will be somebody with type 2 diabetes as part of your metabolic syndrome.
胰岛素抵抗发生部分是因为基因水平上的易感体质（表现为双螺旋）。此外，还可因为不良的生活方式-多食、超重、缺乏锻炼-比如进食速食汉堡和油炸食品。那种情况下，如果机体能产生足够的胰岛素，血糖会维持正常，不过机体虽仍有这种新陈代谢的激素，但各种那个危险因子会导致胰岛素抵抗。如果是那些不能产生足够胰岛素的25%的患者，那血糖就会升高，最终某天成为2型糖尿病患者。

Slide 8. Elevated FFAs May Play a Key Role in Insulin Resistance
幻灯8：升高的游离脂肪酸在胰岛素抵抗中可能起到关键的作用

I would like to underscore the importance of free fatty acids. When released from adipose tissue, they end up in a number of tissues critical to the insulin resistant and dysglycemic state. In the liver, the net effect is to antagonize insulin action. We see less glucose staying in the liver and more gluconeogenesis and glycogenolysis, contributing to both fasting and postprandial hyperglycemia. But a large contribution to hyperglycemia comes from free fatty acids being deposited in muscle, since over 80% of glucose is taken up in muscle tissue. Free fatty acids can end up in the beta cell as well, where again there are structural and functional impairments of insulin synthesis and insulin release due to the lipotoxic part of beta-cell dysfunction.
我想强调游离脂肪酸的重要性。当其从脂肪组织中释放，它们进入各种组织，并决定胰岛素抵抗和血糖代谢障碍。肝脏的网状效应会对抗胰岛素效应。我们看到少量的糖原停留在肝脏，大量的糖基生成和肝糖分解，影响空腹和餐后高血糖。不过高血糖更多来源于肌肉组织中的游离脂肪酸，因为80%的糖原是在肌肉组织中被吸收。游离脂肪酸同样也能终止于β细胞组织，那里因为部分β细胞的障碍会有胰岛素合成和释放的损伤。

Insulin Physiology: Normal and Diabetic States
胰岛素生理学：正常和糖尿病状态

Slide 9. Physiologic Insulin Secretion: 24-hour Profile
幻灯9：胰岛素生理学分泌：24h模式

The objective of insulin therapy is to recreate normal physiology. In the basal fasting state, blood glucose stays fairly constant. The level of insulin is low, but a basal amount is always present. Superimposed on the basal level will be bursts or spikes (sometimes referred to as a bolus) of insulin being released periodically into the circulatory system, to assimilate the carbohydrates that we have ingested. This concept of basal and bolus insulin as found in normal physiology is the platform upon which our insulin strategies are based.
胰岛素治疗的目的是为了重建胰岛素正常的生理学。在基本的空腹状态，血糖是一个连续的情况。胰岛素水平低下，不过基本量还是存在的。为了配合我们摄取的碳水化合物，基于基础水平的胰岛素（有时我们看作大量来参考）有层次的阶段性的释放到循环系统。这个关于基础和分泌胰岛素的概念是我们胰岛素治疗依靠的平台。

Slide 10. Fasting Plasma Glucose and the Acute Insulin Response
幻灯10：快速血糖和急性胰岛素应答

When people develop diabetes, they always produce insufficient amounts of insulin relative to the level of blood glucose and insulin resistance that exists. Type 1 diabetes patients have no insulin at all and type 2 diabetes patients have some insulin, but less than they need to keep their blood glucose levels normal. Shown here on the y-axis is insulin response as a percentage increase from baseline for groups of patients who have varying degrees of impaired glucose tolerance and a varying severity of diabetes.
当患者发展到糖尿病，他们一般不能产生足够量的胰岛素，相对于自身存在的血糖水平和胰岛素抵抗来说。1型糖尿病一点不能产生胰岛素，2型糖尿病能产生一些胰岛素，不过远不足于维持血糖于正常水平。这儿显示的，Y轴是胰岛素应答，一个百分比值相对于不同的糖耐量受损患者和严重糖尿病患者。

What you see is more than an overall decrease in insulin production. The first thing to disappear is the "first-phase" or acute insulin response, during which nondiabetic individuals may have as much as an 8-fold increase in insulin production over the basal level. By the time you reach a fasting blood glucose in the highest range, there is practically no acute insulin response. When we construct insulin therapies, short-acting insulins best mimic this phase of insulin release.
你看到的不仅仅是所有的胰岛素生成增加。糖尿病患者第一个消失的就是首相或急性胰岛素应答，而非糖尿病患者相对基线有大约8倍的胰岛素生成。特别当到达快速血糖最高点，此时没有急性胰岛素应答。所以当我们指定胰岛素治疗方案式，最好用短效胰岛素来模拟这一胰岛素释放现象。

Understanding A1C
理解糖化血红蛋白

Slide 11. Glucose Factors Contributing to A1C
幻灯11：影响糖化血红蛋白的血糖因素

Hemoglobin A1C, which is the surrogate for mean integrated average blood glucose over a period of roughly 8 to 12 weeks, may represent many factors. Glucose is released by the liver to prevent hypoglycemia when not eating overnight. When there is decreased insulin activity, this process is dysregulated and you release too much blood glucose.
糖化血红蛋白，代表前一段近8-12周的平均血糖水平，有很多的影响因素。当夜间不进食时，糖由肝脏释放来阻止低血糖，当有升高的胰岛素活动时，这一过程失调，机体释放过多血糖。

We also have a number of factors that not only contribute to fasting glucose, but also contribute to postprandial glucose, including insulin secretory capacity, how much glucose is ingested, and the sensitivity of the tissues to insulin. It is, then, a complex set of factors and regulators that contribute to the overall glycemic burden.
我们也有一些因素不仅影响空腹血糖，而且影响餐后血糖。这包括胰岛素分泌能力，摄入多少糖，和组织对胰岛素的敏感性。然后，这是个复杂的因素和调节问题。

Slide 12. Lower A1C Reduces Incidence of Complications
幻灯12：降低糖化血红蛋白减少并发症的发生率

We know that lowering A1C reduces complications. This is particularly true for microvascular complications, such as retinopathy or nephropathy, but also true, to perhaps a less robust degree, for macrovascular disease.
我们都知道降低A1C能减少并发症。这特别正确尤其对微血管并发症，比如视网膜病变和肾病。对大血管病变也正确，不过并没有那么明显。

A number of studies have demonstrated this protection. The sentinel study for type 1 diabetes is the Diabetes Control and Complications Trial (DCCT), which included type 1 patients who were getting either conventional insulin therapy or an intensified insulin regimen of multiple doses per day, with A1C targets that were more aggressive.
一些研究阐明了这种保护。这种1型糖尿病的前哨研究有糖尿病控制和并发症实验（DCCT），这里面有接受常规胰岛素治疗的1型糖尿病患者和每天多种剂型的糖尿病强化治疗的1型糖尿病患者，他们的A1C目标更严格。

In that study there were substantial reductions in all of the vascular parameters that were followed.
研究发现在所有观察的心血管参数方面有本质的减少。

This same intensive insulin strategy was applied to type 2 patients in the Kumamoto study, and similar results were seen.
在Kumanmoto的研究种，同样强化胰岛素策略也运用于2型糖尿病患者身上，并得到了相似的结果。

In another study of type 2 patients receiving not only insulin but also metformin (the United Kingdom Prospective Diabetes Study or UKPDS), diet and exercise, or a sulfonylurea, the same principle was reinforced; lowering A1C reduces the incidence of complications. To whatever degree that you can reduce A1C, whether it is 1% or 2%, or taking a patient from 10% to 9%, or 9% to 8%, you will convey a protective effect to their tissues.
在关于2型糖尿病的另一个研究种，患者不仅接受了胰岛素，而且也给予了二甲双胍，饮食和运动疗法，或磺脲类，给予同样的补充方式，降低A1C能减少并发症的发生率。不过哪种你要减少的A1C水平，不管是减少1%还是2%，或者有的患者从10%到9%，或从9%-8%，都能起到对组织的保护作用。

Slide 13. DCCT: Relationship of A1C to Risk of Microvascular Complications
幻灯13：DCCT:糖化血红蛋白和微血管并发症危险性的关系

This is another analysis of data from the DCCT, which examines individual complications: retinopathy, nephropathy, neuropathy, and microalbuminuria. All of these would be considered microvascular complications, which are very tightly linked to blood glucose. Macrovascular disease is more complex because we have many other risk factors such as lipids and hypertension that are contributing to the macrovascular disease.
这是DCCT里另一组分析数据，研究了患者并发症情况：视网膜病变，肾病，神经病变和微量蛋白尿。所有这些都考虑微血管并发症，跟血糖水平紧密相连。大血管病变更复杂，因为我们有其它的危险因子，比如脂质和高血压，跟大血管病变有关。

As shown, no matter what the complication, there is a significant relationship between A1C and the relative risk of developing that complication. The higher the A1C, the more the complications or, conversely, the lower the A1C, the less the complications.
如视，不管什么并发症，都跟A1C和其相对影响因子有显著关系。A1C越高，并发症越多；相反，A1C越低，并发症越少。

Slide 14. Schematic Course of DCCT/EDIC: Intensive and Conventional Groups
幻灯14：DCCT/EDIC图解：强化组和常规组

The DCCT investigators did something that was interesting. The original trial duration was 7 years. Patients were either given a conventional type of insulin regimen, perhaps 2 shots per day, or an intensive regimen where patients might get multiple subcutaneous injections and received very intensive management with a high ratio of healthcare personnel to patients. This intensive group had lower A1Cs during the study period.

After these DCCT results were published, the investigators followed patients for another several years. Not surprisingly, when the intensity of management was relaxed, A1Cs rose. In addition, during this period of time, the notion of being more aggressive about insulin therapy took hold in the medical community, and those patients who had initially received "conventional" therapy were actually getting a little bit better therapy than previously, and the two groups met in the middle in terms of A1Cs.

The investigators also tracked complications during this extended observation period. Patients who received conventional therapy at the beginning had a progressive increase in microvascular complications, whereas patients who had the initial intensive care were able to maintain their advantage in terms of reduced rates of retinopathy, nephropathy, and neuropathy. Note that the rate of complications between groups is not parallel; complications increased as A1C went up, but not as much in the intensive therapy group during this extended period of time, as in the conventional therapy group. So it appeared that there was some memory from the period of intensive control. These same trends were also shown for macrovascular disease.

Slide 15. UKPDS Epidemiologic Data in Type 2 Diabetes
幻灯15：UKPDS的2型糖尿病流行学资料

Data from the UKPDS for type 2 diabetes showed that a 1% reduction in mean A1C could result in the substantial percentage reduction shown for all of these various complication endpoints.
UKPDS的2型糖尿病资料显示，平均糖化血红蛋白1%的降低就能本质上减少所有各种心血管终点事件的发生率。

Slide 16. Aggressive Control of Diabetes: Goals of Treatment
幻灯16：糖尿病强化控制：治疗的目标

There is no single agreed-upon A1C target, but most people would agree that the goal is to get A1C to normal without exposing the patient to undue risks of hypoglycemia. Organizational goals are always consensus statements; for the ADA, the A1C goal is less than 7% and for the American College of Endocrinology, it is less than/equal to 6.5%. But both groups acknowledge the fact that if you can get patients to normal, you should do so.
这里不是关于糖化血红蛋白目标的简单个人意见，大多数专家都同意目标是让糖化血红蛋白达标的同时避免给患者带来更多的低血糖危险。这是专家们的共识。美国糖尿病协会推荐糖化血红蛋白水平低于7%，美国内分泌协会则建议低于/等于6.5%。不过两个组织都同意如果能够则应使患者糖化血红蛋白达标。

Patient Education and Monitoring
患者教育和监测

Slide 17. Education at Diabetes Diagnosis
幻灯17：糖尿病诊断的教育

We have a lot of therapeutic tools to offer patients. We have education. The role of Certified Diabetes Educators is inestimably important in terms of the breadth and depth of education they give in a number of areas, not only in disease education but education regarding various therapeutic modalities, explaining the nature of these therapies and getting patients involved in self-monitoring. Educators are able to devote the time and the skills necessary in terms of teaching patients about their diabetes
我们能提供给患者一些治疗性的方法。我们受过相应教育。有资格的糖尿病教育师的角色在于能在各种方面给予宽度和深度上的极重要的教育，不仅仅是疾病本身教育，还包括对待各种治疗形式的态度、解释治疗方法，和介入患者自我监测等的教育。教育师要能有足够的时间和技巧来教育患者糖尿病的知识。

Slide 18. Principles of Medical Nutrition Therapy
幻灯18：医学营养治疗的原则

Medical nutrition therapy forms a large part of this education, and there are a number of goals. Weight loss does not have to be overwhelming to reduce hyperglycemia or other macrovascular risk factors. A reduction of about 5% to 10% of body weight has substantial metabolic benefits. Patients are not always happy with a 5% weight loss; their goals are sometimes more cosmetic or social. But metabolically, even that amount of weight loss will be very beneficial.
医学营养治疗构成了糖尿病教育的一个很大的方面，有很多的目标。单纯的减轻体重远不能减少高血糖症或其他心血管危险因素，但体重减轻5%-10%本质上会有代谢的收益。患者并不一定会乐意于5%的体重减低，他们的目标有时候更华而不实或者受社会风气影响。不过，代谢角度看，即使一点的体重减轻也会有非常大的收益。

Slide 19. SMBG and Glycemic Control: The Northern California Kaiser Permanente Diabetes Registry
幻灯19:SMBG和高血糖控制：北加州凯撒永久糖尿病登记

Self-monitoring of blood glucose is equally important. Not many studies have looked at this, but this was a very good study from Kaiser Permanente Health System of roughly 24,000 patients. Patients who monitored blood glucose at home had better A1Cs; in type 1 patients, it was about 1% lower and in type 2 patients, it was about 0.6% lower. Individuals who practiced self-monitoring of blood glucose with any frequency had some statistically significant lowering of A1C. Working with patients to impart the meaning of their blood glucose can make this is a very useful technique.
血糖的自我监测同样重要。并非所有的研究都注意到这点，不过KPHS的关于严格24，000患者的研究就非常好。在家自我监测血糖的患者有更好的糖化血红蛋白水平，其中，1型糖尿病患者，A1C会相应低约1%，2型约0.6%。采用不同频率自我检测血糖的患者在降低A1C方面有统计学上的差异。

Slide 20. Glucose Monitoring Patterns for Insulin-Treated Patients
幻灯20 胰岛素治疗患者的自我血糖监测模式

There are many different patterns for testing blood glucose. Patients can do "block testing" once or twice daily. If they do it once daily, sometimes we will tell them to do fasting glucose one day and postprandial the next day. Or we may rotate postprandial blood glucose in combination with fasting; a patient will be testing fasting glucose one day, 2 hours after breakfast the next day, 2 hours after lunch on the next day; and 2 hours after dinner on the next. Over a period of time you can develop a grid that yields good information while testing only once a day.
有许多的模式监测血糖，患者可以“区域检测”一天1到2次，如果能每天一次，有时我们会告诉患者第一天空腹血糖，第二天餐后血糖。或者我们改变同时测空腹和餐后血糖。患者会一天测空腹血糖，第二天测早餐后2小时，第三天测中餐后2小时，第四天测晚餐后2小时。过了这段时间，你就可以每天一次描出一个好的血糖表格。

There are more intensive ways of approaching this, such as having patients check their blood glucose 4 or more times daily. This can be used to determine patterns that will help adjust patient insulin programs.
有更严格的方式，比如让患者每天4次或更多的检测血糖。这用来帮助调整患者胰岛素治疗方案。

Slide 21. Monitoring: Patient Issues
幻灯21：监测：患者的原因

There are issues with self-monitoring. It causes pain in some patients more than others. Some patients do not have the manual or visual skills to be able to accomplish self-monitoring. There may be issues with cognitive function. We have to work with those patients, and the educators do a great job. There are also a number of different meters, which tend to work better for one type of patient than the other.
这些是自我监测的问题。在某些患者疼痛更常见。一些患者因为不能手动或视觉的技巧而不能完成自我监测。还可能有个认知功能的问题。我们必要同这些患者交流，这里教育师能起到很大的作用。还有一些其它的计量器，更适合某一类的患者。

Then we have the excuses that patients give us as to why they do not want to do testing, which do not have anything to do with physical issues. But they are, nonetheless, real-life issues, particularly the expense.
有的患者告诉我们他们不愿意检测，我们有理由相信这跟身体情况没有关系。不过那是真实的情况，特别是费用问题。

Oral Agents for Diabetes Treatment

Slide 22. Oral Antidiabetes Medication Monotherapy: Maximum Therapeutic Effect on A1C
幻灯22 口服抗糖尿病单一疗法：A1C的最大治疗效果
In terms of oral therapy, we have a number of tools. The medications we tend to use the most are the ones capable of conveying a 1% to 2% reduction in A1C, either as monotherapies or as add-on therapies. Remember that the degree of reduction in A1C is going to be conditioned by the A1C at which the patient starts treatment; the lower the A1C at baseline, the smaller the decrease in A1C that is likely to occur with the addition of a therapy. All of these medications are good as monotherapies or in combination, with the obvious exception of using 2 insulin secretagogues together or 2 thiazolidinediones (TZDs) together. But each class of drugs is effective as a mono- or combination therapy.
在口服治疗上，我们有一些药物可以选择。我们最常使用的药物能使A1C降低1%-2%，不管是单一用药还是加药联合方法。要知道A1C能降低的程度多取决于患者开始治疗的情况，A1C基线越低，治疗可能降低的越小。所有这些药物的治疗效果上，单一用药和联合用药效果一样好，除了同时联用2种胰岛素促泌剂或2种噻唑烷二酮（TZDs)类。不过不管单一还是联用治疗，每种药物都有效。

Slide 23. Most Current Therapies Do Not Control Glucose Long-term
幻灯23 大部分目前的治疗方法并不能长期良好控制血糖
During the early years of the UKPDS, all study arms were effective in lowering A1C, whether insulin, metformin, or a sulfonylurea was the treatment modality. But as time went on, there was a decline in glycemic control. Not surprisingly, this was associated with a decrease in beta-cell function. The implication is that most patients end up using combination therapy, similar to the way in which hypertension and dyslipidemia are treated.
UKPDS的前些年间，不管胰岛素、二甲双胍，还是磺脲类用药方式，所有的研究目的都在于降低A1C的有效性上。不过随着时间发展，人们发现血糖的控制效果下降了。不过并不奇怪，这都跟β细胞功能下降有关。这说明了大部分病人最后都会中止联合口服用药的治疗方式，就跟高血压和高血脂的治疗情况相似。

Numerically, the rise in A1C was about 0.2% to 0.3% per year despite being on a given monotherapy, and is much the same whether the result of diet failure, sulfonylurea failure, or metformin failure. All treatment groups experienced failure at more or less the same rate, and the decline in beta-cell function was also approximately the same for all of them. As such, combination therapy is routinely needed.
从数字上看，A1C每年会升高约0.2%到0.3%，尽管给予了单一治疗，而且不管是没能控制体重，还是用磺脲类和二甲双胍类失效，情况都一样。所有治疗组都多多少少同一水平上经历了失败，而且所有组β细胞功能的降低也有近似同样的情况。因此，通常这种情况需要联合用药。

In addition, if your patient has been on combination therapy (2 agents) that is inadequate, you could add a third oral agent, exenatide or insulin. A number of insulins are available: long-acting basal insulin; premixed insulin (70/30, 75/25); and prandial insulin coverage, the latter being short- or extremely short-acting insulins that target postprandial blood glucose.
此外，如果患者接受了不足量的联合治疗（2种药物），你还能加第三种口服药，或胰岛素。有很多胰岛素可以选择：长效胰岛素，预混胰岛素（70/30,75/25），和餐时胰岛素，后几种为短效或速效胰岛素，目的是控制餐后血糖。

Insulin Therapy for Diabetes
糖尿病的胰岛素治疗

Slide 24. Insulin Therapy of Type 2 Diabetes
幻灯24 2型糖尿病的胰岛素治疗

Insulin therapy is not the course of last resort. Many patients view it as the end of the road for their diabetes. Of course it is not that, it is just a tool for controlling blood glucose. But many patients have heard that their parents or their grandparents got insulin just before they died, their kidneys failed, or they had an amputation. Insulin is an appropriate therapy for any patients who have not reached targets by other means.
胰岛素治疗并不是上次治疗的求助。许多患者把它看成是他们糖尿病治疗之路的终点。显然并不是这样，它仅是另一种治疗方法。不过许多患者曾听过他们的父母或祖父母去世前用过胰岛素，他们有肾衰或截肢。胰岛素对任何那些用其它方法治疗效果不好的患者来说是一个合适的治疗方法。

I used to think that people did not like the idea of injections. But then I realized that injecting insulin is not as uncomfortable as self-glucose monitoring. Exenatide, which is an injectable administered twice a day, comes with the promise of weight loss, and suddenly it becomes very acceptable. Although there are occasional patients who are truly phobic, the fear of injections is not as widespread as we once thought it was.
我过去认为人们并不喜欢注射的方式。不过然后我意识到其实胰岛素注射作为自我血糖的监测并非那么不舒服。一天2次的注射方式能控制体重，突然变得可以接受。尽管有偶尔的患者实际上比较畏惧，但是我们曾认为对注射的担忧并非那么广泛。

Slide 25. Estimated Pharmacokinetics of Current Insulin Preparations
幻灯25 当前胰岛素制剂的药代动力学

What types of insulin are available? There are rapid-acting insulins that begin to work in about 15 minutes, and peak somewhere between 1 and 2 hours. Examples of such rapidly acting insulins are insulin lispro, insulin aspart, or insulin glulisine. These are very appealing insulin choices because they have a quick onset of action, and their peak action tends to coincide with the time that postprandial glucose levels are at their peak.
什么类型的胰岛素有效？有速效的胰岛素15分钟起效，1-2小时到达峰值。这种速效胰岛素有lispro，aspart和glulisine。这些胰岛素非常有吸引力因为他们起效快，到达峰值的时间刚好与餐后血糖高峰相一致。

In addition, we have inhaled insulin, which is also quick-acting. Regular insulin pharmacokinetics are similar to the rapid-acting insulins, but with some significant time course differences. There are also intermediate-acting insulins, such as neutral protamine Hagedorn (NPH), which has a peak 7 to 8 hours after you take it. The longer-acting analogs, such as insulin glargine or insulin detemir, are "24-hour" insulins.
此外，还有吸入胰岛素，同样起效快。常规胰岛素药代动力学与速效胰岛素相似，不过也有一些显著的时间差别。也有中效胰岛素，如中精胰岛素（NPH），用后7-8小时达到峰值。长效同类产品，如甘精胰岛素或地特胰岛素，都是药效24小时的胰岛素。

Slide 26. Action Profiles of Injectable Insulins
幻灯26：注射胰岛素作用模式

This schematic gives you the profiles for injectable insulin. The longer-acting insulins, such as glargine or detemir, are theoretically 24-hour insulins; they have a duration of action of about 24 hours, and they tend to mimic basal insulin levels.
此图标给你显示了注射胰岛素的模式。长效胰岛素如甘精胰岛素或地特胰岛素理论上都是24小时的胰岛素，药效能达24小时，并可以模仿基础胰岛素水平。

In terms of shorter-acting insulins, we have the rapid-acting ones, aspart, glulisine, or lispro, which have a fairly rapid peak of onset, but their effect is dissipated fairly quickly, in a few hours. The rapid dissipation of these insulins results in less hypoglycemia but also can leave a void in insulin activity in some patients between meals. NPH has a significantly longer profile.
在快速胰岛素方面，我们有速效的，门东胰岛素, glulisine, 或赖脯胰岛素，它们都有个比较快的起效峰值，不过药效衰减的也比较快，几小时之内。这些胰岛素的快速衰减导致更少的低血糖的发生，不过也给患者在两餐间留下胰岛素空白期。NPH有一个更长的模式。

Slide 27. Comparison of Insulin Formulations in Controlling Postprandial Glucose Levels
幻灯27 胰岛素组分在控制餐后血糖水平的对比

If one examines the glucose profiles over a period of 4 hours in nondiabetic controls and in individuals given either glucose and NPH, a mixture of 70% NPH/30% regular, or 75%/25%, (a mixture of an NPH-type insulin with a short-acting insulin, either lispro or aspart), the insulins that have a quicker onset tend to suppress the rise in postprandial glucose to a greater degree.
如果研究在非糖尿病患者和接受了血糖和NPH，预混胰岛素（70/30），或预混胰岛素（75/25）的血糖模式，某种程度上起效更快的胰岛素在控制餐后血糖方面效果更好。

Slide 28. Inhaled Insulin: A Rapid-Acting Insulin With Unique Pharmacodynamic Profile
幻灯28 吸入式胰岛素：独特药代动力学模式的速效胰岛素

Inhaled insulin fits in between the more rapid-acting insulins, in this case lispro or regular. In terms of the onset of action, it is rapid, close to the more rapid-acting insulin, but it is not gone quite as quickly, which is more like regular. So, to a certain extent, you get some of both when using the inhaled insulin.
吸入式胰岛素药代动力学在速效胰岛素（这里指赖脯胰岛素）和普通胰岛素之间。在起效上，吸入式胰岛素更快，接近于速效胰岛素，不过药效衰减并不快，这点像普通胰岛素。所以，在这个范围，当使用吸入式胰岛素可以起到这两种的部分效果。

Slide 29. Time to Peak Effect (Tmax)
幻灯29 到达峰值的时间（最大时间）

This is a more quantitative bar graph of the time to peak effect of these 3 insulins. And you can see, when viewed in this format, the inhaled insulin is more like the rapid-acting insulin, lispro, than it is like the regular insulin.
这是个3种胰岛素到达峰值时间对比的柱状图。你可以发现，吸入式胰岛素更接近速效胰岛素（赖脯胰岛素）。

Insulin Effects on A1C
胰岛素治疗在A1C上的效果

Slide 30. Type 1 Diabetes: Conventional Therapy
幻灯30 1型糖尿病：常规治疗

Many studies have compared the effect of inhaled insulin to subcutaneous insulin. This is a 6-month study in which type 1 diabetes patients either receive subcutaneous insulin or inhaled insulin as part of their program. As shown, there was essentially no difference in A1C at the end of 6 months between the two groups.

许多研究对比了吸入胰岛素和皮下胰岛素治疗的效果，这是一个6个月的研究，其中1型糖尿病患者给予皮下注射胰岛素或吸入胰岛素作为计划的一部分。如显示的，两组6个月后在A1C上没有本质的差别。

Slide 31. Type 2 DM: Conventional Insulin Therapy
幻灯31 2型糖尿病：常规胰岛素治疗
This is a study of type 2 diabetes patients being treated either with subcutaneous insulin or inhaled insulin. Again, at the end of 6 months, there is essentially no difference in A1Cs.
这个研究是对比2型糖尿病患者给予胰岛素皮下注射和吸入治疗的不过效果。6个月结束后，两组A1C再次没有本质差别。

Slide 32. Type 2 DM: Conventional Insulin Therapy
幻灯32 2型糖尿病：常规胰岛素治疗
If you compare inhaled insulin with subcutaneous insulin in terms of percentage of patients who reached some predetermined A1C goal, more of the patients on inhaled insulin got to a target of less than 7% than those on subcutaneous insulin.
如果按患者A1C达标水平的百分比来比较吸入胰岛素和皮下胰岛素，吸入胰岛素组比皮下组有更多的患者达到小于7%的目标。

Slide 33. Mealtime Inhaled Insulin in Patients With Type 2 Diabetes: Decrease in A1C
幻灯33 2型糖尿病餐时吸入胰岛素：A1C的降低

These data show decreases in A1C in patients who are being treated with combinations of oral agents, with inhaled insulin, or both. These patients all qualified for the study because they had been on combinations of an insulin sensitizer, either metformin or a TZD, plus a secretagogue such as a sulfonylurea. In those in whom no therapy change was made, there was no further decrease in A1C. In patients taken off the combination and started on inhaled insulin, an A1C decrease of 1.4% was seen. If left on oral agents and adding inhaled insulin, the largest decrease of 1.9% occurred.
这些资料显示了各个组患者的A1C降低情况，有口服药物组联合组、吸入胰岛素组和混合组。这些患者都符合研究的要求，因为他们都用了胰岛素增敏剂，不管是二甲双胍类还是TZD，加上胰岛素促泌剂如磺脲类。那些治疗没有改变的患者没有A1C的更多降低，而发现那些放弃口服药物联合治疗开始吸入胰岛素治疗的患者降低A1C 1.4%。如果留下口服药物并增加吸入胰岛素，则有1.9%的最大降低量。

Slide 34. Mealtime Inhaled Insulin in Patients With Type 2 Diabetes: Target A1C
幻灯34 2型糖尿病餐时吸入胰岛素：A1C目标

This study involved stratification according to the achievement of predetermined targets for A1C in that same group of patients, i.e., patients maintained on oral agents, switched to inhaled insulin, or combining the two. A larger percentage of patients reached a target of either less than 8% or less than 7% with the combination of inhaled insulin and oral agents.
研究将同一组患者按预设定目标的结果分成几类，如，维持口服药的患者，转用吸入胰岛素的患者，或混合治疗的患者。用吸入胰岛素和口服药物混合治疗的患者有更多比例达到治疗目标，不管是小于8%还是小于7%。

Safety With Inhaled Insulin: Adverse Events and Pulmonary Safety
吸入胰岛素的安全性：不良反应和肺部安全

Slide 36. Inhaled Insulin Safety Profile: Chest Discomfort
幻灯36 吸入胰岛素的安全问题：胸部不适

Chest discomfort is a vaguely described group of symptoms that patients often report when they have taken inhaled insulin, with about 5% incidence in the trials. Most of the patients classified it as either mild or moderate. There were few patients who discontinued therapy because of this particular sensation, and there was not any increase in reported ischemic cardiac adverse events in the inhaled insulin group.
当患者采用吸入式胰岛素治疗时，常常报告胸部不适感，这是个含糊描述的症状群，实验中约有5%的发生率。大部分患者把胸部不适归为轻度或中度。仅有很少量的患者因为这一特殊感觉而停止治疗，同时胰岛素吸入组各种心肌缺血事件并未增加。

Slide 37. Inhaled Insulin Safety Profile: Cough
幻灯37 吸入胰岛素的安全问题：咳嗽

Cough was another symptom that occurred with enough frequency to draw attention. It tends to occur early, soon after the insulin is inhaled, is characterized as relatively mild, and is associated with some but relatively modest sputum production. There was a tendency for patients to develop some tolerance to this symptom. Overall, in the clinical trials, slightly over 1% of patients discontinued specifically because of the cough.
咳嗽是又一个要引起注意的很常见的症状。它在胰岛素吸入后不久的早期容易发生，特征性的相对较温和，并伴随一些适量的痰液生成。患者有倾向能更容忍这种症状。总的来说，临床实验中，仅有少量超过1%的患者因为咳嗽而特意停止治疗。

Slide 38. Pulmonary Studies Summary
幻灯38 呼吸研究摘要

The reasons for paying attention to pulmonary safety with an inhaled drug are obvious. It will be chronically administered, is a growth-promoting factor, and can stimulate immune responses, systemically and locally. Therefore, it is important to pay attention to patients receiving inhaled insulin and to symptoms that may develop.
关注吸入药物呼吸安全的原因很明显。它会长期给药，是一个促进发育的因素，并能系统和局部地刺激免疫应答。因此，关注患者接受吸入胰岛素治疗和关注可能发展的症状很重要。

Pulmonary studies generally have shown a small decline in some aspects of pulmonary function. It is usually recommended to do a pulmonary function test both before and 6 months after you start the inhaled insulin. If a decline from baseline of over 20% in any pulmonary function test is seen, the dose of inhaled insulin should be decreased or the drug discontinued altogether. No anatomic findings were noted on computed tomography scanning.
呼吸研究通常显示肺功能在某些方面的降低。通常推荐在开始吸入胰岛素治疗之前和6月后个进行一次肺功能实验。如果发现在任何一次肺功实验中降低基线超过20%，那么吸入胰岛素的计量则应减少或完全停止。但在CT扫描上并没有发现解剖学改变。

Slide 39. Type 1 DM: Intensive Insulin Therapy
幻灯39 1型糖尿病：强化胰岛素治疗

These data represent pulmonary function tests in patients on inhaled vs subcutaneous insulin. In this study of these specific parameters of pulmonary function over a 6-month period, no major change was noted.
这些资料表示的是患者吸入式和皮下式胰岛素治疗对比的肺功实验结果。从这次研究中超过6个月的肺功特定参数看，没注明有较大改变。

Slide 40. Acceptance of Insulin Therapy: Inhaled Insulin vs Injected Insulin
幻灯40 胰岛素治疗的接受：吸入胰岛素vs注射胰岛素
Patient acceptance of inhaled insulin is very good, since most patients who gravitate towards this modality do so because they do not like self-administered injection. It has been well received in those studies that have addressed this issue.
患者如能接受吸入胰岛素最好，因为大部分患者并不喜欢自我给药的注射方式，而被这种模式吸引。那些发表的研究种吸入式被广泛接受。

2007-10-14 21:53