Diabetes Mellitus
内科学-糖尿病第7版
DM 定 义（三）
由遗传和环境因素等多种因素相互 作用所致的临床综合征。
1型糖尿病(T1DM) Type 1 Diabetes Mellitus
• 多基因遗传因素： 包括HLA基因和非HLA 基因，其中6号染色体短臂的HLA基因为主 效基因
• 易感基因只能赋予个体对该病的易感性，是否发病有赖于多个易感基 因共同参与及环境因素的影响。
糖化,多元醇通道活性增加等 • 遗传因素
慢性并发症大血管病变
• 全身性动脉粥样硬化 主动脉、冠状动脉……….冠心病 脑动脉…………缺血性或出血性脑血管病 肾动脉…………肾动脉硬化 肢体外周动脉…肢体动脉硬化
慢性并发症 大血管病变
• 2型糖尿病大血管疾病特点 • 动脉粥样硬化患病率高、发病年纪轻、病
• *LADA （Latent autoimmune diabetes in adult）：成年人、症状隐匿、体型偏瘦、 多年内不发生DKA，可保留残存的β细胞功 能、但胰岛功能逐渐减退，最终胰岛素分 泌绝对缺乏，需要胰岛素。
特发性1型糖尿病（1B型）
• 特发性 很少见 见于非洲及亚洲某些种族，遗传性状强 缺乏胰岛β细胞自身免疫依据
情进展快 • T2DM最主要的致死致残病因 致死病例数更多
慢性并发症
微血管病变（DM特有）
管径小于100微米,微循环障碍、微血管瘤形 成、基底膜增厚，是糖尿病微血管病变的典型改 变
糖尿病肾病（T1DM主要死亡原因） 糖尿病视网膜病变 其他(糖尿病心肌病等)
糖尿病肾病
• 病理：结节性肾小球硬化症（高度特异 性）；弥漫性肾小球硬化症（最常见，影 响最大）；渗出性病变
糖尿病
Diabetes Mellitus (DM)
温州医科大学第一临床医学院 内分泌科 朱虹
世界卫生组织1999年糖尿病诊断标准英文版
世界卫生组织1999年糖尿病诊断标准英文版The 1999 World Health Organization Diagnostic Criteria for Diabetes Mellitus。
Introduction:Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels. It is a global health concern, affecting millions of people worldwide. In order to diagnose diabetes accurately and consistently, the World Health Organization (WHO) established diagnostic criteria in 1999. These criteria provide healthcare professionals with guidelines to identify individuals with diabetes and ensure appropriate management and treatment. This article will discuss the 1999 WHO Diagnostic Criteria for Diabetes Mellitus.1. Fasting Plasma Glucose (FPG) Criteria:The FPG criteria are based on measuring blood glucose levels after an overnight fast. According to the 1999 WHO criteria, a fasting plasma glucose level equal to or higher than 7.0 mmol/L (126 mg/dL) indicates diabetes. This measurement should be confirmed by repeat testing on a different day, unless the individual presents with classic symptoms of hyperglycemia.2. Oral Glucose Tolerance Test (OGTT) Criteria:The OGTT involves ingesting a standard glucose solution, followed by measuring blood glucose levels after two hours. According to the 1999 WHO criteria, a plasma glucose level equal to or higher than 11.1 mmol/L (200 mg/dL) two hours after the glucose load indicates diabetes. Similar to FPG criteria, this measurement should also be confirmed by repeat testing on a different day, unless the individual presents with classic symptoms of hyperglycemia.3. Symptoms of Hyperglycemia:In addition to the FPG and OGTT criteria, the 1999 WHO Diagnostic Criteria also consider the presence of symptoms suggestive of hyperglycemia, such as excessive thirst,frequent urination, unexplained weight loss, and blurred vision. If an individual presents with these symptoms and a random plasma glucose level equal to or higher than 11.1 mmol/L (200 mg/dL), diabetes can be diagnosed without the need for repeat testing.4. Gestational Diabetes Mellitus (GDM):The 1999 WHO Diagnostic Criteria also include guidelines for diagnosing gestational diabetes mellitus. GDM is a condition characterized by high blood glucose levels during pregnancy. According to these criteria, GDM can be diagnosed if any of the following plasma glucose values are met: fasting plasma glucose equal to or higher than 7.0 mmol/L (126 mg/dL), one-hour plasma glucose equal to or higher than 10.0 mmol/L (180 mg/dL), or two-hour plasma glucose equal to or higher than 8.6 mmol/L (155 mg/dL) during an OGTT.Conclusion:The 1999 World Health Organization Diagnostic Criteria for Diabetes Mellitus provide healthcare professionals with standardized guidelines for diagnosing diabetes and gestational diabetes mellitus. These criteria take into account fasting plasma glucose levels, oral glucose tolerance test results, and the presence of symptoms suggestive of hyperglycemia. Accurate and timely diagnosis is crucial for effective management and treatment of diabetes, ultimately improving the quality of life for individuals affected by this chronic condition.。
利拉鲁肽的器官保护作用及研究进展
糖尿病（diabetes mellitus，DM）是由于胰岛素绝对或相对缺乏的代谢紊乱性疾病，可造成肾、脑、心等器官的慢行进行性退变。
目前，我国糖尿病患者已达1.14亿，居世界首位。
现阶段治疗方法主要是口服降糖药物或注射胰岛素。
胰高血样素肽-1（glucagon-likepetide-1，GLP-1）是一种内源性肠促胰岛素激素，可促进胰岛素的分泌。
利拉鲁肽是GLP-1类似物，能发挥类似GLP-1的作用。
近年来，大量研究发现利拉鲁肽在降低血糖的同时，对其他器官损伤也有保护作用，本文将对利拉鲁肽的脏器保护作用及其机制与研究进展做一综述，以供临床参阅与借鉴。
1脑损伤及利拉鲁肽对脑损伤的保护作用1.1与糖尿病相关的脑损伤贾贺[1]的研究发现，糖尿病对大鼠的神经系统有着进行性的损伤，如脑卒中、记忆力减退等。
在糖尿病发展的过程中，海马体自嗜相关分子如Beclin-1、LC3B、Atg9a等表达下调，氧化应激相关分子（IL-6、TNF-a、nNOS）表达增强，造成认知功能障碍[2-3]。
有研究报告指出[4]，高血糖脑损伤可能与氧化应激、线粒体功能障碍、乙酰胆碱酯酶活性紊乱、糖尿病性神经炎症、神经细胞凋亡、脑神经营养因子损伤、边缘-下丘脑-肾上腺-垂体轴失调等有关。
1.2利拉鲁肽对糖尿病脑损伤的保护作用研究发现利拉鲁肽对神经系统的保护作用独立于血糖改善作用[5]。
其主要机制是上调VEFG（促血管生长因子）和抑制氧化应激。
抗氧化应激方面，利拉鲁肽可利拉鲁肽的器官保护作用及研究进展黄俊颖1，管少迪1，伍虹燕1，尹颢霖1，罗涛1综述周军1，2审校1.西南医科大学麻醉学系（泸州646000）；2.西南医科大学附属医院麻醉科（泸州646000）【摘要】利拉鲁肽（LiraglutideInjection）是胰高血糖素样肽（GLP-1）类似物，主要用于控制成人2型糖尿病患者的血糖，若糖尿病患者单用二甲双胍或磺脲类药物治疗后血糖仍控制不佳，可考虑与利拉鲁肽联合应用控制。
糖尿病(diabetes mellitus,DM)(3)
一、1 型糖尿病和 2 型糖尿病的鉴别1型糖尿病和2型糖尿病的鉴别1型2型发病率<5% >75% 发病年龄多<30岁，LADA常可>30岁多>40岁起病方式多起病急骤，甚至以疾病酮症起病一般较缓慢而隐袭，有的以慢性并发症来就诊而被发现临床症状三多一少症状明显多较轻或无症状体重状况多消瘦体型80%超重或肥胖急性并发症酮症倾向老年人在诱因下易患非酮症高渗性糖尿病昏迷慢性并发症多以微血管病变为主以大血管并发症为主胰岛炎60%-90% 无胰岛素反应性敏感常有抵抗自身免疫指标CA病初80%阳性 GAD病初75%--90%阳性< 3%阳性阴性基础胰岛素水平IAA病初40%--50%阳性低于正常< 5%阳性可正常，轻度降低或高于正常胰岛素、C肽释放实验曲线低平升高幅度降低，高峰延迟遗传学改变与HLA 系统关联与HLA系统无关联，为多基因遗传同卵双生子同病率约50% 95%--100% 胰岛素治疗终身使用一般不需要，多在晚期或急慢性并发症时使用病情稳定性不稳定相对稳定二、肝脏疾病在正常情况下，进食后血中葡萄糖含量增加，但不超过 8.9mmol/L，这是由于通过肝脏迅速把葡萄糖转化为肝糖原并储存起来，从而使血糖不致过高。
空腹时，机体为保持血糖的稳定，肝糖原释放并转化为葡萄糖，从而使血糖不至于过低。
严重肝病患者导致肝功能低下，肝糖原合成减少，出现餐后高血糖，特点是在食后 1 小时左右出现血糖高峰，并超出正常高值，尿糖阳性，高峰后血糖迅速下降，一般 2～3 小时内恢复至空腹水平，当肝功能严重受损时，高血糖持续时间较长。
有些病人在空腹或餐后 3～5 个小时可有反应性低血糖，这是由于肝脏缺少足够的糖原储备，不能通过糖原异生转变为葡萄糖。
测定胰岛素或 C 肽释放试验基本正常，与血糖平行。
三、餐后糖尿胃大部切除患者及某些正常人如一次进食大量碳水化合物，由于小肠吸收速度太快，负荷过重，血糖浓度升高暂时超过肾糖阈值而发生尿糖阳性。
糖尿病教学课件
型 l胰腺外分泌病变 —— 炎症，肿瘤，手术及外伤，囊性纤维化，纤 维钙化，血色病 l内分泌疾病 —— 肢端肥大症，库欣综合症，胰高糖素瘤，嗜铬细 胞瘤，醛固酮瘤
糖尿病教学
其他特殊类型糖尿病
分 型
l药物或化学品 —— 烟酸，糖皮质激素，甲状腺激素，噻嗪类利尿 剂，β-肾上腺能拮抗剂， 苯妥英钠，干扰 素，二氮嗪等
发
DQA-52Arg（+），DQB-57Asp（-）
病 2、环境因素 病毒感染：柯萨奇，腮腺炎，风疹，巨细胞病毒等
机
制 化学毒性物质和饮食因素：链脲佐菌素、牛奶
糖尿病教学
1型糖尿病
病
因 3、自身免疫
与
1）体液免疫：
发
胰岛细胞抗体ICA
病
胰岛素抗体IAA
机
谷氨酸脱羧酶抗体GADA
制
蛋白质酪氨酸磷酸酶样蛋白抗体IA-2
北美
25.0 39.7 59%
中美 南美
10.4 19.7 88%
38.2
44.2 欧洲 16%
亚州
非洲
13.6 26.9 98%
中东
18.2 35.9 97%
World
2003 = 189 million
2025 = 324 million 增加 72％
81.8 156.1 91%
大洋洲 1.1 1.7 59%
糖尿病
Diabetes Mellitus（DM）
讲者：尹晓燕
糖尿病教学
1
内容
• 概述 • 分型 • 病因与发病机制 • 临床表现及并发症 • 诊断 • 治疗
糖尿病基础知识-英文
PhD Public Health, Suez Canal University, Egypt Diabetes MSc, Cardiff University, United Kingdom
Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.
Was previously called non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. Type 2 diabetes may account for about 90% to 95% of all diagnosed cases of diabetes. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Native Hawaiians or Other Pacific Islanders are at particularly high risk for type 2 diabetes.
糖尿病教学
病因、发病机制和自然史
目前普遍认为 1 型糖尿病的发生、发展可分为6个阶段
第1期—遗传学易感性 1型糖尿病 第2期—启动自身免疫反应 第3期—免疫学异常 第4期—进行性胰岛B细胞功能丧失 第5期—临床糖尿病 第6期 在 1 型糖尿病发病后数年，多数患者胰岛B细
胞完全破坏，胰岛素水平极低，失去对刺激物 的反应，糖尿病临床表现明显
糖尿病----1型糖尿病（三）
特发性1型糖尿病(idiopathic type 1 diabetes mellitus)
某些人种如美国黑种人及南亚印度人常见 常有糖尿病家族史 初发时可有酮症,需胰岛素治疗 起病后数月或数年可不需胰岛素治疗。 无自身免疫机制参与，胰岛B细胞自身抗体多 阴性。
非洲 1、7 百万 (2.5) 2、1千5百万 (3)
东南亚 1、3千9百万 (5.5) 2、8千2 百万 (7.5)
Diabetes Atlas committee. Diabetes Atlas, second edition. 2003
中国糖尿病患病率屡创新高
11.0%
10.0%
9.70% 7.40%
糖尿病----1型糖尿病（一）
免疫介导糖尿病
胰岛B细胞发生自身免疫反应性损伤引起 有HLA某些易感基因 ，DQA、DQB、DR基因 有胰岛B细胞自身抗体如GAD65；IA-2；ICA；IAA 可伴随其他自身免疫性疾病 B细胞破坏的程度很大的不同
婴儿和青少年破坏迅速，依赖胰岛素。 而成年人则缓慢即LADA
糖尿病----概述
糖尿病本身已经让我们付出沉重的代价 … ，而且, 流行性日益加剧， 在全球的危胁日益加剧… … 糖尿病患者* 糖尿病每年给全世界带来的影响 百万人 全球 举例*
DM
DIABETES MELLITUSDiabetes mellitus (DM) is a group of clinical syndrome characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. CLINICAL MANIFESTATIONSymptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia. Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis （DKA）or the nonketotic hyperosmolar syndrome(NKHS). Long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes.DIAGNOSTIC CRITERIA FOR DIABETES MELLITUSThe criteria for the diagnosis of diabetes are shown in Table 1. Three ways to diagnose diabetes are possible, and each, in the absence of unequivocal hyperglycemia, must be confirmed, on a subsequent day, by any one of the three methods given in Table 1. The use of the hemoglobin A1c(A1C) for the diagnosis of diabetes is not recommended at this time.Table 1—Criteria for the diagnosis of diabetes mellitus1. Symptoms of diabetes （polyuria, polydipsia, and unexplained weight loss）plus casual plasma glucose concentration≥200 mg/dl (11.1 mmol/ l). Casual is defined as any time of day without regard to time since last meal.OR2. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.OR3. 2-h postload glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use.Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) recognized an intermediate group of subjects whose glucose levels, although not meeting criteria for diabetes, are nevertheless too high to be considered normal. This group is defined as having fasting plasma glucose (FPG) levels ≥100 mg/dl (5.6 mmol/l) but <126 mg/dl (7.0mmol/l) or 2-h values in the oral glucose tolerance test (OGTT) of≥140 mg/dl (7.8 mmol/l) but<200 mg/dl (11.1 mmol/l).PATHOGENESIS OF DIABETES MELLITUSThe pathogenesis of DM is not yet clear. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the β-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycemia.The degree of hyperglycemia may change over time, depending on the extent of the underlying disease process(figure 1). A disease process may be present but may not have progressed far enough to cause hyperglycemia. The same disease process can cause impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without fulfilling the criteria for the diagnosis of diabetes. In some individuals with diabetes, adequate glycemic control can be achieved with weight reduction, exercise, and/or oral glucoselowering agents. These individuals therefore do not require insulin. Other individuals who have some residual insulin secretion but require exogenous insulin for adequate glycemic control can survive without it. Individuals with extensive β-cell destruction and therefore no residual insulin secretion require insulin for survival. The severity of the metabolic abnormality can progress, regress, or stay the same. Thus, the degree of hyperglycemia reflects the severity of the underlying metabolic process and its treatment more than the nature of the process itself.Patients with IFG and/or IGT are now referred to as having ―pre-diabetes‖ indicating the relatively high risk for development of diabetes in these patients. In the absence of pregnancy, IFG and IGT are not clinical entities in their own right but rather risk factors for future diabetes as well as cardiovascular disease. They can be observed as intermediate stages in any of the disease processes.IFG and IGT are associated with the metabolic syndrome, which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-HDL type, and hypertension. It is worth mentioning that medical nutrition therapy aimed at producing 5–10% loss of body weight, exercise, and certain pharmacological agents have been variably demonstrated to prevent or delay the development of diabetes in people with IGT; the potential impact of such interventions to reduce cardiovascular risk has not been examined to date. Note that many individuals with IGT are euglycemic in their daily lives. Individuals with IFG or IGT may have normalor near normal glycated hemoglobin levels. Individuals with IGT often manifest hyperglycemia only when challenged with the oral glucose load used in the standardized OGTT.Figure 1—Disorders of glycemia: etiologic types and stages. Even after presenting in ketoacidosis, these patients can briefly return to normoglycemia without requiring continuous therapy (i.e., “honeymoon” remission); in rare instances, patients in these categories (e.g., Vacor toxicity, type1 diabetes presenting in pregnancy) may require insulin for survival.CLASSIFICATION OF DIABETES MELLITUS AND OTHER CATEGORIES OF GLUCOSE REGULATIONAssigning a type of diabetes to an individual often depends on the circumstances present at the time of diagnosis, and many diabetic individuals do not easily fit into a single class. Thus, for the clinician and patient, it is less important to label the particular type of diabetes than it is to understand the pathogenesis of the hyperglycemia and to treat it effectively.Type 1 diabetes The pathogenesis of this type is β-cell destruction, usually leading to absolute insulin deficiency. It has two subtypes: Immune-mediated diabetes and Idiopathic diabetes.Immune-mediated diabetes. This form of diabetes, which accounts for only 5–10% of those with diabetes, previously encompassed by the terms insulin-dependent diabetes, type I diabetes, or juvenile- onset diabetes, results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas. Markers of the immune destruction of theβ-cell include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β. Also,the disease has strong HLA associations, with linkage to the DQA and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective.Autoimmune destruction of β-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. Although patients are rarely obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diagnosis. These patients are also prone to other autoimmunedi sorders such as Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo,celiac sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.In this form of diabetes, the rate of β-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some patients, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection or other stress. Still others, particularly adults, may retain residual β-cell function sufficient to prevent ketoacidosis for many years; such individuals eventually become dependent on insulin for survival and are at risk for ketoacidosis. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immunemediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the 8th and 9th decades of life. Idiopathic diabetes.Some forms of type 1 diabetes have no known etiologies. Some of these patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity. Although only a minority of patients with type 1 diabetes fall into this category, of those who do, most are of African or Asian ancestry. Individuals with this form of diabetes suffer from episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. This form of diabetes is strongly inherited, lacks immunological evidence for β-cell autoimmunity, and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may come and go.Type 2 diabetes The pathogenesis of this type ranges from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance. This form of diabetes, which accounts for 90–95% of those with diabetes, previously referred to as non-insulindependent diabetes, type II diabetes, or adult-onset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency. At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive. There are probably many different causes of this form of diabetes. Although the specific etiologies are not known, autoimmune destruction of β-cells does not occur, and patients do not have any of the other causes of diabetes listed above or below.Most patients with this form of diabetes are obese, and obesity itself causes some degree of insulin resistance. Patients who are not obese by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region. Ketoacidosis seldom occurs spontaneously in this type of diabetes; when seen, it usually arises in association with the stress of another illness such as infection. This form of diabetes frequently goes undiagnosed for many years because the hyperglycemia develops gradually and at earlier stages is often not severe enough for the patient to notice any of the classic symptoms of diabetes. Nevertheless, such patients are at increased risk of developing macrovascular and microvascular complications. Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated,the higher blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their β-cell function been normal. Thus, insulin secretion is defective in these patients and insufficient to compensate for insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycemia but is seldom restored to normal. The risk of developing this form of diabetes increases with age, obesity, and lack of physical activity. It occurs more frequently in women with prior GDM and in individuals with hypertension or dyslipidemia, and its frequency varies in different racial/ ethnic subgroups. It is often associated with a strong genetic predisposition, more so than is the autoimmune form of type 1 diabetes. However, the genetics of this form of diabetes are complex and not clearly defined.Other specific types of diabetesGenetic defects of the β-cell. Several forms of diabetes are associated with monogenetic defects in β-cell function. These forms of diabetes are frequently characterized by onset of hyperglycemia at an early age (generally before age 25 years). They are referred to as maturityonset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal or no defects in insulin action. They are inherited in an autosomal dominant pattern. Abnormalities at six genetic loci on different chromosomes have been identified to date.The most common form is associated with mutations on chromosome 12 in a hepatic transcription factor referred to as hepatocyte nuclear factor (HNF)-1α. A second form is associated with mutations in the glucokinase gene on chromosome 7p and results in a defective glucokinase molecule. Glucokinase converts glucose toglucose-6-phosphate, the metabolism of which, in turn, stimulates insulin secretion by the β-cell. The less common forms result from mutations in other transcription factors, including HNF-4α,HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1. Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness. The most common mutation occurs at position 3243 in the tRNA leucine gene, leading to an A-to-G transition. An identical lesion occurs in the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome); however, diabetes is not part of this syndrome, suggesting different phenotypic expressions of this genetic lesion.Genetic defects in insulin action.There are unusual causes of diabetes that result from genetically determined abnormalities of insulin action. The metabolic abnormalities associated with mutations of the insulin receptor may range from hyperinsulinemia and modest hyperglycemia to severe diabetes. Some individuals with these mutations may have acanthosis nigricans. Women may be virilized and have enlarged, cystic ovaries. In the past, this syndrome was termed type A insulin resistance. Leprechaunism and the Rabson-Mendenhall syndrome are two pediatric syndromes that have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance. The former has characteristic facial features and is usually fatal in infancy, while the latter is associated with abnormalities of teeth and nails and pineal gland hyperplasia. Alterations in the structure and function of the insulin receptor cannot be demonstrated in patients with insulinresistant lipoatrophic diabetes. Therefore, it is assumed that thelesion(s) must reside in the postreceptor signal transduction pathways.Other specific types of diabetes, such as diseases of the exocrine pancreas, endocrinopathies, drug- or chemical-induced diabetes,infections, uncommon forms of immune-mediated diabetes)are listed in Table 1.Gestational diabetes mellitus (GDM)GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The definition applies regardless of whether insulin or only diet modification is used for treatment or whether the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with the pregnancy. The prevalence may range from 1 to 14% of pregnancies, depending on the population studied. GDM represents nearly 90% of all pregnancies complicated by diabetes. Deterioration of glucose tolerance occurs normally during pregnancy, particularly in the 3rd trimester.Diagnosis of GDMRisk assessment for GDM should be undertaken at the first prenatal visit. Women with clinical characteristics consistent with a high risk for GDM (those with marked obesity, personal history of GDM, glycosuria, or a strong family history of diabetes) should undergo glucose testing as soon as possible. High-risk women not found to have GDM at the initial screening and average-risk women should be tested between 24 and 28 weeks of gestation. Testing should follow one of two approaches:● One-step approach: perform a diagnostic 100-g OGTT● Two-step approach: perform an initial screening by measuring the plasma or serum glucose concentration 1 h after a 50-g oral glucose load (glucose challenge test [GCT]) and perform a diagnostic 100-g OGTT on that subset of women exceeding the glucose threshold value on the GCT. When the two step approach is used, a glucose threshold value ≥140 mg/dl identifies 80% of women with GDM, and the yield is further increased to 90% by using a cutoff of ≥130 mg/dl.● Diagnostic criteria for the 100-g OGTT are as follows: ≥95 mg/dl fasting, ≥180 mg/dl at 1 h, ≥155 mg/dl at 2 h, and≥140 mg/dl at 3 h. Two or more of the plasma glucose values must be met or exceeded for a positive diagnosis.The test should be done in the morning after an overnight fast of 8–14 h. The diagnosis can be made using a 75-g glucose load, but that test is not as wellTable 2—Etiologic classification of diabetes mellitusI. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)A. Immune mediatedB. IdiopathicII. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)III. Other specific typesA. Genetic defects of β-cell function1. Chromosome 12, HNF-1α (MODY3)2. Chromosome 7, glucokinase (MODY2)3. Chromosome 20, HNF-4α (MODY1)4. Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4)5. Chromosome 17, HNF-1β (MODY5)6. Chromosome 2, NeuroD1 (MODY6)7. Mitochondrial DNA8. OthersB. Genetic defects in insulin action1. Type A insulin resistance2. Leprechaunism3. Rabson-Mendenhall syndrome4. Lipoatrophic diabetes5. OthersC. Diseases of the exocrine pancreas1. Pancreatitis2. Trauma/pancreatectomy3. Neoplasia4. Cystic fibrosis5. Hemochromatosis6. Fibrocalculous pancreatopathy7. Others D. Endocrinopathies1. Acromegaly2. Cushing’s syndrome3. Glucagonoma4. Pheochromocytoma5. Hyperthyroidism6. Somatostatinoma7. Aldosteronoma8. OthersE. Drug- or chemical-induced1. Vacor2. Pentamidine3. Nicotinic acid4. Glucocorticoids5. Thyroid hormone6. Diazoxide7. β-adrenergic agonists8. Thiazides9. Dilantin10. α-Interferon11. OthersF. Infections1. Congenital rubella2. Cytomegalovirus3. OthersG. Uncommon forms ofimmune-mediated diabetes1. ―Stiff-man‖ syndrome2. Anti–insulin receptor antibodies3. OthersH. Other genetic syndromes sometimes associated with diabetes1. Down’s syndrome2. Klinefelter’s syndrome3. Turner’s syndrome4. Wolfra m’s syndrome5. Friedreich’s ataxia6. Huntington’s chorea7. Laurence-Moon-Biedl syndrome8. Myotonic dystrophy9. Porphyria10. Prader-Willi syndrome11. OthersIV. Gestational diabetes mellitus (GDM)MECHANISMS OF DIABETIC COMPLICATIONSThe DCCT (Diabetes Control and Complications Trial) and the UKPDS (U.K. Prospective Diabetes Study) established that hyperglycemia is the initiating cause of the diabetic tissue damage.This process is also modified by both genetic determinants of individual susceptibility, and by independent accelerating factors such as hypertension. Several major theories have been proposed to explain how hyperglycemia might lead to the chronic complications Of DM.Increased flux through the polyol pathway.The polyol pathway focuses on the enzyme aldose reductase. Aldose reductase normally has the function of reducing toxic aldehydes in the cell to inactive alcohols, but when the glucose concentration in the cell becomes too high, aldose reductase also reduces that glucose to sorbitol,which is later oxidized to fructose. In the process of reducing high intracellular glucose to sorbitol, the aldose reductase consumes the cofactor NADPH, which is also the essential cofactor for regenerating a critical intracellular antioxidant, reduced glutathione. By reducing the amount of reduced glutathione, the polyol pathway increases susceptibility to intracellular oxidative stress.Intracellular production of AGE precursors.The second discovery is the intracellular production of AGE precursors, which appear to damage cells by three mechanisms. The first mechanism is the modification of intracellular proteins including,most importantly, proteins involved in the regulation of gene transcription. The second mechanism, shown on the left, is that these AGE precursors can diffuse out of the cell and modify extracellular matrix molecules nearby, which changes signaling between the matrix and the cell and causes cellular dysfunction. The third mechanism, is that these AGE precursors diffuse out of the cell and modify circulating proteins in the blood such as albumin. These modified circulating proteins can then bind to AGE receptors and activate them, thereby causing the production of inflammatory cytokines and growth factors,which in turn cause vascular pathology.PKC activation.The third mechanism was the PKC pathway. Hyperglycemia inside the cell increases the synthesis of a molecule called diacylglycerol, which is a critical activating cofactor for the classic isoforms of protein kinase-C, -ß,-, and -. When PKC is activated byintracellular hyperglycemia, it has a variety of effects on gene expression.In each case, the things that are good for normal function are decreased and the things that are bad are increased. For example, the vasodilator producing endothelial nitric oxide (NO) synthase (eNOS) is decreased,while the vasoconstrictor endothelin-1 is increased. Transforming growth factor-ß and plasminogen activator inhibitor-1are also increased.Increased hexosamine pathway activity.When glucose is high inside a cell, most of that glucose is metabolized through glycolysis, going first to glucose-6phosphate, then fructose-6 phosphate, and then on through the rest of the glycolytic pathway. However, some of that fructose-6-phosphate gets diverted into a signaling pathway in which an enzyme called GFAT (glutamine:fructose-6 phosphateamidotransferase) converts the fructose-6 phosphate to glucosamine-6 phosphate and finally to UDP (uridine diphosphate) N-acetyl glucosamine.What happens after that is the N-acetyl glucosamine gets put onto serine and threonine residues of transcription factors, just like the more familiar process of phosphorylation, and overmodification by this glucosamine often results in pathologic changes in gene expression. For example, increased modification of the transcription factor Sp1 results in increased expression of transforming growth factor-ß1and plasminogen activator inhibitor-1, both of which are bad for diabetic blood vessels.Hyperglycemia-induced mitochondrial superoxide production activates the four damaging pathways by inhibiting GAPDH.Figure 2 shows the scheme for how all of these data link together. This model is based on a critical observation: diabetes in animals and patients, and hyperglycemia in cells, all decrease the activity of the key glycolytic enzyme glyceraldehyde-3 phosphate dehydrogenase (GAPDH). The level of all the glycolytic intermediates that are upstream of GAPDH increase. Increased levels of the upstream glycolytic metabolite glyceraldehyde-3-phosphate activates two of the four pathways. It activates the AGE pathway because the major intracellular AGE precursor methylglyoxal is formed from glyceraldehyde-3 phosphate. It also activates the classic PKC pathway, since the activator of PKC, diacylglycerol, is also formed from glyceraldehyde-3 phosphate. Further upstream, levels of the glycolytic metabolite fructose-6phosphate increase, which increases flux through the hexosamine pathway, where fructose-6 phosphate is converted by the enzyme GFAT to UDP–N-acetylglucosamine (UDP-GlcNAc). Finally,inhibitionof GAPDH increases intracellular levels of the first glycolytic metabolite, glucose. This increases flux through the polyol pathway, where the enzyme aldose reductase reduces it, consuming NADPH in the process.Thus, when intracellular hyperglycemia develops in target cells of diabetic complication s, it causes increased mitochondrial production of ROS. The ROS cause strand breaks in nuclear DNA, which activate PARP. PARP then modifies GAPDH, thereby reducing its activity.Finally, decreased GAPDH activity activates the polyol pathway,increases intracellular AGE formation, activates PKC and subsequently NF B, and activates hexosamine pathway flux.Diabetic nephropathyDiabetic nephropathy occurs in 20–40% of patients with diabetes and is the leading cause of end-stage renal disease (ESRD).Glomerular hyperfusion and renal hypertrophy occur in the first years after the onset of DM and are reflected by increased glomerular filtration rate(GFR). During next 5 yearsof DM , thickening of the glomerular basement membrane, glumerular hypertrophy, and meseangial volume expansion occur as the GFR returns to normal. The earliest clinical evidence of nephropathy is the appearance of low but abnormal levels (30 mg/day or 20 g/min) of albumin in the urine, referred to as microalbuminuria, and patients with microalbuminuria are referred to as having incipient nephropathy. Microalbuminuria is also a well-established marker of increased CVD risk. Without specific interventions, 80% of subjects with type 1 diabetes who develop sustained microalbuminuria have their urinary albumin excretion increase at a rate of 10–20% per year to the stage of overt nephropathy or clinical albuminuria(300 mg/24 h or200 g/min) over a period of 10–15 years, with hypertension also developing along the way. Once overt nephropathy occurs, without specific interventions, the glomerular filtration rate (GFR) gradually falls over a period of several years at a rate that is highly variable from individual to individual. ESRD develops in 50% of type 1 diabetic individuals with overt nephropathy within 10 years and in 75% by 20 years. A higher proportion of individuals with type 2 diabetes are found to have microalbuminuria and overt nephropathy shortly after the diagnosis of their diabetes, because diabetes is actually present for many years before the diagnosis is made and also because the presence of albuminuria may be less specific for the presence of diabetic nephropathy, as shown by biopsy studies. Without specific interventions,20–40% of type 2 diabetic patients with microalbuminuria progress to overt nephropathy, but by 20 years after onset of overt nephropathy, only 20% will have progressed to ESRD. Once the GFR begins to fall, the rates of fall in GFR are again highly variable from one individual to another, but overall, they may not be substantially different between patientswith type 1 and patients with type 2 diabetes.Diabetic retinopathyDiabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes. The prevalence of retinopathy is strongly related to the duration of diabetes. Vision-threatening retinopathy is rare in type 1 diabetic patients in the first 3–5 years of diabetes or before puberty. During the next two decades, nearly all type 1 diabetic patients develop retinopathy. Up to 21% of patients with type 2 diabetes have retinopathy at the time of first diagnosis of diabetes, and most develop some degree of retinopathy over time. Diabetic retinopathy is estimated to be the most frequent cause of new cases of blindness among adults aged 20–74 years.Diabetic retinopathy progresses from mild nonproliferative abnormalities, to moderate and severe nonproliferative diabetic retinopathy (NPDR). Nonproliferative diabetic retinopathy is characterized by increased vascular microaneurysms, blot hemorrhages, and cotton wool spots. Mild nonproliferative retinopathy to more extensive disease is characterized by changes in venous vessel caliber, inttaretinal microvascular abnormalities, and more numerous microaneurysms and hemorrhages. The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow, and abnormal retinal microvasculature, all of which lead to retinal ischemia. Proliferative diabetic retinopathy (PDR) is characterized by the growth of new blood vessels on the retina and posterior surface of the vitreous. This newly formed blood vessels rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment.Macular edema, characterized by retinal thickening from leaky blood vessels, can develop at all stages of retinopathy.Intensive diabetes management with the goal of achieving near normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset of diabetic retinopathy. In addition to hyperglycemia, high blood pressure is an established risk factor for the development of macular edema and is associated with the presence of proliferative diabetic retinopathy (PDR).Diabetic neuropathyDiabetic neuropathy can affect any part of the nervous system. This nerve disorder should be suspected in all patients with type 2 diabetes and in patients who have had type 1 diabetes for more than five years. In some instances, patients with diabetic neuropathy have few complaints, but their physical examination reveals mild to moderately severe sensory loss. Idiopathic neuropathy has been found to precede the onset of type 2 diabetes or to occur as an early finding in the disease. The primary types of diabetic neuropathy are sensorimotor and autonomic. A patient may have only one type of neuropathy or might develop different combinations of neuropathies. Sensory neuropathies can be classified as distal symmetric polyneuropathy, focal neuropathy (e.g., diabetic mononeuropathy), and diabetic amyotrophy. Motor neuropathies are identified。