1. 糖尿病定义1. Definition Definition
糖尿病（Diabetes Mellitus, DM）是一组以慢性高血糖为特征的代谢性疾病， 由胰岛素分泌缺陷、胰岛素作用障碍或两者并存所致。长期高血糖会导致 多组织（眼、肾、神经、心血管）的慢性损害与功能障碍。
Diabetes mellitus (DM) is a group of metabolic disorders characterized by chronic hyperglycemia, caused by defects in insulin secretion, impaired insulin action, or both. Long-term hyperglycemia leads to chronic damage and dysfunction of multiple tissues (eyes, kidneys, nerves, cardiovascular system).
Diabetes mellitus refers to a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
- 胰岛素抵抗 (Insulin Resistance, IR)：靶组织（肝、骨骼肌、脂肪）对胰岛素反应减弱
- β 细胞功能障碍 (β-cell Dysfunction)：胰岛 β 细胞分泌胰岛素能力下降
- HbA1c (糖化血红蛋白)：反映过去 2–3 个月的平均血糖水平
- C-肽 (C-peptide)：胰岛素生物合成的副产物，反映内源性胰岛素分泌
- Insulin Resistance (IR): reduced response of target tissues (liver, skeletal muscle, fat) to insulin
- β-cell Dysfunction: declining capacity of pancreatic islet β-cells to secrete insulin
- HbA1c (glycated hemoglobin): reflects average blood glucose over the past 2–3 months
- C-peptide: a by-product of insulin biosynthesis, reflecting endogenous insulin secretion
2. 糖尿病分型2. Classification Classification
ADA 与 WHO 将糖尿病分为四大类：1 型、2 型、其他特殊类型与妊娠期糖尿病。 近年 LADA、MODY 等特殊亚型的识别对个体化治疗具有重要意义。
ADA and WHO classify diabetes into four main categories: type 1, type 2, other specific types, and gestational diabetes. In recent years, recognition of special subtypes such as LADA and MODY has become important for individualized treatment.
| 类型 | 占比 | 核心机制 | 典型特征 |
|---|---|---|---|
| 1 型 T1D | 5–10% | 自身免疫性 β 细胞破坏 | 儿童/青少年起病，依赖外源性胰岛素，易酮症 |
| 2 型 T2D | ~90% | 胰岛素抵抗 + 进行性 β 细胞功能障碍 | 成人起病，常伴肥胖与代谢综合征 |
| 妊娠期 GDM | 妊娠妇女 6–14% | 妊娠胎盘激素导致的胰岛素抵抗 | 妊娠中晚期诊断，多数产后缓解 |
| LADA | ~10% 表型为 T2D 者 | 成人潜在自身免疫性糖尿病 | GAD 抗体阳性，进展较慢 |
| MODY | 1–2% | 单基因突变（HNF1A、GCK 等） | 家族聚集，<25 岁起病 |
| 其他特殊型 | 少见 | 胰腺疾病、药物、内分泌病等继发 | 胰源性糖尿病、激素诱导等 |
| Type | Share | Core mechanism | Typical features |
|---|---|---|---|
| Type 1 (T1D) | 5–10% | Autoimmune β-cell destruction | Onset in childhood/adolescence, dependent on exogenous insulin, prone to ketosis |
| Type 2 (T2D) | ~90% | Insulin resistance + progressive β-cell dysfunction | Adult onset, often with obesity and metabolic syndrome |
| Gestational (GDM) | 6–14% of pregnant women | Insulin resistance from placental hormones in pregnancy | Diagnosed in mid-to-late pregnancy, mostly resolves postpartum |
| LADA | ~10% of those with a T2D phenotype | Latent autoimmune diabetes in adults | GAD antibody positive, slower progression |
| MODY | 1–2% | Monogenic mutations (HNF1A, GCK, etc.) | Familial clustering, onset before age 25 |
| Other Specific Types | Rare | Secondary to pancreatic disease, drugs, endocrinopathies, etc. | Pancreatogenic diabetes, hormone-induced, etc. |
2.1 1 型糖尿病2.1 Type 1 Diabetes Type 1 Diabetes (T1D)
T1D 是由 T 细胞介导的自身免疫性疾病，导致胰岛 β 细胞选择性破坏。 自身抗体包括 GAD65、IA-2、ZnT8、胰岛素自身抗体（IAA）等。临床前期可持续数年， ADA 已将 T1D 分为三期：
T1D is a T-cell-mediated autoimmune disease causing selective destruction of pancreatic islet β-cells. Autoantibodies include GAD65, IA-2, ZnT8, and insulin autoantibodies (IAA). The preclinical stage can last several years, and ADA divides T1D into three stages:
- Stage 1：≥2 种自身抗体阳性，血糖正常
- Stage 2：≥2 种抗体 + 血糖异常（糖耐量受损/空腹血糖升高）
- Stage 3：临床发病（出现高血糖症状）
- Stage 1: ≥2 autoantibodies positive, normal blood glucose
- Stage 2: ≥2 antibodies + abnormal glucose (impaired glucose tolerance / elevated fasting plasma glucose)
- Stage 3: clinical onset (symptomatic hyperglycemia)
Teplizumab (抗 CD3 单抗) 是首个获 FDA 批准用于延缓 Stage 2 进展至 Stage 3 T1D 的药物（2022 年获批，TN-10 试验）。其作用机制是结合 CD3/TCR 复合体并使 T 细胞失能。 Meta 分析显示 teplizumab 组在 6–24 个月随访中 C-肽 AUC 保留显著优于对照组。
Teplizumab (an anti-CD3 monoclonal antibody) is the first drug approved by the FDA to delay progression from Stage 2 to Stage 3 T1D (approved in 2022, TN-10 trial). Its mechanism is to bind the CD3/TCR complex and render T cells anergic. Meta-analyses show that the teplizumab group preserved C-peptide AUC significantly better than controls over 6–24 months of follow-up.
来源：Source: Frontiers Endocrinol. 2025 — Teplizumab review · Diabetes Care 2026 — DMT in T1D
2.2 2 型糖尿病2.2 Type 2 Diabetes Type 2 Diabetes (T2D)
T2D 是最常见的糖尿病类型，约占 90%。核心病理是胰岛素抵抗 叠加进行性 β 细胞功能障碍。多因素病因包括：
T2D is the most common type of diabetes, accounting for about 90%. Its core pathology is insulin resistance combined with progressive β-cell dysfunction. Multifactorial causes include:
- 遗传背景：TCF7L2、KCNQ1 等数十个易感基因
- 肥胖与脂肪异位沉积：肝脏与骨骼肌内脂质积聚导致 IR
- 慢性低度炎症：脂肪组织来源的 TNF-α、IL-6 等炎症因子
- 肠道菌群失调：影响肠促胰素分泌与胆汁酸代谢
- 线粒体功能障碍：能量代谢失衡，氧化应激增加
- Genetic background: dozens of susceptibility genes such as TCF7L2, KCNQ1
- Obesity and ectopic fat deposition: lipid accumulation in liver and skeletal muscle drives IR
- Chronic low-grade inflammation: adipose-tissue-derived inflammatory factors such as TNF-α, IL-6
- Gut microbiota dysbiosis: affects incretin secretion and bile acid metabolism
- Mitochondrial dysfunction: imbalanced energy metabolism, increased oxidative stress
2.3 妊娠期糖尿病2.3 Gestational Diabetes Gestational Diabetes (GDM)
GDM 是妊娠中晚期首次发现的糖耐量异常。胎盘分泌的人绒毛膜促性腺激素、 胎盘催乳素、皮质醇等使胰岛素抵抗增加，超过 β 细胞代偿能力即出现高血糖。 多数产后缓解，但未来 T2D 风险增加 7–10 倍。
GDM is glucose intolerance first detected in mid-to-late pregnancy. Placental secretion of human chorionic gonadotropin, placental lactogen, and cortisol increases insulin resistance; when it exceeds the β-cell compensatory capacity, hyperglycemia appears. Most cases resolve postpartum, but the future risk of T2D increases 7–10 fold.
胰岛素仍是 GDM 一线治疗。指南建议：空腹血糖 > 95 mg/dL (5.3 mmol/L) 或餐后 > 140 mg/dL (7.8 mmol/L) 时启动胰岛素。二甲双胍可作为替代（但部分研究提示 后代体重指标可能略高），格列本脲不再首选。
Insulin remains first-line therapy for GDM. Guidelines recommend initiating insulin when fasting plasma glucose > 95 mg/dL (5.3 mmol/L) or postprandial glucose > 140 mg/dL (7.8 mmol/L). Metformin may be used as an alternative (though some studies suggest offspring weight measures may be slightly higher), and glyburide is no longer preferred.
2.4 其他特殊类型2.4 Other Specific Types Other Specific Types
包括 MODY (单基因 β 细胞缺陷)、胰源性糖尿病 (慢性胰腺炎、囊性纤维化、胰腺切除)、 内分泌病 (库欣、肢端肥大、嗜铬细胞瘤)、药物诱发 (糖皮质激素、抗精神病药、免疫检查点抑制剂)。 准确分型对治疗策略选择至关重要。
These include MODY (monogenic β-cell defects), pancreatogenic diabetes (chronic pancreatitis, cystic fibrosis, pancreatectomy), endocrinopathies (Cushing's, acromegaly, pheochromocytoma), and drug-induced diabetes (glucocorticoids, antipsychotics, immune checkpoint inhibitors). Accurate classification is crucial for selecting a treatment strategy.
3. 病理生理机制3. Pathophysiology Pathophysiology
3.1 胰岛素信号通路3.1 Insulin Signaling Insulin Signaling
胰岛素结合胰岛素受体 (IR) 后，激活 IRS-1/2 → PI3K → AKT → GLUT4 转位通路， 促进骨骼肌与脂肪的葡萄糖摄取，并抑制肝脏糖异生。MAPK 通路则介导生长与有丝分裂效应。
After insulin binds the insulin receptor (IR), it activates the IRS-1/2 → PI3K → AKT → GLUT4 translocation pathway, promoting glucose uptake in skeletal muscle and fat and suppressing hepatic gluconeogenesis. The MAPK pathway mediates growth and mitogenic effects.
3.2 β 细胞功能障碍3.2 β-cell Dysfunction β-cell Dysfunction
T2D 病程中 β 细胞功能呈进行性下降，机制包括：
During the course of T2D, β-cell function declines progressively. Mechanisms include:
- 糖毒性 (Glucotoxicity)：慢性高血糖增加 ROS 产生，损害胰岛素分泌与基因表达
- 脂毒性 (Lipotoxicity)：游离脂肪酸与神经酰胺积累导致 β 细胞凋亡
- 内质网应激 (ER Stress)：未折叠蛋白反应过度激活
- 线粒体功能障碍：ATP 生成减少，葡萄糖刺激的胰岛素分泌 (GSIS) 受损
- β 细胞去分化 (Dedifferentiation)：近年研究热点，β 细胞失去成熟身份恢复祖细胞状态
- 淀粉样蛋白沉积：胰岛淀粉样多肽 (IAPP/Amylin) 形成的小纤维毒性
- Glucotoxicity: chronic hyperglycemia increases ROS production, impairing insulin secretion and gene expression
- Lipotoxicity: accumulation of free fatty acids and ceramides causes β-cell apoptosis
- ER Stress: excessive activation of the unfolded protein response
- Mitochondrial dysfunction: reduced ATP generation impairs glucose-stimulated insulin secretion (GSIS)
- β-cell Dedifferentiation: a recent research focus — β-cells lose their mature identity and revert to a progenitor state
- Amyloid deposition: fibril toxicity from islet amyloid polypeptide (IAPP/Amylin)
3.3 胰岛素抵抗3.3 Insulin Resistance Insulin Resistance
胰岛素抵抗是 T2D 的核心病理特征，主要发生在三大胰岛素靶组织：
Insulin resistance is the core pathological feature of T2D, occurring mainly in the three major insulin target tissues:
外周组织 (Peripheral)
- 骨骼肌：GLUT4 转位障碍，糖摄取下降
- 脂肪：抗脂解作用减弱，FFA 释放增加
肝脏 (Hepatic)
- 糖异生抑制减弱 → 空腹高血糖
- 糖原合成减少
- 脂肪从头合成增加 → MAFLD
Peripheral tissues
- Skeletal muscle: impaired GLUT4 translocation, reduced glucose uptake
- Fat: weakened anti-lipolytic action, increased FFA release
Hepatic
- Weakened suppression of gluconeogenesis → fasting hyperglycemia
- Reduced glycogen synthesis
- Increased de novo lipogenesis → MAFLD
3.4 "八重奏" 病理3.4 The "Ominous Octet" "Ominous Octet" (DeFronzo)
DeFronzo 提出 T2D 不仅是 IR 与 β 细胞缺陷的"双重"问题，而是八个组织/通路 共同失调的结果：
DeFronzo proposed that T2D is not merely a "dual" problem of IR and β-cell defects, but the result of joint dysregulation of eight tissues/pathways:
- 骨骼肌 — 葡萄糖摄取下降
- 肝脏 — 糖异生增加
- 胰岛 β 细胞 — 胰岛素分泌不足
- 脂肪细胞 — 脂肪分解增加
- 胃肠道 — 肠促胰素效应减弱（incretin effect ↓）
- 胰岛 α 细胞 — 胰高血糖素分泌过多
- 肾脏 — 葡萄糖重吸收增加（SGLT2 上调）
- 脑 — 食欲调控失常
- Skeletal muscle — reduced glucose uptake
- Liver — increased gluconeogenesis
- Islet β-cells — insufficient insulin secretion
- Adipocytes — increased lipolysis
- Gastrointestinal tract — diminished incretin effect (incretin effect ↓)
- Islet α-cells — excessive glucagon secretion
- Kidney — increased glucose reabsorption (SGLT2 upregulation)
- Brain — dysregulated appetite control
这一模型解释了为什么单一靶点治疗常不足，多通路联合治疗是 T2D 管理的核心策略。
This model explains why single-target therapy is often insufficient; multi-pathway combination therapy is a core strategy in T2D management.
4. 诊断标准4. Diagnostic Criteria (ADA 2026) Diagnostic Criteria (ADA 2026)
满足以下任意一项可诊断糖尿病（在无明显症状时，需在不同日重复验证）：
Meeting any one of the following criteria establishes a diagnosis of diabetes (in the absence of clear symptoms, confirmation by repeat testing on a separate day is required):
| 指标 | 糖尿病 | 糖尿病前期 | 正常 |
|---|---|---|---|
| HbA1c | ≥ 6.5% (48 mmol/mol) | 5.7–6.4% | < 5.7% |
| 空腹血糖 (FPG) | ≥ 126 mg/dL (7.0 mmol/L) | 100–125 mg/dL (5.6–6.9) | < 100 mg/dL |
| OGTT 2h 血糖 | ≥ 200 mg/dL (11.1 mmol/L) | 140–199 mg/dL (7.8–11.0) | < 140 mg/dL |
| 随机血糖 + 症状 | ≥ 200 mg/dL + 典型症状 | — | — |
| Measure | Diabetes | Prediabetes | Normal |
|---|---|---|---|
| HbA1c | ≥ 6.5% (48 mmol/mol) | 5.7–6.4% | < 5.7% |
| Fasting plasma glucose (FPG) | ≥ 126 mg/dL (7.0 mmol/L) | 100–125 mg/dL (5.6–6.9) | < 100 mg/dL |
| OGTT 2h glucose | ≥ 200 mg/dL (11.1 mmol/L) | 140–199 mg/dL (7.8–11.0) | < 140 mg/dL |
| Random plasma glucose + symptoms | ≥ 200 mg/dL + typical symptoms | — | — |
- HbA1c 受贫血、血红蛋白病、近期输血等影响，应结合 FPG/OGTT 综合判断
- 无明显症状者需两次异常检查方可确诊
- 急性应激（重症感染、外伤、手术）期间的血糖升高需在应激解除后复评
- HbA1c is affected by anemia, hemoglobinopathies, recent transfusion, etc., and should be interpreted together with FPG/OGTT
- Asymptomatic individuals require two abnormal tests to confirm the diagnosis
- Hyperglycemia during acute stress (severe infection, trauma, surgery) should be reassessed after the stress resolves
5. 急慢性并发症5. Complications Complications
5.1 急性并发症5.1 Acute Complications Acute
糖尿病酮症酸中毒 (DKA)
多见于 T1D，由胰岛素绝对缺乏导致。 三联征：高血糖 + 酮症 + 代谢性酸中毒。SGLT2i 治疗时罕见"血糖正常型 DKA"。
高血糖高渗状态 (HHS)
多见于老年 T2D。血糖通常 > 600 mg/dL， 血浆渗透压 > 320 mOsm/kg，无明显酮症。死亡率高于 DKA。
低血糖
血糖 < 70 mg/dL (Level 1)、< 54 mg/dL (Level 2 临床显著)、 重度需他人协助 (Level 3)。最常因胰岛素或磺脲类过量。
乳酸酸中毒
罕见但严重，与二甲双胍蓄积（肾功能不全时）相关。 eGFR < 30 mL/min/1.73m² 应停用二甲双胍。
Diabetic ketoacidosis (DKA)
Most common in T1D, caused by absolute insulin deficiency. Triad: hyperglycemia + ketosis + metabolic acidosis. With SGLT2i therapy, "euglycemic DKA" is rare.
Hyperosmolar hyperglycemic state (HHS)
Most common in elderly T2D. Blood glucose is usually > 600 mg/dL, plasma osmolality > 320 mOsm/kg, without significant ketosis. Mortality is higher than DKA.
Hypoglycemia
Blood glucose < 70 mg/dL (Level 1), < 54 mg/dL (Level 2, clinically significant), severe requiring assistance from others (Level 3). Most often due to excess insulin or sulfonylureas.
Lactic acidosis
Rare but serious, associated with metformin accumulation (in renal insufficiency). Metformin should be discontinued when eGFR < 30 mL/min/1.73m².
5.2 慢性并发症 — 微血管5.2 Chronic Complications — Microvascular Microvascular
微血管并发症由长期高血糖引发，共享的分子通路包括： 多元醇通路、己糖胺通路、PKC 激活、 晚期糖基化终产物 (AGEs) 与氧化应激。
Microvascular complications are driven by long-term hyperglycemia, with shared molecular pathways including: the polyol pathway, the hexosamine pathway, PKC activation, advanced glycation end-products (AGEs), and oxidative stress.
| 并发症 | 核心机制 | 临床特征 |
|---|---|---|
| 糖尿病视网膜病变 (DR) | PKC 依赖性周细胞凋亡、毛细血管闭塞、VEGF 上调 | 非增殖期 → 增殖期 → 黄斑水肿；首要致盲原因 |
| 糖尿病肾病 (DKD) | TGF-β 介导的足细胞丢失、系膜扩张、肾小球高滤过 | 蛋白尿 → eGFR 下降 → ESRD；ESRD 首位病因 |
| 糖尿病神经病变 (DPN) | 醛糖还原酶激活、肥大细胞功能异常、线粒体损伤 | 远端对称性多发性神经病；自主神经病；最常见慢并发症 |
| Complication | Core mechanism | Clinical features |
|---|---|---|
| Diabetic retinopathy (DR) | PKC-dependent pericyte apoptosis, capillary occlusion, VEGF upregulation | Non-proliferative → proliferative → macular edema; leading cause of blindness |
| Diabetic kidney disease (DKD) | TGF-β-mediated podocyte loss, mesangial expansion, glomerular hyperfiltration | Proteinuria → declining eGFR → ESRD; leading cause of ESRD |
| Diabetic peripheral neuropathy (DPN) | Aldose reductase activation, mast cell dysfunction, mitochondrial damage | Distal symmetric polyneuropathy; autonomic neuropathy; most common chronic complication |
5.3 慢性并发症 — 大血管5.3 Chronic Complications — Macrovascular Macrovascular
动脉粥样硬化性心血管疾病 (ASCVD) 是 T2D 死亡的首要原因，包括冠心病、脑卒中、外周动脉疾病。 高血糖通过内皮功能障碍、炎症、血小板活化、脂质异常促进 AS。 心衰（HFpEF 与 HFrEF）也是糖尿病心血管负担的重要组成部分。
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in T2D, including coronary heart disease, stroke, and peripheral artery disease. Hyperglycemia promotes atherosclerosis through endothelial dysfunction, inflammation, platelet activation, and dyslipidemia. Heart failure (HFpEF and HFrEF) is also an important component of the cardiovascular burden in diabetes.
5.4 其他相关疾病5.4 Comorbidities Comorbidities
- MASLD/MASH（代谢功能障碍相关脂肪性肝病/脂肪性肝炎）：约 1/3 成人受累，T2D 患者中达 50–70%
- 认知障碍与糖尿病性脑病：T2D 痴呆风险增加 1.5–2 倍
- 糖尿病足：神经病变 + 血管病变 + 感染的协同结果
- 骨质疏松：T1D 显著；T2D 骨密度可正常但骨折风险升高
- 感染易感性：泌尿系、皮肤、肺部
- MASLD/MASH (metabolic dysfunction-associated steatotic liver disease/steatohepatitis): affects about 1/3 of adults, reaching 50–70% among T2D patients
- Cognitive impairment and diabetic encephalopathy: T2D increases dementia risk 1.5–2 fold
- Diabetic foot: a combined result of neuropathy + vascular disease + infection
- Osteoporosis: pronounced in T1D; in T2D bone density may be normal but fracture risk is elevated
- Susceptibility to infection: urinary tract, skin, lungs
微血管并发症共享的炎症与免疫通路（涉及 26 条共享生物通路）使得抗炎/抗纤维化药物 (如非奈利酮 finerenone、SGLT2i) 跨适应症显示获益。 器官保护已成为糖尿病新药开发的核心评价维度，而非单纯降糖。
The inflammatory and immune pathways shared by microvascular complications (involving 26 shared biological pathways) mean that anti-inflammatory/anti-fibrotic drugs (such as finerenone and SGLT2i) show benefit across indications. Organ protection has become a core evaluation dimension in diabetes drug development, rather than glucose-lowering alone.