1. Pancreatic hormones & antidiabetic drugs
Shi-Hong Zhang 张世红

2. 胰高血糖素
胰岛素
生长抑素

3. Persistent hepatic glucose output ↓
Overview of Glucose Regulation by Insulin
Glucose absorption
Lipolysis↓
Insulin secretion
Lipogenesis↑
In nondiabetic individuals, glucose is absorbed from the gut and stimulates beta cell insulin secretion. Insulin then acts on its three main target tissues: the liver, where it blunts hepatic glucose output; the muscle, where it stimulates glucose disposal; and the adipocyte, where it diminishes lipolysis and enhances lipogenesis. There are three main defects in diabetes, and these include diminished insulin secretion; resistance to insulin action in insulin responsive tissues, and persistent elevation of glucagon with resultant persistent hepatic glucose output
Persistent hepatic glucose output ↓
Glucose disposal ↑
Glycogenesis ↑
Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24. 3

4. Different types of diabetes mellitus

5. prediabetic metabolic syndrome
正常血糖值在 mmol/L( mg/dl)。诊断糖尿病前一般会发生糖尿病前代谢综合症（prediabetic metabolic syndrome）。发病前，胰岛素抵抗已经存在，胰岛素分泌代偿性增加。但后期，胰岛素分泌下降。
“Beta-cell failure”

6. Symptoms
of diabetes

7. Complications of diabetes mellitus
Acute complications
Diabetic ketoacidosis (酮症酸中毒)
Hyperosmotic nonketotic coma (高渗性非酮症性昏迷）
Chronic complications
Cardiovascular diseases
Renal damage
Retinal damage
Nerve degeneration
Infection
Myopathy
etc.
胰岛素信号障碍或血糖过低，机体利用脂肪分解供能，产生过多酮体。高血糖也能引起血浆渗透压升高，造成脑组织脱水

8. Pharmacological therapy
Insulin
Oral hypoglycemic drugs
Insulin sensitizers 胰岛素增敏剂:
Biguanides 双胍类
Thiazolidinediones (TDs，噻唑烷二酮类)
Insulin secretagogues (促胰岛素分泌药):
Sulfonylureas 磺酰脲类
Meglitinides (Non-SU) 格列奈类
GLP-1 agonists and DPP-4 inhibitors
α-glucosidase inhibitors α-葡萄糖苷酶抑制剂
Amylin analogue 胰淀粉样多肽类似物
Aldose reductase inhibitor 醛糖还原酶抑制剂
Meglitinides (Non-SU) 格列奈类，苯丙胺酸衍生物
GLP-1 agonists 和Amylin analogue需注射给药

9. A. Insulin
1965年，我国中科院上海生化所、中科院上海有机化学研究所，北京大学生物系三个单位联合合成了牛胰岛素。胰岛素是由51个氨基酸组成的双链结构。猪胰岛素与人胰岛素的不同之处是在B链30位由丙氨酸取代了苏氨酸；牛胰岛素与人胰岛素有3个氨基酸不同，A8和B30不是苏氨酸，而是丙氨酸，A10位上的异亮氨酸被缬氨酸取代

10. Frederick Sanger （ ），英格兰化学家，共获两次诺贝尔奖。1958年，for his work on the structure of proteins, especially that of insulin; In 1980, shared with Walter Gilbert for their contributions concerning the determination of base sequences in nucleic acids. 迄今只有四人曾获两次诺贝尔奖，他们是居里夫人，化学家鲍林，桑格，物理学家巴丁
Frederick Sanger ( )

11. A. Insulin 1. Pharmacological effects
(1) Carbohydrate metabolism: reduces blood glucose levels by glycogenolysis , glycogen synthesis , gluconeogenesis  , glucose transport .
(2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids , ketone bodies .
(3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism 
(4) Cardiac stimulation
(5) Promote cellular K+ uptake

12. Mechanism of insulin actions: Interact with insulin receptors
酪氨酸激酶信号转导途径
Mechanism of insulin actions: Interact with insulin receptors

13. A. Insulin 2. Clinical uses (1) Type I diabetic mellitus
(2) Type II diabetic mellitus : extreme high blood glucose or after failure to other drugs
(3) Diabetic complications: diabetic ketoacidosis (酮症酸中毒), hyperosmotic nonketotic coma（高渗性非酮症性昏迷）
(4) Critical situations of diabetic patients: fever, severe infection, pregnancy, trauma, operation
(5) Promotion of K+ uptake into the cells

14. Monocomponent insulin 单组分胰岛素
A. Insulin
3. Preparations
Fast-acting insulin
Regular insulin 正规胰岛素
Monocomponent insulin 单组分胰岛素
High solubility
Can be given intravenously
Start working 0.5-1h after injection, reach peak 2-4h, and last 5-7h.

15. A. Insulin 3. Preparations Fast-acting insulin analogs
Insulin aspart 门冬胰岛素 （B28 脯氨酸变为门冬氨酸）
Insulin lispro 赖脯胰岛素（颠倒B28、29脯赖顺序）
Start working 5-15 minutes after injection, reach peak at 1h, and last ~4 hours.
Used for IDDM and NIDDM with high postmeal glucose.

16. A. Insulin 3. Preparations Intermediate-acting insulin (lente)
Neutral protamine hagedorn (NPH, isophane insulin )
中性（低）精蛋白锌胰岛素
Globin zinc insulin 珠蛋白锌胰岛素
Start working 1-1.5h after injection, reach peak 8-12h, and last 24h.

17. Protamine zinc insulin (PZI) 精蛋白锌胰岛素
A. Insulin
3. Preparations
Long-acting insulin (ultralente)
Protamine zinc insulin (PZI) 精蛋白锌胰岛素
Start working 4-8h after s.c. injection, reach peak 14-20h, and last 24-36h.

18. A. Insulin 3. Preparations Super-long acting insulin analogs
Insulin glargine 甘精胰岛素（B链C端加两个精氨酸，A21甘氨酸替代门冬酰胺）
Insulin detemir地特胰岛素（去除B30苏氨酸，B29赖氨酸加脂肪酸侧链）
Less soluble than native human insulin at physiological pH, and precipitates in skin following subcutaneous injection, resulting in delayed absorption.
Onset 1-2 h after injection and continues to work for as long as 24 hours.
Used to treat type 1 or type 2 diabetes mellitus.

19. Human insulin isophane 低精蛋白锌胰岛素+
A. Insulin
3. Preparations
Mixed insulin
Human insulin isophane 低精蛋白锌胰岛素+
Human insulin 人胰岛素
Start working 0.5h after injection, reach peak 2-12h, and last 16-24h.

20. 根据起效快慢分成半慢，慢和超慢胰岛素。锌离子的存在对于维持胰岛素的结构和功能非常重要。一个胰岛素分子内含两个锌原子

21. For patients who eat meals out, may consider use of an insulin pen.
Most insulins now available as pen

22. Insulin Pump and Glucose Monitoring
Insulin Pump – “Open Loop”
Patient sets basal infusion rate and superimposed
boluses
Continuous Glucose Monitor
Merging of Technologies
The ultimate goal is to eliminate the patient’s role – create an artificial pancreas by merging the continuous sensing of the CGMS (continuous glucose monitoring system) and the insulin delivery of a pump into one unit.
“Closed Loop” insulin pump system is ultimate goal: infusion rate adjusted based on input from continuous glucose monitor. 22

23. A. Insulin 4. Adverse effects
(1) Hypoglycemia: adrenaline secretion (sweating, hunger, weakness, tachycardia, blurred vision, headache, etc.), treated with 50% glucose.
(2) Hypersensitivity: treated with H1 antagonists, glucocorticoids
(3) Insulin resistance: acute, chronic
(4) Lipoatrophy脂肪萎缩 and lipohypertrophy脂肪增生
(5) Others: weight gain, refractive errors (屈光不正), edema
因血糖降低迅速导致晶状体、玻璃体内水分外溢而视物模糊。

24. B. Oral hypoglycemic drugs
Insulin action enhancers 胰岛素增敏剂:
Biguanides 双胍类
Thiazolidinediones (TDs，噻唑烷二酮类)
Insulin secretagogues （促胰岛素分泌药）:
Sulfonylureas 磺酰脲类
Meglitinides (Non-SU) 格列奈类(苯丙胺酸衍生物)
GLP-1 agonists and DPP-4 inhibitors
α-glucosidase inhibitors α-葡萄糖苷酶抑制剂
Amylin analogue 胰淀粉样多肽类似物
Aldose reductase inhibitor 醛糖还原酶抑制剂

25. Insulin action enhancers
Biguanides （双胍类）
Metformin 二甲双胍
Thiazolidinediones (TZDs) 噻唑烷酮类化合物
Rosiglitazone 罗格列酮
Pioglitazone 吡格列酮
吡格列酮有增加膀胱癌发病的嫌疑；而罗格列酮曾被指控能增加心脑血管意外的风险

26. Metformin 1. Pharmacologicla effects
Increases insulin sensitivity, enhances glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles;
Decreases glucose absorption in gut and glucagon release, inhibits hepatic gluconeogenesis

27. Metformin 2. Clinical uses 3. Adverse effects
First line drug for type II diabetes, esp. patients with obesity; polycystic ovary syndrome
Major advantages: lack of weight gain, absence of hypoglycemia, decrease in risk of CV events, low cost with generic prep.
3. Adverse effects
GI reactions, severe lactic acidosis, malabsorption of vitamin B12 and folic acid  

28. Thiazolidinediones 1. Pharmacological effects
Selective agonists for nuclear peroxisome proliferator activated receptor- (PPAR , 过氧化物酶增殖体激活受体), increase glucose transport into muscle and adipose tissue.
(1) Lower insulin resistance
(2) Lipid metabolism regulation: TG, free fatty acid 
(3) Prevent diabetic complications: anti-platelet, renal protection, anti-atherosclerosis
(4) Improve  cell function
PPARs有三种亚型：alpha亚型增高HDL，降低TG；gama亚型降低TG，改善胰岛素抵抗；delta增高HDL，降低TG，改善胰岛素抵抗。
脂联素是脂肪细胞分泌的一种蛋白质，与脂肪储量负相关，是一种胰岛素增敏因子。

29. linoleic acid：亚油酸
FABP: fatty acid binding protein
Lipoprotein lipase: 脂蛋白脂酶

30. Thiazolidinediones 2. Clinical uses
Used for treatment of insulin-resistant diabetic patients or type 2 patients;
Delayed onset of action – takes 8-12 weeks to achieve maximal effect;
Absence of hypoglycemia when used as monotherapy;
No reliance on renal excretion

31. Thiazolidinediones 3. Adverse effects
Edema: at higher doses and used with insulin, in older patients, patients with multiple medical problems, patients with underlying CAD or CHF
Increased risk of cardiac events
Headache
Myalgia (肌痛)
GI reactions
Hepatic damage (troglitazone).
Contraindicated with Class III or IV heart failure or significant liver disease.
CAD: coronary artery disease
CHF: congestive heart failure
TZD引起水肿是因为肾集合管的PPAR gama的激活导致重吸收减少。

32. Sulfonylureas（磺酰脲类） Tolbutamide (D860) 甲苯磺丁脲 Chlorpropamide 氯磺丙脲
Gliburide 格列本脲 （优降糖）
Glipizide 格列吡嗪（美吡达）
Gliclazide 格列齐特 （达美康）
Glimepiride 格列美脲（亚莫利）
临床使用以第二代格列类药物为主。

33. Sulfonylureas 1. Pharmacological effects
1) Increase insulin release: block ATP sensitive K+ channel, Ca2+ inflow 

34. Sulfonylureas 1. Pharmacological effects
2) Increase receptor affinity to insulin (long-term use)
3) Promote glucose uses（促进合成糖原和脂肪）
4) Increase sensitivity of β cells to glucose
5) Anti-uretic effect (格列本脲/氯磺丙脲) ：ADH 
6) Anti-platelet effect (格列齐特)
促进合成糖原和脂肪

35. Sulfonylureas 2. Clinical uses
(1) Type II diabetic mellitus: first line oral hypoglycemic drug, alone or combined with insulin
(2) Diabetes insipidus (尿崩症): 氯磺丙脲

36. Sulfonylureas 3. Adverse effects (1) GI reactions
(2) CNS reactions（嗜睡、眩晕）
(3) Hypoglycemia: especially in elderly, with hepatic or renal insufficiencies
(4) Others: leukopenia (白细胞减少), cholestatic jaundice (胆汁郁积性黄疸), hepatic damage
中枢反应包括嗜睡、眩晕等

37. Non-SU Insulin Secretagogues
Act by binding to SUR1 on beta cells to promote insulin secretion.
Repaglinide (瑞格列奈) and Nateglinide (那格列奈) are currently available agents.
Efficacy of repaglinide appears to be similar to SU’s
Major advantage is rapid onset and offset, can dose just prior to meals with better postmeal control.
Lower risk to induce hypoglycemia than SUs.
Are additive with metformin (二甲双胍).
Used for type 2 patients.
第一个进餐时服用的葡萄糖调节药物，模仿胰岛素的生理性分泌，有效地控制餐后高血糖

38. Non-SU Insulin Secretagogues
Hepatic metabolism permits use in patients with impaired renal function.
Many drug interactions. Most concerning is gemfibrozil (吉非罗齐) which increases repaglinide concentration and may result in prolonged effect.
Cost may be an issue (1 or 2 mg tabs: $122.09/month at drugstore.com) 38

39. GLP-1 agonists and DPP-4 inhibitors
GLP-1: glucogons-like protein-1
Exenatide (依可那肽): GLP-1 agonist，stimulates insulin secretion, only available as injection.
Sitagliptin (西他列汀), vildagliptin (维格列汀): DPP-4（二肽基肽酶Ⅳ）inhibitor.
二肽基肽酶Ⅳ降解GLP-1

41. Alpha-Glucosidase inhibitors
Acarbose-Precose 阿卡波糖
Miglitol-Glyset 米格列醇
Voglibose 伏格列波糖

42. Alpha-Glucosidase inhibitors
Acarbose (阿卡波糖) is an oligosaccharide (低聚糖), hardly absorbed
Miglitol (米格列醇) resembles a monosaccharide, fairly well-absorbed.
Reducing intestinal absorption of starch (淀粉), dextrin (糊精), and disaccharides (二糖) by inhibiting the action of intestinal brush border -glucosidase（葡萄糖苷酶）.
Acarbose also blocks pancreatic alpha-amylase (淀粉酶).
Used for diabetes mellitus type 2, particularly with regard to postprandial餐后的 hyperglycemia.

43. Alpha-Glucosidase inhibitors
Must be taken at the start of main meals to have maximal effect.
Efficacy will depend on the amount of complex carbohydrates in the meal.
Absence of hypoglycemia when used as monotherapy.
Side effects: gastrointestinal side effects such as flatulence and diarrhea; voglibose (伏格列波糖), in contrast to acarbose, has less of GI side effects and more economical.

44. Amylin analogues 淀粉样多肽类似物
Mechanism of action:
Inhibits glucagon secretion, thereby reducing hepatic glucose production
Slows gastric emptying
Promotes satiety reduces caloric intake
Pramlintide (Symlin普兰林肽) is the only amylin analog on the market
As adjunct therapy for patients with type 1 or 2 diabetes to control postprandial glucose
Increases the risk of severe hypoglycemia
The other main side effect is nausea.
Riddle and Drucker. Diabetes Care 2006; 29:

45. Alsose reductase inhibitors 醛糖还原酶抑制剂
Rational: aldose reductase activity increases in those tissues that are not insulin sensitive, including lenses, peripheral nerves and glomerulus, may be involved in diabetic complications.
Epalrestat (依帕司他) inhibits aldose reductase， delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease.

47. 中国 2 型糖尿病防治指南（2013 年版）

48. Case report
A 45-year-old man first consulted his physician because of nocturia (夜尿), mild thirst, and some fatigue. At the time, he was somewhat overweight and sedentary (久坐) in his habits. Laboratory tests showed an elevated fasting blood glucose level of 15 mmol/L, glucose but no ketones in the urine. Diabetes was diagnosed and he was placed on diabetic diet low in free sugar and fat. Two months later, he was found to have higher fasting blood glucose, 2-hr postlunch glucose, glycosylated hemoglobin (HbA1C). Therefore, He was started on glyburide 5mg before breakfast and 5 mg before dinner, but the blood glucose remained elevated. The dosage was therefore raised to 10 mg twice daily, and this achieved a good result.

49. Case report
After 3 years, he developed unstable angina pectoris, and the blood glucose and HbA1C levels were again found to be elevated. Addition of metformin to his treatment produced some improvement, but his cardiac symptoms gradually worsened over the next 3 years. He showed intermittent glycosuria and proteinuria. His weight had fallen to a normal level. His physician therefore decided to transfer him to insulin therapy, started on a regimen of 22 units of Lente insulin and 12 units of regular insulin every morning before breakfast. The dosage was gradually raised to 35 units according to the glucose level in the blood and urine. During the next year he had three mild hypoglycemic reactions. He was found to have stable background retinopathy, mild nephropathy and mild numbness and tingling in both feet, but the blood pressure remained normal.