1. Pancreatic hormones & antidiabetic drugs
Huifang Tang
Department of pharmacology

2. History of Diabetes
1869 Paul Langerhans discovers islet cells in the pancreas.
1889
Mehring and Minkowski produce DM in dogs by removing the pancreas.
1921 Banting and Best find a pancreatic extract that lowers blood glucose in pancreatectomized dogs.
VOL 101 / NO 4 / APRIL 1997 / POSTGRADUATE MEDICINE

3. Dr. F. G. Banting, Mr. C. H. Best, Mr. J. B. Collip and Prof. J. J. R
Dr. F.G. Banting, Mr. C.H. Best, Mr. J.B. Collip and Prof. J.J.R. MacLeod discovered insulin in 1921 at the University of Toronto.

8. Defective insulin secretion
Overview of Glucose Regulation
Alpha glucosidase inhibitors
Glucose
Defective insulin secretion
Sulfonylureas
Meglitinides
b-cell insulin secretion
Persistent Hepatic Glucose Output
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
Incretin analogs
DPP-IV Inhibitors
Insulin action
Thiazolidinediones
Resistance to insulin action
Metformin
Amylin analogs
Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24. 8

9. Different forms of diabetes mellitus

10. 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.

11. Pharmacological therapy
Insulin.
Oral hypoglycemic drugs
Insulin sensitizers
Insulin secretagogues
α-glucosidase inhibitors

12. A. Insulin

13. Insulin A. Insulin 1. Pharmacological effects
(1) Carbohydrate metabolism: reducing blood glucose levels by gycogenolysis , glycogen synthesis , gluconeogenesis  (ketone badies )
(2) lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids 
(3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism 
(4) Mechanism of insulin actions
Interacting with insulin receptor

15. Interaction between insulin and its receptor
IRS: insulin receptor
substrate
tyr: tyrosine
P: phosphate

16. Insulin promotes the translocation of glucose transporters into the membrane

17. A. Insulin 2. Clinical uses
(1) Insulin-dependent patients with diabetes mellitus (type 1 diabetes mellitus)
(2) Insulin-independent patients: 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) Others: promotion of K+ uptake into the cells, pshychiatric disorders

18. A. Insulin
3. Preparations

19. Approximate Pharmacokinetic Profiles of Human Insulins and Insulin Analogues
Hirsch. NEJM. 2005; 352:

20. A. Insulin 4. Adverse effects
(1) Hypersensitivity: treated with H1 receptor antagonist, glucocorticoids
(2) Hypoglycemia: adrenaline secretion (sweeting, hunger, weakenss, tachycardia, blurred vision, headache, etc.), treated with 50% glucose
(3) Insulin resistance:
Acute: stress induced, need large dose of insulin
Chronic: need >200U/d and no complication
(4) Lipoatrophy: localized in injection sites

21. B. Oral hypoglycemic drugs
History
In 1942, Janbon and colleagues noted that some sulfonamides (磺胺 类)caused hypoglycemia in experiment animal.---Carbutamide （氨磺丁 脲）became the first clinically useful sulfonylurea （磺酰脲类）for treatment of diabets.
In the early 1950s, Clinical trials of tolbutamide（甲苯磺丁脲）, the first widely used member of this group, were instituted in type 2 DM patients.
During the 1920s, biguanides were investigated for use in diabets, but they are overshadowed by the discovery of insulin.
In 1997, the first member of a new class of oral insulin secretagogues called meglitinide(美格替奈) was approved for clinical use.
In 1997, Thiazolidinediones were introduced as the second major class of insulin sensitizers.In 2000, the first of these agents, troglitazone was withdrawn from use in the United Stats.

22. B. Oral hypoglycemic drugs
Insulin secretagogues(促胰岛素分泌剂):
Sulfonylureas(磺酰脲类)
Repaglinide (瑞格列奈)
GLP-1 receptor agonist
DPP-4 inhibitor
Insulin sensitizers （胰岛素增敏剂）:
Thiazolidinediones (TDs)
Biguanides
α-glucosidase inhibitors

24. B. Oral hypoglycemic drugs -1
1. Sulfonylureas
Tolbutamide (D860) 甲苯磺丁脲
Chlorpropamide 氯磺丙脲
Glibenclamide 格列本脲 (优降糖)
Glipizide 格列吡嗪
Gliclazide 格列齐特 (达美康)

25. 甲苯磺丁脲
氯磺丙脲
格列本脲 (优降糖)
格列吡嗪
格列齐特 (达美康)
格列美脲

26. Mechanisms of Action of sulfonylureas

27. B. Oral hypoglycemic drugs -1
Sulfonylureas
1. Pharmacological effects
Act by binding to specific receptors (SUR1) on the beta cells and promoting insulin secretion.
Blocking K+ channel: Ca2+ inflow , insulin release ,
Stimulating insulin secretion
Increasing insulin sensitivity (long-term use)
1st generation agents (tolbutamide, tolazemide, chlorpropamide) rarely used today
2nd generation agents (glyburide, glipizide and glimeperide) are more potent and all ~equally effective in maximal dose.

28. Sulfonylureas – Caveats in Use
B. Oral hypoglycemic drugs -1
Sulfonylureas – Caveats in Use
Glyburide(格列本脲)
Longer duration of action, active hepatic metabolites, renally excreted
May want to avoid in adults >65 years old
Glipizide（格列吡嗪）
Shorter duration of action
Glimepiride（格列美脲）
Largely excreted in bile
All are hepatically metabolized and should be used cautiously with advanced liver disease
Start with lowest dose and titrate slowly

29. B. Oral hypoglycemic drugs -1
2. Clinical uses
(1) Insulin-indenpedent diabetic patients (type 2): alone or combined with insulin
(2) Diabetes insipidus (尿崩症):
Chlorpropamide (氯磺丙脲): antiuretic hormone (ADH) 

30. B. Oral hypoglycemic drugs-1
3. Adverse effects
Major side effects
- weight gain
- hypoglycemia, especially in the elderly or in patients with impaired renal function.
Major advantages
- low price (generic glip $10-20/month)
- long track record of safety.
Others: leukopenia, cholestatic jaundice(胆汁淤积性黄疸), hepatic damage

31. B. Oral hypoglycemic drugs -1
4. Drug interactions
(1) Potentiation of hypoglycemic effects
replacement in plasma protein binding: salicylic acid, sulfates, indomethacin, penicillin, warfarin, etc.
inhibition of hepatic microsomal enzymes: chloramphenicol, warfaren
(2) Attenuation of hypoglycemic effects
induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc.
interactions in pharmacodynamics: glucagon, thiazides, etc.

32. 2.Meglitinides (Non-SU Insulin Secretagogues)
B. Oral hypoglycemic drugs -2
2.Meglitinides (Non-SU Insulin Secretagogues)
Prandial glucose regulators (餐时血糖调节剂)
Act by binding to SUR1 on beta cells to promote insulin secretion.
Repaglinide (Prandin，瑞格列奈) and Nateglinide (Starlix， 那格列奈) are current agents in class.
Major side effect is hypoglycemia.
Major advantage is rapid onset and offset
Can dose just prior to meals with better post-prandial control
Fewer overnight lows
Ability to skip the dose if skip the meal.
Efficacy for repaglinide appears to be similar to SU’s

33. Mechanism of action

34. 3. GLP-1 （glucogen-like peptide1)receptor agonist and DPP-4 inhibitor
B. Oral hypoglycemic drugs -3
3. GLP-1 （glucogen-like peptide1)receptor agonist and DPP-4 inhibitor

35. GLP-1 receptor agonist and DPP-4 inhibitor
B. Oral hypoglycemic drugs-3
GLP-1 receptor agonist and DPP-4 inhibitor

36. GLP-1 receptor agonist and DPP-4 inhibitor
B. Oral hypoglycemic drugs
GLP-1 receptor agonist and DPP-4 inhibitor

37. GLP-1 （glucogen-like peptide1)receptor agonist
依克那肽
利拉鲁肽

38. GLP-1 （glucogen-like peptide1)receptor agonist
B. Oral hypoglycemic drugs
GLP-1 （glucogen-like peptide1)receptor agonist
Exenatide(依克那肽)
Exenatide is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster that was first isolated by Dr. John Eng in 1992.
a 39-amino-acid peptide, an insulin secretagogue, with glucoregulatory effects
Mechanism of action: It displays biological properties similar to human glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretion

39. B. Oral hypoglycemic drugs
Exenatide(依克那肽)
Must be taken as a BID injection w/in 60 mins prior to meal
Major side effects: nausea, vomiting, diarrhea. Increases the risk of Acute pancreatitis.
Not recommended in severe renal impairment.
Not recommended as monotherapy
To be used as add on therapy with SU, metformin, or TZD’s
Increases the risk of Hypoglycemia when added to SU treatment.
Major advantage : weight loss (~5 kg) as well as maintained effect (preserved beta cell function).
Efficacy: decreases A1C ~1.0%.

40. DPP-4 (dipeptidyl peptidase 4 enzyme) inhibitor
B. Oral hypoglycemic drugs
DPP-4 (dipeptidyl peptidase 4 enzyme) inhibitor
Sitagliptin phosphate(磷酸西列他汀）
Mechanism of action:
Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal GLP-1 levels
Acts as an incretin enhances insulin secretion in response to an oral glucose load.
Suppresses post-prandial glucagon secretion in a glucose- dependent manner
Preserves beta cell mass by reducing apoptosis and increased neogenesis (animal models).

41. Sitagliptin phosphate(磷酸西列他汀）
B. Oral hypoglycemic drugs
Sitagliptin phosphate(磷酸西列他汀）
Sitagliptin (Januvia) is first DPP-IV inhibitor on market.
Effective as monotherapy or when used in conjunction with metformin or a thiazolidinedione.
Appears to maintain efficacy (preserved beta cell fxn).
Efficacy: decreases A1C ~0.8%.

42. B. Oral hypoglycemic drugs-2
Insulin sensitizers
Biguanides
Metformin 二甲双胍
Phenformin 苯乙双胍
1. Pharmacological effects
increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles
decreasing glucose absorption in gut and glucagon release
 2. Clinical uses
mild insulin-independent patients with obesity 
3. Adverse effects
severe lactic acidosis, malabsorption of vitamin B12 and folic acid 

43. Mechanism of action

44. B. Oral hypoglycemic drugs -2
Biguanides
Mechanism of action not well understood, but causes inhibition of hepatic glucose production.
Metformin is only agent in this class available in US.
Major side effect
GI intolerance (20-30%): bloating, anorexia, diarrhea, and flatulence. Lactic acidosis is rare, but may be severe.
Major advantages:
Lack of weight gain
Absence of hypoglycemia
Low cost with generic prep.

45. B. Oral hypoglycemic drugs-2
Thiazolidinediones (TZDs) 噻唑烷酮类化合物
Rosiglitazone 罗格列酮
Pioglitazone 吡格列酮
Troglitazone 曲格列酮

46. B. Oral hypoglycemic drugs-2
Rosiglitazone
罗格列酮
Pioglitazone
吡格列酮

47. B. Oral hypoglycemic drugs -2 Insulin action enhancers
1. Pharmacological effects
Selective agonists for nuclear peroxisome proliferator-activated receptor- (PPAR , 过氧化物酶增殖体激活受体), by enhancing peripheral insulin sensitivity, esp. at muscle and adipose tissue, via activation of PPARγ, increasing glucose transport into muscle and adipose tissue.
(1) Lowering insulin resistance
(2) Lipid metabolism regulation: TG, free fatty acid 
(3) Antihypertensive effects

48. Mechanism of action

49. B. Oral hypoglycemic drugs-2
2. Clinical uses
used for treatment of insulin-resistant diabetic patients or type 2 patients
3. Adverse effects
Edema, headache, myalgia, GI reactions, hepatic damage (troglitazone)

50. B. Oral hypoglycemic drugs -3
Alpha-Glucosidase inhibitors
Acarbose-Precose 阿卡波糖 1996
Miglitol-Glyset 米格列醇
Voglibose 伏格列波糖

51. B. Oral hypoglycemic drugs -3
Acarbose 阿卡波糖
Reducing intestinal absorption of starch (淀粉), dextrin (糊精), and disaccharides (二糖) by inhibiting the action of alpha- glucosidase enzymes in the brush border of the small intestines.

52. B. Oral hypoglycemic drugs-3
Mechanism of Acarbose

53. Alpha-Glucosidase Inhibitors – Caveats in Use
Acarbose has minimal systemic absorption, but some hepatic metabolism occurs.
Contraindicated with advanced liver disease
Miglitol has greater systemic absorption
Not metabolized by the liver
Renally excreted, and hence should not be used in renal failure (creatinine >2)
Voglibose in contrast to acarbose, has less of GI side effects. It is also more economical compared to acarbose.

54. B. Oral hypoglycemic drugs -3
Alpha-Glucosidase inhibitors
Major side effect : GI intolerance, including bloating, cramping, and flatulence, diarrhea… need to titrate very slowly.
Major advantage: absence of hypoglycemia when used as monotherapy.

55. Summary Medication Site of Action/Mechanism Side-Effects
Sulfonylurea (eg. glyburide)
Augments insulin secretion, binds SUR
Hypoglycemia, caution renal insufficiency, elderly
Thiazolidinediones (eg. rosiglitazone)
PPARg receptor/increased insulin sensitivity
Liver, LE edema, congestive heart failure, MI
Biguanide (metformin)
Reduced hepatic gluconeogenesis
GI upset, Lactic acidosis (very rare), only use if creatinine<1.5 mg/dl
Glinides (repaglinide)
Bind SUR, short action
Hypoglycemia, caution in renal insufficiency
Alpha-glucosidase inhibitors (acarbose)
Inhibits brush border enzyme/Reduce glucose absorption
Flatulence, diarrhea
Incretins/GLP-1 (exenatide)
Stimulates insulin, delays gastric emptying, satiety
Nausea, vomiting (given by injection)
DPP4 Inhibitors (vildagliptin)
Inhibits GLP1 breakdown
GI side effects

56. Thanks