Pancreatic Hormone & Antidiabetic Drugs

GAO Fen-Fei

Background

• Diabetes mellitus classification: 1. insulin-dependent diabetes mellitus (IDDM):

pancreatic B cell destruction (immune-mediated in most cases)

2. non-insulin-dependent diabetes

mellitus (NIDDM): ＞ 90%,

defects of insulin secretion

and action, insulin resistance.

Insulin

• Small protein containing 51 amino acids arranged in two chains (A and B) linked by disulfide bridges.

• Released from pancrearic B cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose.

Pharmacokinetics

• Insulin is a protein, which can be destructed by digestive enzyme. Oral is invalid.

• Absorption is rapid when subcutaneous injection (i.h.)

• Inactivation in liver and kidney.

Pharmacological Effects• Promotes the storage of fat as well as glucose within liver,

adipose(脂肪 ) tissue, muscle.1. Promotes fat synthesis, decreases free fatty acid and keto

gensis(酮体生成 ), increases fatty acid and glucose transport,

2. Promotes glycogen synthesis, increases glucose catabolism(分解代谢 ), inhibits glycogenolysis(糖原分解 ) and gluconeogenesis(糖原异生 )→blood glucose↓

3. Promotes protein synthesis by increasing amino acid transport and by stimulating ribosomal(核糖体 ) activity, decreases protein catabolism(分解代谢 ).

4. Heart rate↑, myocardial contractility↑, blood flow of kidney ↓

Mechanism of Action

• Insulin receptor on the membranes consists of two heterodimers(异二聚体 ), each containing– An α subunit, entirely extracellular and constitu

tes the recognition site.– An β subunit, spans the membrane and contains

a tyrosine(酪氨酸 ) kinase(激酶 ).

Clinical Uses

• Therapy of all insulin deficient diabetes.1. IDDM (type 1)2. NIDDM (type 2) which cannot be controled by die

t therapy or oral hypoglycemic agents.3. Diabetes with acute or severe complication(并发症 ).

4. Diabetes accompanied severe infection, wasting disease(消耗性疾病 ), high fever, pregnance, trauma(创伤 ), and operation.

5. Intracellular K+ deficience.

Insulin Preparations

1. Ultra-short-acting insulins: insulin lispro(赖脯胰岛素 ), produced by recombinant technology, B28 (proline脯氨酸 ) B29 (lysine赖氨酸 ) Advantage: low propensity(倾向 ) to form hexamers

(六聚体 ) in contrast to human insulin, absorbed very rapidly.

The duration, in contrast to RI, is only minimally prolonged by increasing the dosage of the insulin.

2. Short-acting insulins: regular insulin (RI) The only type that can be administered intravenously.

Particularly useful for management of diabetic ketoacidosis, after surgery or during acute infections.

As with all older insulin formulations, the duration of action as well as the time of onset and the intensity of peak action increase with the size of the dose.

3. Intermediate-acting insulins: NPH, GZI4. Long-acting insulins: PZI5. Monocomponent insulin (McI): reduce contamin

ating proteins → antigenicity(抗原性 )↓

Adverse Reactions1. Hypoglycemia(低血糖症 )

2. Allergic reaction 3. Insulin resistance:

Acute resistance: induced by stress(应激 ). ①insulin antagonist (eg, GC, adrenaline)↑; ②pH↓→ insulin-R↓; ③free fatty acid and ketone body in blood↑→ inhibit glucose utilizati

on. Chronic resistance: ①pro-receptor abnormality: anti-insulin antibodyies;②receptor level change: number↓, or affinity↓③post-receptor abnormality: abnormal glucose transport system or en

zyme system in target cell.

4. Lipoatrophia(脂肪萎缩 )

Oral Hypoglycemic Agents

Insulin sensitizerInsulin sensitizer

Sulfonylureas(磺脲类 )

Sulfonylureas(磺脲类 )

Acarbose(阿卡波糖 ) and repaglinide(瑞格列奈 )

Acarbose(阿卡波糖 ) and repaglinide(瑞格列奈 )

Biguanides(双胍类 )

Biguanides(双胍类 )

Insulin Sensitizer

• Insulin resistance – Acquired: type 1 diabetes —— control blood gl

ucose– Hereditary: type 2 diabetes —— insulin sensiti

zer• Thiazolidinediones(噻唑烷酮类化合物 ): rosi

glitazone(罗格列酮 ), pioglitazone(吡格列酮 ), troglitazone(曲格列酮 ), ciglitazone(环格列酮 ), englitazone(恩格列酮 ).

Pharmacological Effects

1. Reduce insulin resistance, restore blood glucose levels into the normal: increasing glucose uptake and metabolism in muscle and adipose(脂肪 ) tissues.

2. Ameliorate(改善 ) lipid metabolism:3. Prevent and cure vascular complication of

type 2 diabetes: 4. Ameliorate function of pancreatic B cell:

Mechanism of Action

• Competitively activate peroxisome(过氧化物酶 ) proliferator-activated receptor-γ(PPAR γ) nuclear receptor → transcription →

1. adipose cell differentiation → many small adipose cells →insulin sensitivity↑

2. Enhance insulin signal transduction3. Reduce gene expression of leptin(瘦素 ) and TNF-α4. Ameliorate function of pancreatic B cell5. GLUT 1 and GLUT 4↑ → glucose uptake and transpo

rt↑

Adverse Reactions

• Incidence of hypoglycemia is low.

• Mild anemia(贫血 ), drowsiness(嗜睡 ), muscle and skeleton pain, gastrointestinal disorder.

• Troglitazone(曲格列酮 ) → idiosyncratic(特异质的 ) liver damage, liver failure or death.

Sulfonylureas (磺脲类 )

• First-generation: tolbutamide(甲苯磺丁脲 ;甲糖宁 ; D860), chlorpropamide(氯磺丙脲 )

• Second-generation: glyburide(格列本脲 ;优降糖 ;降糖灵 ,glibenclamide), glipizide(格列吡嗪 ,吡磺环己脲 ), glimepiride(格列美脲 )

• Third-generation: gliclazide(格列齐特 ,达美康 )

Pharmacokinetics

• Well absorbed in gastrointestinal tract.

• Plasma protein binding rate is high → Vd↓.

• Most drug metabolized in the liver.

• Excretion from urine.

Pharmacological Effects

1. Reduce blood glucose levels:1) Increase insulin release from pancreatic B cells: 2) Reduce serum glucagon(胰高血糖素 ) levels: indirect i

nhibition. 3) Potentiate the action of insulin on its target tissues

2. Stimulation of ADH(抗利尿激素 ) secretion and potentiation of its action at the renal tubule → dilutional hyponatremia(稀释性低钠血症 ), therapy of diabetes insipidus(尿崩症 ).

3. Effects on blood coagulation: platelet adhesiveness↓, plasminogen(纤溶酶原 ) synthesis↑—— third-generation sulfonylureas

sulfonylureas

+

B cell inward rectifier-type ATP-sensitive potassium

channel

close

receptor

depolarization

Voltage-gated Ca2+ channel open

efflux of K+ ↓

Ca2+ influxpreformed insulinRelease of

Clinical Uses

1. Type 2 diabetes with pancreas islet function but invalid to diet therapy.

2. diabetes insipidus(尿崩症 ): chlorpropamide(氯磺丙脲 ) 0.125~0.5g/d

Adverse Reactions

• Cutaneous anaphylaxis(皮肤过敏 ), gastrointestinal disorder, liver damage

• Hematologic toxicity: leukopenia(白细胞减少 ), blood platelet↓, hemolytic anemia

• Persistent hypoglycemia• Contraindicated in patients with hepatic or r

enal insufficiency.

Drug Interaction

1. high plasma protein binding rate of sulfonylureas → competitive replacement by other drugs (eg, phenylbutazone 保泰松 , dicoumarol 双香豆素 , etc) or bilirubin(胆红素 ) → hypoglycemia.

2. Alcohol inhibit gluconeogenesis(糖原异生 ) and transport of liver glucose → aggravating hypoglycemia.

3. Chlorpromazine(氯丙嗪 ), GC, thiazides(噻嗪类利尿药 ), oral contraceptives(口服避孕药 ) → inhibit blood glucose-lowering effect of sulfonylureas.

Biguanides (双胍类 )

• Metformin(甲福明 ,二甲双胍 ), phenformin(苯乙福明 ;苯乙双胍 ;降糖灵 )

• Phenformin was discontinued in the USA because of its association with lactic acidosis(乳酸酸中毒 ) and because there was no documentation of any long-term benefit from its use.

• Not bound to plasma proteins, not metabolized, excreted by the kidneys as the active compound.

• Mechanism of action remain elusive(难捉摸的 ), maybe include: ①direct stimulation of glycolysis in tissues, with increase

d glucose removal from blood;

②reduced hepatic gluconeogenesis;

③slowing of glucose absorption from the gastrointestinal tract, with increase glucose to lactate(乳酸盐 ) conversion by enterocytes;

④reduction of plasma glucagon levels.

• Clinical Uses: 1. for patients with refractory(难控制的 ) obesity whose

hyperglycemia is due to ineffective insulin action. Biguanides is an insulin-sparing agent and does not increase weight or provoke hypoglycemia.

2. In combination with sulfonylureas in type 2 diabetics(糖尿病患者 ) in whom sulfonylureas therapy alone is inadequate.

• Adverse Reaction: – lactic acidosis, ketonemia(酮血症 )

– gastrointestinal (anorexia 食欲减退 , nausea, vomiting, abdominal discomfort, diarrhea),

Acarbose (阿卡波糖 )

• α-glucosidase(葡萄糖苷酶 ) inhibitors• Mechanism: competed glycoside-hydrolase with c

arbohydrate on the small intestine epithelium brush border → hydrolysis of carbohydrate↓→ delay the absorption of glucose.

• Pharmacological Effect: lower the postprandial(餐后 ) blood glucose levels.

• Adverse Reactions: gastrointestinal discomfort.

Repaglinide (瑞格列奈 )

• Repaglinde is a member of the meglitindes(氯茴苯酸 ) group.

• A new class of insulin secretagogues(促分泌的 ).

• Advantage is to imitate the physiological secretion of insulin.

• There is overlap with the sulfonylureas in their molecular sites of action with two common binding sites and one unique.

• Unlike the sulfonylureas, they have no direct effect on insulin exocytosis.

• Repaglinide has a very fast onset and short duration of action, and is indicated for use in controlling postprandial glucose excursions.

• Metabolism in liver, 92% of metabolite is excreted via bile.

• Can be taken alone as monotherapy of in combination with biguanides.

• There is no sulfur in the structure, so repaglinide may be indicated for use in type 2 diabetic individuals with sulfur or sulfonylurea allergy.