Download Insulin

Insulin & Antidiabetic Drugs
Peng Qing
Objectives


Be able to describe the insulin preparations, the
effects of insulin, clinical uses and adverse reactions
of insulin.
Be able to list the major oral drug classes used and
give example.
Background

Diabetes mellitus classification:
1.
2.
Type I. insulin-dependent diabetes mellitus (IDDM):
pancreatic B cell destruction (immune-mediated in
most cases)
Type II. non-insulin-dependent diabetes
mellitus (NIDDM): ＞90%,
defects of insulin secretion
and action, insulin resistance.
3. Type 3, other;
4. Type 4, gestational diabetes mellitus
Insulin


Small protein containing 51 amino acids
arranged in two chains (A and B) linked by
disulfide bridges.
Insulin and C-peptide are released from
pancreatic B cells at a low basal rate and at
a much higher stimulated rate in response
to a variety of stimuli, especially glucose.
Insulin
Effects of Insulin on Its Targets


Insulin promotes synthesis and storage of glycogen, triglycerides, and
protein in its major target tissues: liver, fat, and muscle.
The release of insulin from the pancreas is stimulated by increased
blood glucose, incretins, vagal nerve stimulation, and other factors.
Principal types and duration of action of
insulin preparations

Four principal types of injected insulins are
available:
(1) rapid-acting, with very fast onset and
short duration;(insulin aspart, insulin lispro)
(2) short-acting, with rapid onset of action;
(Regular insulin )
(3) intermediate-acting; (protamine zinc insulin)
(4) long-acting, with slow onset of action
(Insulin glargine )
Pharmacokinetics



Insulin is a protein, which can be
destructed by digestive enzyme.
Oral adminstration is invalid.
Absorption is rapid when
subcutaneous injection (i.h.)
Inactivation in liver and 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
constitutes the recognition site.
An β subunit, spans the membrane and
contains a tyrosine kinase(激酶).
Phosphorylations results in
multiple effects, including
-translocation of glucose
transporters to the cell
membrane with a resultant
increase in glucose uptake;
- increased glycogen
synthase activity and
increased glycogen
formation;
-multiple effects on protein
synthesis, lipolysis, and
lipogenesis; and enhance
DNA synthesis and cell
growth and division.
Clinical Uses

1.
2.
3.
4.
5.
Therapy of all insulin deficient diabetes.
IDDM (type 1)
NIDDM (type 2) which cannot be controled by diet
therapy or oral hypoglycemic agents.
Diabetes with acute or severe complication
(Diabetic ketoacidosis, hyperosmolar
hyperglycemic syndrome).
Diabetes accompanied severe infection, wasting
disease(消耗性疾病), high fever, pregnance, trauma
and operation.
Hyperkalemia.
Adverse Reactions
1.Hypoglycemia:
most common complication of insulin therapy.
relieved by glucose administration
2.Insulin allergy:
local or systemic urticaria results from histamine
release from tissue mast cells sensitized by antiinsulin IgE antibodies.
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 utilization.

Chronic resistance:
①pro-receptor abnormality: anti-insulin antibodies;
②receptor level change: number↓, or affinity↓
③post-receptor abnormality: abnormal glucose
transport system or enzyme system in target cell.
4. Lipoatrophia at injection site(脂肪萎缩)
Oral Hypoglycemic Agents
Insulin secretagogues
Insulin sensitizer
Biguanides
a-glucosidase inhibitors
Insulin secretagogues :sulfonylureas


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);
gliclazide(格列齐特,达美康)
Sulfonylureas

Mechanism of Action
-increase insulin release from the pancreas .
-a reduction of serum glucagon levels
sulfonylureas
+
receptor
efflux of K+ ↓
close
depolarization
B cell inward rectifier-type
ATP-sensitive potassium
channel
Voltage-gated Ca2+ channel open
Release of preformed insulin
Ca2+ influx
Pharmacological Effects
1.
Reduce blood glucose levels:
2.
Stimulation of ADH secretion and
potentiation of its action at the renal tubule
→ therapy of diabetes insipidus(尿崩症).
3.
Effects on blood coagulation: platelet
adhesiveness↓, plasminogen(纤溶酶原)
synthesis↑
Clinical Uses
1.
Type 2 diabetes with a functioning
pancreas islet but invalid to diet therapy.
2.
Diabetes insipidus(尿崩症):
chlorpropamide(氯磺丙脲)
Adverse Reactions




Cutaneous anaphylaxis(皮肤过敏),
gastrointestinal disorder, liver damage
Hematologic toxicity: leukopenia, blood
platelet↓, hemolytic anemia
Persistent hypoglycemia
Contraindicated in patients with hepatic or
renal insufficiency.
Insulin secretagogues: meglitinides




Repaglinide, the first member of the
group, was approved for clinical use in
1998
modulate B-cell insulin release by
regulating potassium efflux through the
potassium channels.
has a very fast onset of action
use in controlling postprandial glucose
excursions for type 2 diabetics.
Insulin Sensitizer

Insulin resistance
Acquired: type 1 diabetes —— control
blood glucose
 Hereditary: type 2 diabetes —— insulin
sensitizer
 Thiazolidinediones(Tzds,噻唑烷酮类化合
物): rosiglitazone(罗格列酮), pioglitazone(吡

格列酮)
Pharmacological Effects
1.
2.
3.
4.
Tzds reduce insulin resistance
Ameliorate lipid metabolism disturbance
Prevent vascular complications in type 2
diabetics
Improve the function of pancreatic B cell
Mechanism of Action
Competitively activate
peroxisome(过氧化物酶)
proliferator-activated
receptor-γ(PPAR γ, nuclear
receptor ) →
modulate the expression of
the genes involved in lipid
and glucose metabolism,
insulin signal transduction,
and adipocyte and other
tissue differentiation.
Precautions and adverse effects

fluid retention, especially when used in
combination with insulin or insulin secretagogues.

increased risk of heart failure
Anovulatory women may resume ovulation and
should be counseled on the increased risk of
pregnancy.

hepatotoxicity

increased bone fracture in women.

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 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
maybe includes:
①direct stimulation of glycolysis in tissues,
with increased glucose removal from
blood;
②reduced hepatic gluconeogenesis;
③slowing of glucose absorption from the
gastrointestinal tract
④reduction of plasma glucagon levels.

Clinical Uses:
1.

for patients whose hyperglycemia is due
to ineffective insulin action. Biguanides
does not increase weight or provoke
hypoglycemia.
Adverse Reaction:


lactic acidosis
gastrointestinal reaction(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 carbohydrate 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.