Insulin & Oral Antidiabetic Drugs

The
Pancreas:is
exocrine.

both

endocrine

&

The endocrine part secretes

the following hormones from
islet of Langerhans:
A- cells(- cells) secrete glucagon.
B cells( or -cells) secrete insulin and
amylin.
D cells(or -cells) secrete somatostatin.

 F-cells(or PP cells) secrete pancreatic

p olypeptide.
1

All these hormones are

polypeptides which control

glucose concentration in blood.
Insulin is a polypeptide hormone

consisting of two chains(A chain

with 21 aminoacids and B chain
with 30 aminoacids) combined
by

two disulfide bridges.

2

Endogenous insulin is secreted by B cells

of islets of
Langerhans

Islet of Langerhans:
-Alpha cell:20%, glucagon
-Beta cell: 75%, insulin

-Delta cell:5% somatostatin

-PP cell: pancreatic
polypeptide

Glucose Metabolism and its Regulation

by Insulin or
Glucagon

Diabetes
mellitus:

Insulin or
its responses
blood glucose

Acute or chronic
symptoms

Main factor that controls insulin

synthesis

and release is blood glucose

level.
Other stimuli to insulin
release are:

aminoacids (arginine and

leucine),fatty acids, peptide
hormones from gut (eg
gastrin, secretin,
cholycystokinin, gastric

inhibitory polypeptide,
glucagon- like peptide-1),
parasympathetic stimulation,
and some drugs such as
sulfonylureas
5

B cells also secrete amylin(islet

amyloid

peptide)which:
- delays gastric
emptying
-opposes insulin by stimulating glycogen
breakdown in
striated muscle.
A(alpha) cells secrete glucagon which
increases blood

glucose and causes breakdown of fat and

protein. It stimulates glycogen breakdown
(glycolysis) and gluconeogenesis and
inhibits glycogen synthesis and glucose

oxidation. It also increases rate and force

of
contraction of heart.
Somatostatin inhibits secretion of insulin &
glucagon

Diabetes mellitus:
Definition: a syndrome of disordered
metabolism of carbohydrates due to relative
or absolute insulin deficiency or resistance.
Classification: is divided into two types:
Type 1,insulin dependent diabetes mellitus:
Lack of insulin caused by autoimmune
destruction of B cells.
Type 2,noninsulin dependent diabetes
mellitus: Cells resistance to insulin,or
insulin deficiency.Associated with
obesity.Treated by oral

insulin

hypoglycemic drugs &/or

Other types of diabetes mellitus include:

Secondary DM due to diseases such as
acromegally, pheochromocytoma,Cushings
syndrome, and drugs.
Gestational diabetes occuring during
pregnancy which can lead to
macrosomia (abnormaly large fetus body)
and
shoulder dystocia(difficult
delivery).Treated by diet,
exercise& insulin

Signs and symptoms:

Very thirsty(polydipsia), feeling of tiredness,
constant hunger(polyphagia).
Using the toilet often to urinate(polyurea)
Weight loss.
High level of glucose in urine & in fasting

blood
Exogenous insulin is required to prevent
ketoacidosis, which is due to increased
breakdown of fat to acetyl-CoA that is converted
to acetocetate and hydroxybutrate.
9

Comparison of type 1 and type 2

diabetes
Age of onset
Nutritional
status
at
time of onset
Prevalence
Genetic

predisposition
Defect or
deficiency

10

Type 1(IDDM)
Usually during
childhood or
puberty
Commonly
undernorished
5---10% of
diagnosed
diabetics
Moderate

B cells are
destroyed,
triggered by
viral infection or
chemical toxin
leading to

Type 2(NIDDM)

diabetics

Commonly
age 35

Very

over

strong

Obesity usually
present
9095%
diagnosed

0f

Inability of B
cells to produce
appropriate
quantities
of
insulin,
insulin
resistance or

Harms (complications) in the long term include:

Acute
Diabetic ketoacidosis (DKA) in untreated type 1.
Nonketotic hyperosmolar coma in type 2 diabetics.
Chronic
Microvascular disease: impotence & poor wound
healing
Atherosclerosis :Strokes, coronary heart disease
Neuropathy,retinopathy, nephropathy
Infective disease: Tuberculosis
11

Treatment
Type 1: Insulin must be injected or inhaled
Type 2: Food control, exercise, medicines:

1) agents which increase insulin secretion;

2) agents which increase the sensitivity of target

organs to insulin or decrease resistance;

3) agents which decrease glucose

4) Insulin needed for patients with serious

complications or in an emergency.

12

absorption

Section 1 Insulin
Chemistry:a

peptide molecule with 51 aa arranged

in two chains (A & B) linked by 2 disulfide bridges.

Secretion: By cells in pancreatic islet of
Langerhans .Similar structurally in most mammals
Degradation: Liver & kidney
Endogenous: Liver (60 %) & kidney (35 %-40 %)
Exogenous: Liver (35 %-40 %) & kidney (60 %)
T1/2 in plasma: 3-5 min
13

Release of insulin
Release of insulin from B cells is
stimulated by

increased blood levels of glucose,

mannose, certain
aminoacids(leucine,arginine),glucagon,
glucagon-like polypeptide-1(GLP-1), and
glucose- dependent insulinotropic
peptide(GIP) collectively called incretins,
cholecystokinin & vagal nerve
stimulation, and some drugs including
sulfonylureas, theophyline, -adrenergic
agonists.

Its release is inhibited by somatostatin,

leptin and

chronically elevated levels of glucose

and
aminoacids
14

Glucose enters -cells via GLUT2,then it is

phosphorylated by glucokinase and
converted
to pyruvate in
cytoplasm.
Pyruvate enters mitochondria to
give ATP.

ATP inhibits ATP-sensitive K+ channels

causing

membrane depolarization,
opening

Ca++channels which enters cells and

facilitate
exocytosis of insulin.
Release is inhibited
by:

2deoxyglucose,somatostatin,catecholam
ines,
-adrenergic agonists, -blockers,
diazoxide,
thiazide diuretics, phenytoin and
alloxan

15

16

Physiologic & pharmacologic actions of

insulin
1.Insulin is an anabolic & growth
promoting hormone
2. it acts on cell membranes receptors.
3. Effects divided into:
Rapid effects(within seconds)
including: 1.Increased entry of glucose,

aminoacids & K + into cells(increased

17

glucose uptake).

Intermediate effects (within minutes):

Increases glycogen synthesis and inhibits its .1
catabolism and of fat, and protein.inhibits
gluconeogenesis,(increases glycogen stores).
Activates lipoprotein lipase(increases .2
triglyceride synthesis) and inhibits hormone
sensitive lipase(inhibits lipolysis).
Delayed effects(within hours):
Increases mRNAs for enzymes involved in .1

an18 abolism(increase protein synthesis &growth)

Effects of insulin on carbohydrate, fat &

protein
Live cells
Fat cells
Muscle
Type of
metabolism
metabolis
m
Carbohydrat Decreased
e
gluconeogenesis
Metabolism Decreased
glycogenolysis

Increased glycolysis
Increased
glycogenesis
Increased
Fat
Metabolism Lipogenesis
Decreased lipolysis

19

Protein

Decreased protein

Increased
glucose
uptake
Increased

Increased
glucose
uptake
Increased

glycerol
syntheis

Glycolysis

Increased
synthesis
of triglycerides

Increased fatty
acid
synthesis
Decreased
lipolysis
-

Increased
glycogenesis

Increased

Mechanism of its action

Insulin receptor

in cell membrane mediates its effects.

Is composed of2 subunits, which constitute the

recognition site, and 2 subunits, which contains a
tyrosine kinase.
Steps of mechanism of

action:

Insulin is attached to its binding site on subunit

Tyrosine kinase activity on -subunits is triggered
producing autophsphorylationof the -subunit.
The autophosphorylation allows phosphorylation of
some proteins and dephosphorylation of others.
T20he phosphorylated proteins mediateinsulins effects.

Insulin receptor

21

Effect of insulin on glucose uptake and metabolism. Insulin binds to its

receptor (1) which in turn starts many protein activation cascades (2). These
include: translocation of Glut-4 transporter to the plasma membrane and influx
of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis
(6).

22

Effects of insulin on taarget

cells:promotes synthesis
and storage glycogen, triglycerides and
proteins in
tussues(liver,fat and muscle)

23

 Sources of exogenous insulin:

Bovine

& porcine insulin

Human insulin by replacement of porcine insulin

30- alanine in B chain by threonine

Recombinant human insulin by Escherichia coli

Clinical use
1. Diabetes mellitus
The only effective drug for type 1 diabetes
The following situations of type 2 diabetes
(1) Not effectively controlled by food
limitation & oral antidiabetic drugs;
24

2) Accompanies DKA & nonketotic

hyperosmolar hyperglycemia coma;

3) Accompanies serious infection,

hyperpyrexia, injury, gestation and
consumptive diseases.
2. Others
Hyperkalemia
A component of a solution used for limiting
myocardial infarction & arrhythmias
25

Adverse reactions

1. Insulin allergy: itching, redness, swelling,

anaphylactic shock
2. Insulin resistance
3. Hypoglycemia: nausea, hungry, tachycardia,
sweating, and tremulousness.

First aids needed while convulsions &

coma happens

4. Lipodystrophy at injection sites: atrophy

26

Insulin preparations in clinical

use:
Pharmaceutical preparation are
designed to

avoid wide fluctuations in plasma

concentrations.
Different formulations vary in their
timing of

onset of action, peak effect and

duration of
action.

Soluble insulin produces a rapid and

short-lived

effect.
Longer acting preparations are
made by

precipitating insulin with protamine

or zinc.

27

(A)Rapid onset &short-acting

preparations17/11/2016
(1) Regular
insulin:
Short-acting, soluble, crystalline zinc
insulin, given

usually S/C or IV. It rapidly lowers

blood glucose.
All rapid-acting insulins
are
now made using

genetically engineered bacteria .Cow

and pig

insulins are no longer

used.
Onset: 0.51hrs

28

Peak: 2 4hrs
Duration: 57hrs

Insulin analogs

Insulin analogs have been synthesized by

modifying

structure of insulin so that the action profile

mimics
physiological
release.
-rapid-acting analogs include: aspart,
lispro, glulisine
-long-acting analogs include: glargine
and detemir
Insulin lispro: like regular insulin it exists in
hexamers. unlike regular insulin it dissociates
into monomers almost instantaneously following
injection and shorter duration

of action compared with regular

insulin.
Advantages: prevalance of hypoglycemia is
reduced
by2030%.Also glucose control is
modest but significantly improved with
insulin lispro as compared
with regular
29
insulin

Insulin
aspart: dissociates rapidly into
monomers

(like lispro) following injection.Has the

same
characteristics as
lispro.
Insulin glulisine: is similar to lispro
and aspart

All insulin analogs are administered

S/C or IV

immediately before or after a

meal.

(2) Intermedi
ate-acting
Insulins:
Lente insulin: is an amorphous precipitate
of insulin

with zinc ion combined with 70% ultralente

insulin.
- Onset is slower but more sustained
than regular
insulin.
- Not given
IV
30

Isophane(NPH)
insulin:

(Neutral Protamine Hagedorn) insulin is a

suspension of
crystalline zinc insulin combined at neutral pH
with the
+vely charged protamine( a polypeptide) to
form a less soluble complex.This delays onset of
action and prolongs its effectiveness. Is usually
given S/C only in combination with regular
insulin.Not suitable for diabetic ketoacidosis or
emergency hyperglycemia

Neutral protamine lispro(NPL) is

a similar


preparation that is used only in
combination with
insulin lispro

31

(3) Long- acting

insulin
preparations:
Ultralente: a suspension of zinc insulin
forming
large particles that dissolve slowly,
delaying onset
and prolongs duration of
action
Glargine insulin:is a clear solution that
precipitates

at physiological pH at injection site

from which absorption occurs slowly.It
has slower onst than NPH with a flat
prolonged duration of action.It is
given s/c.
Detemir insulin:has a fatty acid side
chain which
enhances association with
albumin.Slow
dissociation from albumin gives a long
duration of
action
32

Insulin combinations

Various premixed combinations of human

insulin are

available:
-70%NPH+30% regular
insulin
-50%NPH+50% regular
insulin
-75%NPL+25% insulin
lispro
Synthetic amylin
analogs:
-pramlintide is an amylin analog that is uaed
as an adjunct

to mealtime insulin in diabetics.

-it delays gastric emptying,decreases
postprandial glucagon
secretion and improves satiety
-given s/c,doses of insulin are reduced by
50% to avoid
hypoglycemia
33

Insulin preparations and administration

Duration
of action

Ultrashort
shortacting

Times of action (min)

Insulin
type

Pat
h

Onset

peak

duration

Lispro,aspart
,glulisine.

s/c
i.v

515
min

30-90

35hr

Cito!
(DKA and etc.).

Regular

0.5 h, a.c., t.i.d.

s/c

30~60
5~8

2~3

Isophane

s/c

2~4

4~10

10~16

lente

s/c

3~4

4~10

12~18

or q.i.d.

Medium

Long

Given time

34

1 h, a.c., q.d. or
b.i.d.

Ultralente, Glargine,

Deti
mir

s/c

6~
10

2-4

1o-16

2-4

peakless
6--14

24~36

1 h, a.c., q.d.

35

Glucagon:

A single chain polypeptide secreted by A

cells of

Langerhans and upper

GIT Secretion stimulated by many factors but
mainly high
levels of aminoacid
L-arginine.It is also
stimulated by
low and inhibited by high plasma levels of
glucose
and fatty acids.
Sympathomimetics
via
adrenoceptors and

parasympathomimetc stimulate release.

Somatostatin inhibit release.

It increases blood glucose by stimulating
glycogenolysis,
gluconeogenesis,
lipolysis
and proteolysis and
inhibit glycogen synthesis.It also
36
increase rate and force of heart
contraction

Pharmacologic effects of
glucagon:

(A) Metabolic
Effects:
Acts through G protein coupled
receptors.

Causes catabolism of glycogen raising

plasma

glucose and increases gluconeogenesis

and
ketogenesis.

No effects on muscle glycogen since

there are no

glucagon receptors in skeletal muscle.

It causes release of insulin from B
cells

cells,catechlamines from
adrenal medulla,calcitonin from
medullary carcinoma
cells.

37

(B)- potent inotropic

and
chronotropic
effcets
on the
heart mediated through cAMP
mechanisms.
This effect does not require
functional
adrenocep
tor
(C) effects on smooth muscle: large doses
relax intestine
by unknown
mechanism

Clinical Uses:

Emergency treatment of severe

hypoglycemia in pts

with type 1
diabetes As a diagnostic test for testing
ablity of B cells to
release

insulin in type 1
diabetics
To reverse cardiac effect of an over dose of blockers

As an aid for x-ray visualization of

38
bowel

Section 2 Oral Antidiabetic

Drugs
Classification
(1) Insulin secretagoges
Sulfonylureas, and glinides
(2) Insulin sensitizers:
Thiazolidinediones,biguanides
(3)-glucosidase inhibitors:

Acarbose and meglitol

39

(4)Meglitinides

.insulin

secretagoges

(A) Sulfonylureas:Promote insulin release from B cells

Representative Drugs
1st generation:
Tolbutamide(Orinase),chlorpropamide(Dibenese)
Tolazamide(Tolanase) and Acetohexamide
2nd generation:
Glybenclamide (Glyburide ,Daonil)
Glipizide , Glimepiride
Should be used cautiously in pts with cvs disease or elderly.
3rd generation:
Glyclazide
40

Pharmacological effects
1. Hypoglycemic effect
2. Antidiuretic effect
chlorpropamide & glybenclamide
3. Antiplatelet-aggregation effect
glyclazide

41

Hypoglycemic mechanism:
1. Rapid mechanism: stimulation of insulin secretion
Sulfonylurea receptor in -cell membrane activated
ATP-sensitive K+-channel closed
Cellular membrane depolarized
Ca2+ entry via voltage-dependent Ca2+ channel

Insulin release

2. Long term profit involved mechanism

Inhibition of glucagon secretion by pancreatic cel

Ameliorating insulin resistance

Increase
insulin receptor number & the affinity to in
42

Clinical use

Adverse reactions

1. Type 2 diabetes
mellitus
2. Diabetes

1. Gastrointestinal disorders
2. Allergy, since they are sulfonamides
3. hyperinsulinemia leading to hypoglycemia
Chlorpropamide contraindicated in elderly &
patients with functional disorders in liver or
kidney.
4.Granulocytopenia, cholestasis & hepatic injury

5. weight gain due appetite stimulation

43

B. Glinides: include repaglinide

&nateglinide
Promote insulin release from B cells
similar to

sulfonylureas but have rapid onset and

short
duration of
action
May be combined with
metformin or

glitazones but not with

sulfonylureas

Well absorbed orally,metabolized in

liver and

excreted in
bile
Adverse effects include
hypoglycemia,

44

Pipaglinide produces severe

hypoglycemia

when taken with lipid lowering

agent

.insulin sensitizers
(A)Thiazolidinediones(TZDs alsocalled glitazones):
Representative Drugs
rosiglitazone

troglitazone

pioglitazone

ciglitazone

Pharmacological effects
do

not promote insulin release from B cells

Decrease

insulin resistance at receptor site

Ameliorating
Preventing

fat metabolic disorder

and treating type 2 diabetes mellitus

45

and their cardiovascular complications

Mechanism
(possible):
Peroxisome proliferator-activated receptor-(PPAR-) activated

Nuclear genes involved in glucose & lipid metabolism and

adipocyte differentiation activated resulting in increased insulin
sensitivity

Clinical use:
In insulin resistance & type 2 diabetes mellitus
Adverse reactions
Troglitazone occasionally induces fatal hepatic

injury thus withdrawn from market

46

(B) Biguanides
Representative Drugs
metformin
Key points
insulin
increase

secretion unchanged.

glucose uptake and use by tissues

reduce

hepatic glucose output by inhibiting hepatic

gluconeogenesis.Slow intestinal absorption of sugars
Alone

or co-administered with insulin or sulfonylureas

Metformin

also used to treat atherosclerosis since it

lowers serum lipids( LDL& VLDL) and increases HDL
weight
47

loss due to decreased appetite

111. -glucosidase inhibitors

Representative Drugs
acarbose , meglitol

voglibose ,
Key points

Inhibit digestion of starch & disaccharides via

competitively inhibiting intestinal -glucosidases
(sucrase, maltase, glycoamylase, dextranase)
Used alone or together with sulfonylureas in type 2
diabetes
Main adverse reaction: flatulence, diarrhea, belly ache.
Patients with inflammatory bowel disease & kidney
impaired forbidden.
48

1.Dipeptidylpeptidase-IV
inhibitors(DPPIV)
Sitagliptin and saxagliptin are orally
active DPP-IV

inhibitors
used in type 2 diabetes
Mechanism of action: they inhibit the
enzyme DPP-IV
which inactivates
incretin hormones such as
glucagon
like peptideI(GL-I)

High levels of incretin hormones increase

insulin release

in response to meals and reduce

glucagon secretion
Can be used alone or incombination
with insulin,

metformin, sulfonylureas or
glitazones
Adverse effects include nasopharyngitis
and headache

Pancreatitis with
sitagliptin


49

V. Incretin mimetics:
Oral glucose results in a higher secretion
of insulin
than an equal load of i.v.
glucose:
This effect is called incretin effect,
and is

markedly reduced in type 2 diabetics.

This effect occurs because the gut
releases

incretin hormones, namely GLP-1 and

glucose-

dependent insulinotropic

peptide in
response to
a meal.
Incretin hormones are responsible for 60
70%

of postprandial insulin
release
Exenatide and liraglutide are injectable
incretin

mimetics used in type 2 diabetes as

adjunct
50

Mechanism of
action:

They are analogs of GLP-1 that act

on its

receptor to:
-increase insulin
secretion
-slow gastric
emptying time
-decrease food
intake

-decrease postprandial glucagon

release
-Promote B cells
proliferation Thus weight
gain, and postprandial
hyperglycemia are
reduced
Adverse effects include
nausea,vomiting
51 diarrhea or constipation, and
pancreatitis.

Thank you!

52