What is DM?

Diabetes mellitus

Or Simply Diabetes 
A syndrome of
disordered metabolism
Due to a combination of hereditary and
environmental causes,
Resulting in abnormally high blood
sugar levels- Hyperglycemia
 Diabetes mellitus -TYPES
TYPE 1 TYPE 2 NIDDM
• IDDM • Due to insulin resistance
• Loss of beta [or reduced insulin
sensitivity]
cells → • Combined with reduced
deficiency of insulin secretion 
insulin TYPE 3
“Juvenile • Drug induced
diabetes“ TYPE 4
majority cases • Gestational diabetes 
mellitus   
in children.
 Insulin Biosynthesis

B cells-Proinsulin
[A+C Peptide+B]
↓
Stored in
granules
Proinsulin
↓
Converted B Proinsulin
and secreted A Glucagon
as insulin D Somatostatin
[A+Disulfide
bridge+B
 Control of insulin release from the pancreatic B cell by
Glucose [Chemical][Hormonal, Neural are other stimuli]

Oral>i.v

First phase- Within 2 minutes

Delayed phase
 Control:Insulin Release
• Chemical • Neural
Glucose Adrenergic-a2↓
Incretins Adrenergic-b2↑
• Hormonal Muscarinic
GH  [Vagal] ↑
Counter regulatory Corticosteroids, 
Thyroxine
Glucagon ↑
Somatostatin ↓
 Mol.MOAs of insulin
• Multiple effects
• Translocation of glucose
transporters (especially
GLUT-4, 1,2,3,5)
• Increase in glucose
uptake;
• Glycogen synthase
activity
• Increased glycogen
formation
• Effects on protein
synthesis
• Fat metabolism
endocrine and the sensory systems.

Receptor Super Families

 
References:
                                                                                                            

Ligand gated ion channels

G-Protein coupled[GPCR]

Nuclear receptors
Enzymatic receptors
 D-R
Binding

Drug

Effect

Receptor

Second messengers

RECEPTOR MEDIATED DRUG ACTION

Effects of Insulin on Its Targets
 Effects of INSULIN
Effect on liver Effect on muscle
• Inhibits glycogenolysis • Increased protein
• Inhibits fatty acids and synthesis and inhibit
amino acids → keto proteolysis
acids • Increased glycogen
• Inhibits amino acids → synthesis
glucose • Increases glucose
• Storage as glycogen transport, uptake
and utilization
Effects of INSULIN..
Effect on adipose tissue:
• Increases glucose
uptake and storage
as fat and glycogen
• Inhibits lipolysis
• Inhibits release of
FFA + Glycerol
[Substrate s for
Gluconeogenisis in
liver]
 Gluconeogenesis
Absorption IN LIVER
Glycogenolysis
In
su
Insulin [-] lin

[-]

Processes add glucose Blood

[Hyperglycemia]
lin
Processes utilize glucoseI u
ns In
s
[Hypoglycemia]
ul [+]
in
Insulin
[+]
[+]
Peripheral
utilization
Lipogenesis
Protein Synth. In Muscles
 Source and insulin preperations
Species A Chain B Chain
8th AA 10th AA 30th AA
Human Huma
THR ILEU THR
Pork THR n InsuILEU ALA
Beef
is not
ALA
lin
VAL ALA
Conventional prep.
•Impurities

from •Antigenic

Huma
1. Highly purified pork •Less expensive

n
Insulins •Replaced by
• Monocomponent insulins 2.Highly purified pork

pancr
1. Human insulins
Insulins

eas!!!
• Recombninant DNA
•Human insulins

!!
•Insulin analogues
Technology[E.Coli, porcine, Yeast]

3. Insulin analogues
Changing or replacing AA sequences
3. Lispro
4. Aspart
5. Glulisine
6. Glargine 5. Detemir
 Principal Types and Duration of Action of Insulin
Preparations

Type Duration[hr] Onset Peak Appearance

Rapid acting
I.Lispro 3-5 Clear
I.Aspart 3-5 Clear
I.Glulisine 2-4 Clear
Short acting
Regular[Soluble] 6-8 Clear
Intermediate acting
I.Zinc[Lente] 20-24 Cloudy
Isophane.I [NPH] 20-24 Cloudy
Long acting
Protamine zinc I. 24-36 Cloudy
[Ultra lente]
I.Glargine 24 Clear
Reactions [ADE] to Insulin

Hypoglycemia, serious , can

be fatal
Tt: Oral or i.v Glucose, 
Glucagon 0.5- 1mgi.v

Local reactions and

Allergy are rare with
newer preparations
Drug Interactions
• ß blockers • Alchohol can 
Prolong  precipitate 
[By (-)  hypoglycemia
Comp.mech]  • Quinine, lithium, 
hypoglycemia,  salicylates 
mask warning  etc.enhance 
symptoms insulin secretion 
• Thiazides,  and worsen 
hypoglycemia
frusemide, OCP 
raise blood 
sugar, 
Uses of Insulin
Effective in all types
Must in Type 1 and Gestational

•Indications in Type 2:
•When oral agents are no longer effective
or when not tolerated
•Under weight patients
•Temporarily-Surgery, pregnancy,
infections
•Complications of diabetes, DKA, Gangrene
etc
Indications of highly
purified/Human Insulins

• Insulin resistance
• Allergy
• Lipodystrophy at
injection site
• Short term use
Diabetic Ketoacidocis [Diabetic coma]
• Precipitated by infection, trauma, stress
in insulin dependent patients
• Serious
• Hypotension, shock, tachycardia,
dehydration, hyperventilation, vomiting,
coma
• Treatment:
• Regular insulin-I.V.
• Bolus followed by infusion
• i.v fluids.
• Kcl ???
• NaHco3
• Phosphate
• Antibiotics
Insulin Resistance
• When insulin requirement increases
beyond 200u/day
• Switch over to human/purified
preparations
• Causes
• Antibodies -Chronic
• Pregnancy
• HTN
• Infection
• Surgery
• Stress
Insulin delivery
• 1 mg=28 iu
• Sub cutaneous/ 
i.v.
• Syringes
• Pen devices
• Pumps
• Inhaled insulin
• Oral-Not yet 
available
• What is DM? • ADE-Hypoglycemia
• Types DM • Drug interactions
• Pro insulin-insulin • Uses
• Mol mech. Of secretion • Routes
• Chem-Hormonal-Neural  • DKA, Resistance to 
stimuli insulin
• Insulin receptors
• Effect of Insulin
- CHO -Fat-Protein
• Blod sugar-3+3
- Sources
• Types of insulin-Rapid-
Short-Intermediate-Long
 ORAL ANTIDIABETIC
Insulin Biguanide [
HYPOGLYCAEMIC ] AGENTS
Thiazolidinedion
secretagog s es
ues Metformin
•Rosiglitazone
1. Sulfonylureas •Pioglitazone
I Gen
•Tolbutamide, a-
•Chlorpropamide
•Tolazamide glucosidase
II Gen inhibitors.
•Glibenclamide •Acarbose
•Glipizide
•Gliclazide •Miglitol
•Glimepiride

2. Meglinitides
•Repaglinide

3. D-phenylalanine
derivative
Nateglinide
Sulfonylureas :Mechanism of Action
ACUTE ADMINISTRATION:
INSULIN RELEASE FROM
PANCREATIC Beta CELLS↑

CHRONIC ADMINISTRATION:
1. Down regulation of sulf.receptors on pancreas

Insulinaemia decreased
But antidiabetic action maintained?????????

Increase in the insulin receptors in target tissues

2.Reduction of serum glucagon

concentrations….[Minor action]

Pharmacokinetics?????
Sulfonylureas
Adverse effects Drug interactions with
• Hypoglycemia[> with long  • Salicylates & Sulfa: highly protein 
acting-Chlorpropamide,  bound→
Glibenclamide] Displacement→Hypoglycemia
4. Propranolol-
• G.I.disturbances
a. Blocks b2 →
• Wt.gain
Blocks glycogenolysis &
• Allergic reactions delays recovery of
• Teratogenicity-Not safe in  hypoglyc.
pregnancy b. Blocks b1
• Chlorpropamide- Blocks symptoms of
hypoglycem.
Disulfiram like action
10.Enzyme inducers
[Rifampicin]
And enzyme inhibitors

[Chloramphenicol,Cimetid
 TOXICITIES

Drug
Interactions

Teratogenicity
Not safe in
pregnancy
 ORAL ANTIDIABETIC
Insulin [ HYPOGLYCAEMIC] AGENTS
Biguanide Thiazolidinedion
secretagog s es
ues
1. Sulfonylureas
I Gen
•Tolbutamide, a-
•Chlorpropamide
•Tolazamide glucosidase
II Gen inhibitors.
•Glibenclamide
•Glipizide
•Gliclazide
•Glimepiride

2. Meglinitides
•Repaglinide

3. D-phenylalanine
derivative
Nateglinide
Repaglinide[Meglinitide] Nateglinide[D-Phenylalaninie

• Not related to
sulfonylureas
• MOA similar  to 
Sulfonylureas
• Rapid and short
duration
• Used in post prandial 
hyperglycemia in Type2
 ORAL ANTIDIABETIC
Insulin [ HYPOGLYCAEMIC] AGENTS
Biguanide Thiazolidinedion
secretagog s es
ues Metformin
•Rosiglitazone
1. Sulfonylureas •Pioglitazone
I Gen
•Tolbutamide, a-
•Chlorpropamide
•Tolazamide glucosidase
II Gen inhibitors.
•Glibenclamide •Acarbose
•Glipizide
•Gliclazide •Miglitol
•Glimepiride

2. Meglinitides
•Repaglinide

3. D-phenylalanine
derivative
Nateglinide
Biguanides Gluconeogenesis
:Metformin
Glycogenolysis
t i on M
rp et
Abso [-] fo
rm [-]

in
in

rm
tfo
Me

Processes add glucose Blood

[Hyperglycemia]
in
rm
Processes utilize glucose t f o
[Hypoglycemia] e [+]
M

Blood sugar
reduced
Peripheral
utilization
Lipogenesis
Protein Synth.
Biguanides :Metformin:ADE and
USES

ADE Vit B12 def

•GI No
Disturbances HYPOGLYCEMIA
•Lactic
acidosis
[Common
with USES
Phenformin, Obese, Type2
hence not
used]
 ORAL ANTIDIABETIC
Insulin [ HYPOGLYCAEMIC] AGENTS
Biguanide Thiazolidinedion
secretagog s es
ues Metformin
•Rosiglitazone
1. Sulfonylureas •Pioglitazone
I Gen
•Tolbutamide, a-
•Chlorpropamide
•Tolazamide glucosidase
II Gen inhibitors.
•Glibenclamide
•Glipizide
•Gliclazide
•Glimepiride

2. Meglinitides
•Repaglinide

3. D-phenylalanine
derivative
Nateglinide
 Thio & 
Pio THIAZOLIDINEDIONES (Tzds)
Glitazones
Bind to Reduce
nuclear blood
PPAR-γ glucose
Rec. by

• Increasing Glu tpt

into muscles and
adipose tissues
• Inhibiting hepatic
gluconeogenesis
• Promoting
lipogenesis

Peroxisome Proliferator-Activated
Receptor-gamma (PPAR-γ), 
 THIAZOLIDINEDIONES
ADE
• Hepatotoxicity-Less with 
Newer drugs
• Anemia,
• Weight gain, 
• Edema, and plasma 
volume expansion.
•Increases utilization
glucose • CI-severe CHF
•Increases sensitivity to
insulin
•Reduces insulin resistance
 ORAL ANTIDIABETIC
Insulin [ HYPOGLYCAEMIC] AGENTS
Biguanide Thiazolidinedion
secretagog s es
ues Metformin
•Rosiglitazone
1. Sulfonylureas •Pioglitazone
I Gen
•Tolbutamide, a-
•Chlorpropamide
•Tolazamide glucosidase
II Gen inhibitors.
•Glibenclamide •Acarbose
•Glipizide
•Gliclazide •Miglitol
•Glimepiride

2. Meglinitides
•Repaglinide

3. D-phenylalanine
derivative
Nateglinide
ALPHA-GLUCOSIDASE INHIBITORS

Monosaccharide
Oligosaccharides
[Glucose
Not
and Disaccharides Absorbed
Fructose ]

Uses:
Acarbose Add on drugs in Type 2
Miglitol
ADE:
Flatulence, diarrhea,
and abdominal pain
Indications of oral agents Type 2
•Only in Type 2 Guidelines for management
•Above  40 at onset
•Obesity
•Duration less than
 5 years
•FBS,200mg/dl
•Insulin ,40 u/d
•No complications
 Other Agents
PRAMLINTIDE
• Suppresses glucagon release
• Delays gastric emptying 
• Anorectic effects
• For PP hyperglycemia
•               S.Cutaneous
EXENATIDE
• Incretin analogue
• Potentiation of glucose-mediated insulin secretion
• S.Cutaneous
SITAGLIPTIN
• Inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that 
degrades incretin
• Oral
 The World Diabetes Day logo
NOV 14th 

•The colour blue reflects the sky

that unites all nations and is the
colour of the United Nations flag.
•The blue circle signifies the unity
of the global diabetes community in
response to the diabetes pandemic.