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 and B Proinsulin

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

Insulin [-]
[-]

Processes add glucose Blood

[Hyperglycemia]

Processes utilize glucose

[Hypoglycemia] [+]

Insulin
[+]
Peripheral
utilization
Lipogenesis
Protein Synth. In Muscles
 Source and insulin preperations
Species A Chain B Chain
8th AA 10th AA 30th AA
Human THR ILEU THR
Pork THR ILEU ALA
Conventional prep.
Beef ALA VAL ALA Impurities
Antigenic
1. Highly purified pork Less expensive
Insulins Replaced by
Monocomponent insulins 1. Highly purified pork
Insulins
2. Human insulins
2. Human insulins
Recombninant DNA
3. Insulin analogues
Technology[E.Coli, porcine, Yeast]

3. Insulin analogues
Changing or replacing AA sequences
1. Lispro
2. Aspart
3. Glulisine
4. 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
blockers Alchohol can
Prolong precipitate
[By (-) hypoglycemia
Comp.mech] Quinine, lithium,
hypoglycemia, salicylates
mask warning etc.enhance
symptoms insulin secretion
Thiazides, and worsen
frusemide, OCP hypoglycemia
raise blood
sugar,
Uses of Insulin
Effective in all types
Must in Type 1 and Gestational

Indications in Type 2:
1.When oral agents are no longer effective
or when not tolerated
2.Under weight patients
3.Temporarily-Surgery, pregnancy,
infections
4.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:
1. Regular insulin-I.V.
2. Bolus followed by infusion
3. i.v fluids.
4. Kcl ???
5. NaHco3
6. Phosphate
7. Antibiotics
Insulin Resistance
When insulin requirement increases
beyond 200u/day
Switch over to human/purified
preparations
Causes
1. Antibodies -Chronic
2. Pregnancy
3. HTN
4. Infection
5. Surgery
6. 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 [ HYPOGLYCAEMIC] AGENTS
Insulin Biguanides Thiazolidinediones
secretagogues Metformin
Rosiglitazone
1. Sulfonylureas Pioglitazone
I Gen
Tolbutamide,
Chlorpropamide a-glucosidase
Tolazamide
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
1. Hypoglycemia[> with long
acting-Chlorpropamide,
Glibenclamide]
2. G.I.disturbances
3. Wt.gain
4. Allergic reactions
5. Teratogenicity-Not safe in
pregnancy
6. Chlorpropamide-
Disulfiram like action
Drug interactions with
1. Salicylates & Sulfa: highly protein
bound
DisplacementHypoglycemia
2. Propranolol-
a. Blocks b2
Blocks glycogenolysis &
delays recovery of hypoglyc.
b. Blocks b1
Blocks symptoms of hypoglycem.
3. Enzyme inducers [Rifampicin]
And enzyme inhibitors
[Chloramphenicol,Cimetidine]
USES: Type 2DM
 TOXICITIES

Drug
Interactions

Teratogenicity
Not safe in
pregnancy
 ORAL ANTIDIABETIC [ HYPOGLYCAEMIC] AGENTS
Insulin Biguanides Thiazolidinediones
secretagogues
1. Sulfonylureas
I Gen
Tolbutamide,
Chlorpropamide a-glucosidase
Tolazamide
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 [ HYPOGLYCAEMIC] AGENTS
Insulin Biguanides Thiazolidinediones
secretagogues Metformin
Rosiglitazone
1. Sulfonylureas Pioglitazone
I Gen
Tolbutamide,
Chlorpropamide a-glucosidase
Tolazamide
II Gen
inhibitors.
Glibenclamide Acarbose
Glipizide
Gliclazide Miglitol
Glimepiride

2. Meglinitides
Repaglinide

3. D-phenylalanine
derivative
Nateglinide
Biguanides :Metformin Gluconeogenesis

Glycogenolysis

[-] [-]

Processes add glucose Blood

[Hyperglycemia]

Processes utilize glucose

[Hypoglycemia] [+]

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 [ HYPOGLYCAEMIC] AGENTS
Insulin Biguanides Thiazolidinediones
secretagogues Metformin
Rosiglitazone
1. Sulfonylureas Pioglitazone
I Gen
Tolbutamide,
Chlorpropamide a-glucosidase
Tolazamide
II Gen
inhibitors.
Glibenclamide
Glipizide
Gliclazide
Glimepiride

2. Meglinitides
Repaglinide

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

1. Increasing Glu tpt

into muscles and
adipose tissues
2. Inhibiting hepatic
gluconeogenesis
3. Promoting
lipogenesis

Peroxisome Proliferator-Activated
Receptor-gamma (PPAR-),
 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 [ HYPOGLYCAEMIC] AGENTS
Insulin Biguanides Thiazolidinediones
secretagogues Metformin
Rosiglitazone
1. Sulfonylureas Pioglitazone
I Gen
Tolbutamide,
Chlorpropamide a-glucosidase
Tolazamide
II Gen
inhibitors.
Glibenclamide Acarbose
Glipizide
Gliclazide Miglitol
Glimepiride

2. Meglinitides
Repaglinide

3. D-phenylalanine
derivative
Nateglinide
ALPHA-GLUCOSIDASE INHIBITORS

Oligosaccharides Monosaccharide
and [Glucose
Not
Disaccharides Fructose ] Absorbed

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.