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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
Oral>i.v
References:
Nuclear receptors
Enzymatic receptors
D-R
Binding
Drug
Effect
Receptor
Second messengers
Insulin [-]
[-]
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
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?????????
Pharmacokinetics?????
Sulfonylureas
Adverse effects Drug interactions with
1. Hypoglycemia[> with long 1. Salicylates & Sulfa: highly protein
bound
acting-Chlorpropamide,
DisplacementHypoglycemia
Glibenclamide]
2. Propranolol-
2. G.I.disturbances
a. Blocks b2
3. Wt.gain Blocks glycogenolysis &
4. Allergic reactions delays recovery of hypoglyc.
5. Teratogenicity-Not safe in b. Blocks b1
pregnancy Blocks symptoms of hypoglycem.
3. Enzyme inducers [Rifampicin]
6. Chlorpropamide-
And enzyme inhibitors
Disulfiram like action
[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
[-] [-]
Peripheral
utilization
Lipogenesis
Protein Synth.
Biguanides :Metformin:ADE and USES
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
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