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

• IDDM

• Loss of  beta cells → deficiency of insulin

“Juvenile diabetes“ majority cases

in children.

TYPE 2 NIDDM• Due to insulin resistance

[or reduced insulin sensitivity]

• Combined with reduced insulin secretion 

TYPE 3• Drug induced

TYPE 4• Gestational diabetes

mellitus 

Insulin Biosynthesis

B cells-Proinsulin

[A+C Peptide+B]

↓Stored in granules↓Converted and secreted as insulin[A+Disulfide bridge+B

Proinsulin

B ProinsulinA GlucagonD Somatostatin

Oral>i.v

First phase- Within 2 minutesDelayed phase

Control of insulin release from the pancreatic B cell by Glucose [Chemical][Hormonal, Neural are other

stimuli]

Control:Insulin Release• Chemical

Glucose

Incretins• Hormonal

GH Corticosteroids, Thyroxine

Glucagon ↑Somatostatin ↓

• Neural

Adrenergic-a2↓

Adrenergic-b2↑

Muscarinic[Vagal] ↑

Counter regulatory

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.

                                                                                                             

References:

G-Protein coupled[GPCR]Ligand gated ion channels

Nuclear receptorsEnzymatic receptors

Receptor Super Families

Drug

Receptor

Effect

RECEPTOR MEDIATED DRUG ACTION

D-RBinding

Second messengers

Effects of Insulin on Its Targets

Effects of INSULIN

Effect on liver• Inhibits glycogenolysis• Inhibits fatty acids and

amino acids → keto acids

• Inhibits amino acids → glucose

• Storage as glycogen

Effect on muscle• Increased protein

synthesis and inhibit proteolysis

• Increased glycogen synthesis

• Increases glucose 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]

Blood

AbsorptionGlycogenolysis

GluconeogenesisIN LIVER

Processes add glucose[Hyperglycemia]

Processes utilize glucose[Hypoglycemia]

Protein Synth. In MusclesLipogenesis

Peripheralutilization

[-]Insulin

[-]

Insulin

[+]

Insulin

[+]

Insulin

[+]Insulin

Source and insulin preperations

Species A Chain B Chain

8th AA 10th AA 30th AA

Human THR ILEU THR

Pork THR ILEU ALA

Beef ALA VAL ALAConventional prep.•Impurities•Antigenic•Less expensive1. Highly purified pork

Insulins• Monocomponent insulins

2. Human insulins• Recombninant DNA Technology[E.Coli, porcine, Yeast]

3. Insulin analoguesChanging or replacing AA sequences1. Lispro2. Aspart3. Glulisine4. Glargine 5. Detemir

•Replaced by1.Highly purified porkInsulins2.Human insulins3.Insulin analogues

Human Insulin is not from Humanpancreas!!!!!

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 fatalTt: Oral or i.v Glucose, Glucagon 0.5- 1mgi.v

Local reactions and Allergy are rare with newer preparations

Drug Interactions

• ß blockers

Prolong

[By (-) Comp.mech] hypoglycemia, mask warning symptoms

• Thiazides, frusemide, OCP raise blood sugar,

• Alchohol can precipitate hypoglycemia

• Quinine, lithium, salicylates etc.enhance insulin secretion and worsen hypoglycemia

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 tolerated2.Under weight patients3.Temporarily-Surgery, pregnancy, infections4.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?• Types DM• Pro insulin-insulin• Mol mech. Of secretion• Chem-Hormonal-Neural

stimuli• Insulin receptors• Effect of Insulin- CHO -Fat-Protein• Blod sugar-3+3- Sources• Types of insulin-Rapid-

Short-Intermediate-Long

• ADE-Hypoglycemia• Drug interactions• Uses• Routes• DKA, Resistance to

insulin

ORAL ANTIDIABETIC [ HYPOGLYCAEMIC] AGENTS Insulin secretagogues

Biguanides

Thiazolidinediones

a-glucosidase inhibitors.

1. Sulfonylureas

I Gen•Tolbutamide,•Chlorpropamide•TolazamideII Gen•Glibenclamide•Glipizide•Gliclazide•Glimepiride

2. Meglinitides•Repaglinide

3. D-phenylalanine derivativeNateglinide

Metformin•Rosiglitazone•Pioglitazone

•Acarbose•Miglitol

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?????

SulfonylureasAdverse effects1. 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 with1. Salicylates & Sulfa: highly protein

bound→ Displacement→Hypoglycemia2. Propranolol-a. Blocks b2 →

Blocks glycogenolysis &

delays recovery of hypoglyc.b. Blocks b1Blocks symptoms of hypoglycem.3. Enzyme inducers [Rifampicin] And enzyme inhibitors [Chloramphenicol,Cimetidine]

USES: Type 2DM

Drug Interactions

TOXICITIES

TeratogenicityNot safe in pregnancy

ORAL ANTIDIABETIC [ HYPOGLYCAEMIC] AGENTS Insulin secretagogues

Biguanides

Thiazolidinediones

a-glucosidase inhibitors.

1. Sulfonylureas

I Gen•Tolbutamide,•Chlorpropamide•TolazamideII Gen•Glibenclamide•Glipizide•Gliclazide•Glimepiride

2. Meglinitides•Repaglinide

3. D-phenylalanine derivativeNateglinide

Repaglinide[Meglinitide]

• Not related to sulfonylureas

• MOA similar to Sulfonylureas

• Rapid and short duration

• Used in post prandial hyperglycemia in Type2

Nateglinide[D-Phenylalaninie

ORAL ANTIDIABETIC [ HYPOGLYCAEMIC] AGENTS Insulin secretagogues

Biguanides

Thiazolidinediones

a-glucosidase inhibitors.

1. Sulfonylureas

I Gen•Tolbutamide,•Chlorpropamide•TolazamideII Gen•Glibenclamide•Glipizide•Gliclazide•Glimepiride

2. Meglinitides•Repaglinide

3. D-phenylalanine derivativeNateglinide

Metformin•Rosiglitazone•Pioglitazone

•Acarbose•Miglitol

Blood

AbsorptionGlycogenolysis

Gluconeogenesis

Processes add glucose[Hyperglycemia]

Processes utilize glucose[Hypoglycemia]

Protein Synth.Lipogenesis

Peripheralutilization

[-]

Met

form

in [-]M

etformin

[+]Metform

in

Biguanides :Metformin

Blood sugar reduced

Biguanides :Metformin:ADE and USES

ADE •GI Disturbances•Lactic acidosis[Common with Phenformin, hence not used]

Vit B12 defNoHYPOGLYCEMIA

USESObese, Type2

ORAL ANTIDIABETIC [ HYPOGLYCAEMIC] AGENTS Insulin secretagogues

Biguanides

Thiazolidinediones

a-glucosidase inhibitors.

1. Sulfonylureas

I Gen•Tolbutamide,•Chlorpropamide•TolazamideII Gen•Glibenclamide•Glipizide•Gliclazide•Glimepiride

2. Meglinitides•Repaglinide

3. D-phenylalanine derivativeNateglinide

Metformin•Rosiglitazone•Pioglitazone

THIAZOLIDINEDIONES (Tzds)

Bind to nuclearPPAR-γ

Rec.

1. Increasing Glu tpt into muscles and adipose tissues

2. Inhibiting hepatic gluconeogenesis

3. Promoting lipogenesis

Reduce blood

glucose by

Thio & Pio

Glitazones

Peroxisome Proliferator-Activated Receptor-gamma (PPAR-γ),

THIAZOLIDINEDIONES

ADE

• Hepatotoxicity-Less with

Newer drugs

• Anemia,

• Weight gain,

• Edema, and plasma volume expansion.

• CI-severe CHF•Increases utilization glucose•Increases sensitivity to insulin•Reduces insulin resistance

ORAL ANTIDIABETIC [ HYPOGLYCAEMIC] AGENTS Insulin secretagogues

Biguanides

Thiazolidinediones

1. Sulfonylureas

I Gen•Tolbutamide,•Chlorpropamide•TolazamideII Gen•Glibenclamide•Glipizide•Gliclazide•Glimepiride

2. Meglinitides•Repaglinide

3. D-phenylalanine derivativeNateglinide

Metformin•Rosiglitazone•Pioglitazone

a-glucosidase inhibitors. •Acarbose•Miglitol

ALPHA-GLUCOSIDASE INHIBITORS

Oligosaccharides and Disaccharides

Monosaccharide [GlucoseFructose ]

Acarbose Miglitol

Not Absorbed

Uses:Add on drugs in Type 2

ADE:Flatulence, diarrhea, and abdominal pain

Type 2Guidelines for management

Indications of oral agents

•Only in Type 2•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 logoNOV 14th

•The colour blue reflects the skythat unites all nations and is the colour of the United Nations flag.•The blue circle signifies the unity of the global diabetes community inresponse to the diabetes pandemic.