Definition + Diabetes Mellitus is a group of Metabolic Diseases characterized by Hyperglycemia resulting from defects in insulin secretion, insulin action,

DefinitionDefinition

Diabetes Mellitus is a group of Metabolic Diseases

characterized by Hyperglycemia resulting from

defects in insulin secretion, insulin action, or both.

American Diabetes Association

Diabetes: Clinical FeaturesDiabetes: Clinical Features

Symptoms:Symptoms: PolyuriaPolyuria PolydipsiaPolydipsia == thirstthirst Polyphagia=Polyphagia= appetiteappetite Asthenia & Loss of weightAsthenia & Loss of weight

Signs:Signs:

No specific signs may be No specific signs may be signs of complicationssigns of complications

Signs:Signs:

No specific signs may be No specific signs may be signs of complicationssigns of complications

““Leonard Thompson (14 year Leonard Thompson (14 year old boy) & Elizabeth Hughes old boy) & Elizabeth Hughes (aged 14 years), were the first (aged 14 years), were the first

patients to be treated with patients to be treated with insulin in 1922.insulin in 1922.

““Fredrick BantingFredrick Banting (1921), (1921), successfully, extracted successfully, extracted

insulin, gaining the Nobel insulin, gaining the Nobel prize for this great prize for this great

discovery”.discovery”.

““Claude Bernard and Claude Bernard and Von Mering (1889), Von Mering (1889),

discovered in the same discovered in the same year that pancreatectomy year that pancreatectomy

causes diabetes”causes diabetes”

““Mathew Dobson (1776), Mathew Dobson (1776), identified glycosuria.identified glycosuria.

“ “ Thomas Willis (1621 - Thomas Willis (1621 - 1679), discovered the 1679), discovered the

sweetness of urine, hence, sweetness of urine, hence, the name Diabetes Mellitus the name Diabetes Mellitus

arised”arised”

“ “ Diabetes was long thought Diabetes was long thought to be a kidney disease (Greek to be a kidney disease (Greek

& Arabic Methodology).& Arabic Methodology).

Predisposing FactorsPredisposing FactorsIDDMIDDM

Heredity.Heredity. Histocomptability.Histocomptability. Virus infection.Virus infection. Seasonality.Seasonality. Cell-mediated immunity.Cell-mediated immunity.

Insulin SynthesisInsulin Synthesis

PrePro Insulin

Pro Insulin

C peptideInsulin

Split at position61/62

Insulin Secretion CurveInsulin Secretion Curve

Biphasic insulin response to a constant glucose stimulation(IVGTT - hyperglycemic Clamp)

Insulin rate

Time (min)

Basal

4 60

Fate of Absorbed GlucoseFate of Absorbed Glucose

GGlycogenesis

Glycolysis Muscle Cells 50 %

GGlycolysis

Lipogenesis

GGlycogenesis

Glycolysis

Liver Cells 30 %

Fat Cells 5 %

Hormonal RegulationHormonal Regulation

Blood Glucose Level

< 110 mg/L

Insulin

GlucagonsGrowth Hormone

AdrenalineCortisol

Hypoglycaemic Hormone Counter regulatory Hormones

Diabetes Estimates and Diabetes Estimates and ProjectionProjection

1994 2000 2010

Type 1 11.5 million 18.1million 23.7 million

Type 2 98.9 miilion 157.3 million

215.6 million

Total 110.4 million

175.4 million

239.3 million

Classification of Diabetes Classification of Diabetes MellitusMellitus

Primary DiabetesPrimary Diabetes

Type 1Type 1 insulin dependent insulin dependent

diabetesdiabetes

Type 2Type 2 non insulin non insulin

dependent diabetesdependent diabetes

Secondary DiabetesSecondary Diabetes Gestational diabetesGestational diabetes Malnutrition related diabetesMalnutrition related diabetes Diabetes resulting from:Diabetes resulting from:

Pancreatic diseasePancreatic disease Hormonal diseasesHormonal diseases Drug/chemical inducedDrug/chemical induced Genetic syndromesGenetic syndromes

Secondary DiabetesSecondary Diabetes Gestational diabetesGestational diabetes Malnutrition related diabetesMalnutrition related diabetes Diabetes resulting from:Diabetes resulting from:

Pancreatic diseasePancreatic disease Hormonal diseasesHormonal diseases Drug/chemical inducedDrug/chemical induced Genetic syndromesGenetic syndromes

Classification of Diabetes Classification of Diabetes MellitusMellitus

Key Organs of DiabetesKey Organs of Diabetes

Muscle

Pancreas

Liver

Hyperglycemia

in glucose storage in hepatic glucose production

insulin secretion disorder

Peripheral AbnormalitiesPeripheral Abnormalities

GlycogenogenosisGlycolysis

Gluconeogenesis Lipogenesis

LipolysisGlycogenogenesis

Glycolysis

Gluconeogenesis

Liver Fat tissues Muscles

FFA

Hyperglycaemia

Glucose StorageGlucose production

Pathogenesis of diabetes: Pathogenesis of diabetes: metabolic featuresmetabolic features

Genetic predisposition

Genetic predisposition

Insulinresistance

Insulinresistance

Defectiveinsulin secretion

HyperglycemiaHyperglycemia

Causes of Impaired Insulin Causes of Impaired Insulin SecretionSecretion


Decrease in number of Beta cells by 40-50 %Decrease in number of Beta cells by 40-50 %

{{In Insulin resistance statesIn Insulin resistance states,,

the number is either normal or increased}the number is either normal or increased}

Amyloid depositsAmyloid deposits

Amylin : amyloid materialAmylin : amyloid materialsecreted by B cells secreted by B cells Interferes Interferes with the with the recognition ofrecognition of

the glucose signalthe glucose signal



Reduced activity of the Reduced activity of the glucokinaseglucokinase

ATP production reduced inside B cellsATP production reduced inside B cells

Closure of K channel decreasesClosure of K channel decreases

Entry of Calcium reduced Entry of Calcium reduced

release of Insulin reducedrelease of Insulin reduced


Types of Insulin ResistanceTypes of Insulin Resistance

Receptor defectReceptor defect

Post Receptor defectPost Receptor defect

Types of Insulin Types of Insulin ResistanceResistance

Receptor defectReceptor defect

Decrease in the affinityDecrease in the affinity

Decrease in number (rare)Decrease in number (rare)

Post receptor defectPost receptor defect

Glucose TransportersGlucose Transporters

Intra cellular utilizationIntra cellular utilization

Enzymatic activityEnzymatic activity

Types of Insulin ResistanceTypes of Insulin Resistance

Chronic Hyperglycemia

Insulin secretion disorder

Insulin resistance

Gluco-toxicityGluco-toxicity

Vascular complicationsVascular complications

Micro-vascular complicationsMicro-vascular complications

Macro-vascular complicationsMacro-vascular complications

Micro-vascular complicationsMicro-vascular complications

Retinopathy Retinopathy

NephropathyNephropathy

Neuropathy Neuropathy

Macro-vascular complicationsMacro-vascular complications

CHDCHD

CVDCVD

PADPAD

10 years accelerated 10 years accelerated

Treatment of diabetesTreatment of diabetes::

Life style modificationLife style modification

InsulinInsulin

Oral hypoglycemic agentsOral hypoglycemic agents

Life style modificationLife style modification

Diet controlDiet control

ExerciseExercise

Smoking cessation Smoking cessation

DIET CONTROLDIET CONTROL

All diabetic patients should be on diet All diabetic patients should be on diet

control.control.

Diet control is a must either the patient Diet control is a must either the patient

is taking insulin or oral therapy. is taking insulin or oral therapy.

Over weight should be reduced .Over weight should be reduced .

Diet control should be tried at first Diet control should be tried at first

before the next step [insulin or before the next step [insulin or

tablets] especially in obese tablets] especially in obese

patients, When diet fails drugs are patients, When diet fails drugs are

indicated. indicated.


The diet for a diabetic patient is not so The diet for a diabetic patient is not so

different from the healthy diets for the different from the healthy diets for the

whole population.whole population.

Simple sugars Carbohydrate [as Simple sugars Carbohydrate [as

sucrose], should be limited for the diet sucrose], should be limited for the diet

of diabetic patients.of diabetic patients.


Carbohydrate content should be in a Carbohydrate content should be in a

fiber-rich diet [for example fruits fiber-rich diet [for example fruits

containing fibers as apples]. containing fibers as apples].

… ….. because the fiber content of diet .. because the fiber content of diet

delays absorption of carbohydrates delays absorption of carbohydrates

avoiding the rapid elevation of blood avoiding the rapid elevation of blood

glucose levels. glucose levels.


Calories :Calories : • Calories should be tailored to the need Calories should be tailored to the need

of the patient. of the patient.

Diet should containDiet should contain:: Carbohydrates → 50 - 55% Carbohydrates → 50 - 55% Fat→ 30-35% Fat→ 30-35% Protein →10 - 15%Protein →10 - 15%


Indication of InsulinIndication of Insulin

Type 1 diabetesType 1 diabetes

Unstable diabetesUnstable diabetes

Type 2 diabetes failed on SUs.Type 2 diabetes failed on SUs.

Pregnant diabetic patientsPregnant diabetic patients

Surgery (all diabetic patients)Surgery (all diabetic patients)

Diabetic comaDiabetic coma

Oral hypoglycemic agentsOral hypoglycemic agents

BiguanidesBiguanides

SulfonylureasSulfonylureas

αα- glucosidase inhibitors - glucosidase inhibitors

ThiazolidinedionesThiazolidinediones

Prandial glucose regulatorPrandial glucose regulator


Biguanides are derivatives of the Biguanides are derivatives of the

antimalarial agent Chloroguanide. antimalarial agent Chloroguanide.

Which is found to have hypoglycemic Which is found to have hypoglycemic

action. action.

The most commonly used member of The most commonly used member of

biguanides is Metformin [Cidophage]. biguanides is Metformin [Cidophage].


Indication:Indication:

Type 2 diabetes failed on dietType 2 diabetes failed on diet

Metformin can be given alone or in Metformin can be given alone or in

combination with sulfonylureas or Insulincombination with sulfonylureas or Insulin


Mode of actionMode of action

Biguanides [Metformin] is an Biguanides [Metformin] is an

Antihyperglycemic and not Hypoglycemic Antihyperglycemic and not Hypoglycemic

agent. agent. It does not stimulate pancreas to secrete insulin It does not stimulate pancreas to secrete insulin

and does not cause hypoglycemia (as a side and does not cause hypoglycemia (as a side

effect) even in large doses. effect) even in large doses.

Also it has no effect on secretion of Glucagon or Also it has no effect on secretion of Glucagon or

Somatostatin. Somatostatin.


Mode of action:Mode of action: Decreases the intestinal absorption of Decreases the intestinal absorption of

CHOCHO Increases glucose uptake (GLUT 4)Increases glucose uptake (GLUT 4) Increases glucose utilization Increases glucose utilization

(glycogensynthase)(glycogensynthase) Increases glycolysis via anaerobic Increases glycolysis via anaerobic

pathway (lactic acidosis)pathway (lactic acidosis)


Pharmacokinetics:Pharmacokinetics: Metformin is well absorbed from Metformin is well absorbed from

small intestine, stable, does not small intestine, stable, does not bind to plasma proteins, excreted bind to plasma proteins, excreted unchanged in urine. unchanged in urine.

Half life of Metformin is 1.5 - Half life of Metformin is 1.5 - 4.5 hours, taken in three doses 4.5 hours, taken in three doses with mealswith meals


Side effects:Side effects:

occur in 20-25 % of patients. occur in 20-25 % of patients.

include.. Diarrhea, abdominalinclude.. Diarrhea, abdominal

discomfort, nausea, metallic taste discomfort, nausea, metallic taste

and decreased absorption of and decreased absorption of

vitamin Bvitamin B1212. .


ContraindicationsContraindications Patients with renal or hepatic Patients with renal or hepatic

impairment. impairment. Past history of lactic acidosis. Past history of lactic acidosis. Heart failure, Chronic lung disease. Heart failure, Chronic lung disease.

.. These conditions predispose to .. These conditions predispose to increased lactate production which increased lactate production which causes lactic acidosis which is fatal. causes lactic acidosis which is fatal.

SUs., have been discovered during SUs., have been discovered during

the 2the 2ndnd. World war (sulfonamide).. World war (sulfonamide).

SUs are drugs that used orally to SUs are drugs that used orally to

control blood glucose levels of type 2 control blood glucose levels of type 2

diabetes.diabetes.

SULFONYLUREASSULFONYLUREAS

SULFONYLUREASSULFONYLUREAS Types:Types:

First generation, First generation, Chlorpropamide (Chlorpropamide (PamidinPamidin)) Tolbutamide (Tolbutamide (DiamolDiamol))

Second generation,Second generation, Gliclazide (Gliclazide (DiamicronDiamicron)) Glibenclamide (Glibenclamide (DaonilDaonil)) Glipizide (Glipizide (MinidiabMinidiab))

Third generation,Third generation, Glimepiride (Glimepiride (DiabrideDiabride) () (AmarylAmaryl))


Mechanism of action:Mechanism of action:

Pancreatic effectPancreatic effect

Extra-pancreatic effectExtra-pancreatic effect

Pancreatic effect:Pancreatic effect:

• Increase insulin release from Increase insulin release from

pancreaspancreas

• Suppress secretions of GlucagonsSuppress secretions of Glucagons


SULFONYLUREASSULFONYLUREAS Extra pancreatic effect:Extra pancreatic effect:

Increases the number of insulin Increases the number of insulin receptorsreceptors

Increases post-receptor insulin Increases post-receptor insulin sensitivitysensitivity

Increases glucolysisIncreases glucolysis Increases glycogen storage in muscle Increases glycogen storage in muscle

and liverand liver Decreases the hepatic output of glucoseDecreases the hepatic output of glucose

SULFONYLUREASSULFONYLUREAS Pharmacokinetics:Pharmacokinetics:

They are effectively absorbed from They are effectively absorbed from gastrointestinal tract.gastrointestinal tract.

Food can reduce the absorption of Food can reduce the absorption of sulfonylurea.sulfonylurea.

Sulfonylureas are more effective Sulfonylureas are more effective when given 30 minutes before eating.when given 30 minutes before eating.

Plasma protein binding is high 90 – Plasma protein binding is high 90 – 99 % .. mainly bind to albumen.99 % .. mainly bind to albumen.


Pharmacokinetics:Pharmacokinetics: 11stst generation members have short generation members have short

half lives.half lives.

22ndnd generation is administered once, generation is administered once,

twice or several times daily.twice or several times daily.

33rdrd generation is administered once generation is administered once

daily. daily.

SULFONYLUREASSULFONYLUREAS Pharmacokinetics:Pharmacokinetics:

All sulfonylurea are metabolized by All sulfonylurea are metabolized by

liver and their metabolites are excreted liver and their metabolites are excreted

in urine with about 20 % excreted in urine with about 20 % excreted

unchanged.unchanged.

Sulfonylurea should be administered Sulfonylurea should be administered

with caution to patients with either with caution to patients with either

renal or hepatic insufficiency.renal or hepatic insufficiency.


Adverse Reactions :Adverse Reactions : Very few adverse reactions [4 %] in the first Very few adverse reactions [4 %] in the first

generation and rare in the 2generation and rare in the 2ndnd and 3 and 3rdrd generation. generation.

SUs may induce hypoglycemia especially in SUs may induce hypoglycemia especially in elderly patients with impaired hepatic or elderly patients with impaired hepatic or renal functions-These cases of hypoglycemia renal functions-These cases of hypoglycemia are treated by I/V glucose infusion. are treated by I/V glucose infusion.


Adverse Reactions :Adverse Reactions : First generation may induce other First generation may induce other

side effects as …nausea and side effects as …nausea and vomiting & dermatological vomiting & dermatological reactions reactions

……These side effects are fewer in the These side effects are fewer in the 22ndnd generation and rare in the 3 generation and rare in the 3rdrd generationgeneration..


Drug interactions:Drug interactions: Some drugs may enhance or Some drugs may enhance or

suppress the actions of suppress the actions of sulfonylureas Either by affecting:sulfonylureas Either by affecting: Their metabolism and excretion Their metabolism and excretion The concentration of free The concentration of free

sulfonylureas in plasma through sulfonylureas in plasma through competing them on plasma proteins.competing them on plasma proteins.


Contraindications :Contraindications :

Type 1 DMType 1 DM

Pregnancy and Lactation. Pregnancy and Lactation.

Significant hepatic or renal failure. Significant hepatic or renal failure.

Drug – Drug interactionDrug – Drug interaction

NSAIDsNSAIDs

SalicylatesSalicylates

SulfonamideSulfonamide

ß-blockersß-blockers

ChloramphenicolChloramphenicol

DiazepamDiazepam

MAOIMAOI

BarbituratesBarbiturates

Thiazide and loop Thiazide and loop

diureticsdiuretics

SympathomimeticsSympathomimetics

CorticosteroidsCorticosteroids

Oestrogen / Oestrogen /

Progesterone Progesterone

combinationscombinations

α Glycosidase Inhibititorα Glycosidase Inhibititorα Glycosidase Inhibititorα Glycosidase Inhibititor

Acarbose (Glucobay)Acarbose (Glucobay)

Indicated for type 2 diabetesIndicated for type 2 diabetes In addition with diet In addition with diet

In addition with other anti-diabetic In addition with other anti-diabetic

therapiestherapies


Mode of action:Mode of action: Poorly absorbed 1% (act locally in Poorly absorbed 1% (act locally in

G.I.T.)G.I.T.) Inhibits Inhibits α glucosidase, so inhibits α glucosidase, so inhibits

CHO degradationCHO degradation Dose:Dose:

50mg to 100mg 3 times daily before 50mg to 100mg 3 times daily before mealsmeals


Side effects:Side effects:

Flatulence (77%) Flatulence (77%)

DiarrheaDiarrhea

Abdominal pain (21%)Abdominal pain (21%)

Decreased iron absorptionDecreased iron absorption

ThiazolidenedioneThiazolidenedioneThiazolidenedioneThiazolidenedione

Rosiglitazone (Avandia)Rosiglitazone (Avandia)

Pioglitazone (Actos)Pioglitazone (Actos)

ThiazolidenedioneThiazolidenedione Mode of action:Mode of action:

Insulin sensitizer (increase insulin sensitivity Insulin sensitizer (increase insulin sensitivity in muscle, adipose tissue & liver)in muscle, adipose tissue & liver)

They are not insulin secretagogues (Not They are not insulin secretagogues (Not

insulin releasers)insulin releasers)

ThiazolidenedioneThiazolidenedione Drawbacks:Drawbacks:

They are not effective alone in case of They are not effective alone in case of severe insulin deficiency and should be severe insulin deficiency and should be combined with sulfonylurea or metformin combined with sulfonylurea or metformin or bothor both

Side effects:Side effects: Hepatotoxicity Hepatotoxicity weight gainweight gain Dyslipidaemia (increases LDL) Dyslipidaemia (increases LDL)

Prandial glucose regulators Prandial glucose regulators ((Meglitinide)Meglitinide)

Prandial glucose regulators Prandial glucose regulators ((Meglitinide)Meglitinide)

Example:Example: Repaglinide, Novonorm (NovoNordisk)Repaglinide, Novonorm (NovoNordisk)

Rational:Rational: Fast acting, short duration non-sulfonylureaFast acting, short duration non-sulfonylurea Designed to minimize mealtime blood Designed to minimize mealtime blood

glucose peaksglucose peaks

Repaglinide, NovonormRepaglinide, NovonormRepaglinide, NovonormRepaglinide, Novonorm

Mechanism of action:Mechanism of action: Stimulation of pancreatic insulin Stimulation of pancreatic insulin

release by closing ß-cells Krelease by closing ß-cells KATPATP

channelschannels Very rapid onset of action and short Very rapid onset of action and short

duration (Tduration (TMAXMAX = 1 hour, metabolized = 1 hour, metabolized

by liver Tby liver T1/2 1/2 = 70 minutes)= 70 minutes) No hypoglycemic metabolitesNo hypoglycemic metabolites

Repaglinide, NovonormRepaglinide, NovonormRepaglinide, NovonormRepaglinide, Novonorm

Clinical efficacy:Clinical efficacy: Improves postprandial glycemia Improves postprandial glycemia Less effective in decreasing fasting blood Less effective in decreasing fasting blood

glucose levels and HbAglucose levels and HbA1C1C

drawbacks:drawbacks: Fails to provides a stable 24 hours blood Fails to provides a stable 24 hours blood

glucose controlglucose control Complicated dosage style (3-8 tablets/daily)Complicated dosage style (3-8 tablets/daily) How to adapt the dosage to the meal How to adapt the dosage to the meal

volume?volume?

SEDICOSEDICOPharmaceuticalsPharmaceuticals

Definition + Diabetes Mellitus is a group of Metabolic Diseases characterized by Hyperglycemia resulting from defects in insulin secretion, insulin action,

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