DIABETES MELLITUS

It is a condition in which there is a chronically raised blood glucose concentration.

It is caused by absolute or relative lack of the hormone insulin or there is insulin action for the body’s need.

Different types of Diabetes

Type I Insulin Dependent Diabetes Mellitus (IDDM)

Type II Non-Insulin Dependent Diabetes Mellitus (NIDDM)Non-obeseObese

Gestational Diabetes mellitus

World wide ImpactWorldwide population is 130 million Increase in incidence of diabetes by 195% from 19 million in 1995 to a predicted 57 million by 2005.

85% Type 2 DiabetesPeak age of onset is 60 yearsMost subjects are diagnosed at the age of 40 years5 - 7 % of total population (Western)50% cases are undiagnosed

Prevalenceas high as >50% in pima Indians of ArizonaEurope / USA - 70% patients are >55 yearsAvg. age is 60 years

Prevalence of Type 2 Diabetes

Pancreas

Alfa cells-Secrete GlucagonIncreases glucose in blood

Islets of Langerhans

Beta cells-Secrete InsulinReduce glucose in blood

Delta cells-Secrete Somatostatin Hypothalamic hormone

Insulin

Insulin plays very important role in …

Transport of Glucose inside the cells Conversion of Glucose to energy (Glycolysis) Conversion of Glucose to Glycogen (Glycogenesis) Inhibition of Lipolysis (breakdown of lipids to FFA) Inhibition of Gluconeogenesis

Thus insulin help reduce the plasma Glucose & FFA levels.

How does insulin get secreted from beta cells

G

G

G

GG

GGK

GK

G6P

ATP

K+Ca2+

Ca2+

Ca2+

Ca2+

EXC

GK

GLUT 2

Glucokinase

Insulin

Granule of proinsulin

EXC Exocytosis

DP

1st Phase

2nd Phase

Basal Level

5 Min.

I

At normal glucose level of 80-90mg/dl rate of insulin secretion is minimal ie - 25mg/min/kg

Insulin Receptors

- Glycoprotein consisting of two sub-units- 2 Extra-cellular sub-units - 2 partly intracellular sub-units

Receptor

Tyrosine Kinase activity

Auto-phosphorylation of various tyrosine amino-acid residues

Insulin actionInsulin is taken toLysosomes for degradation

Insulin receptor is recycled& brought back to cell surface

GlycolysisGlycogenesis

GLUT-4 mediated Glucose Uptake

Lipogenesis

How does insulin act on peripheral cells

G

GG

ATPG

G

G

I

I

Glut-1 :Basal & non-insulin mediated glucose uptake in many cells like Rbcs, brainGlut-2 :Glucose uptake in B cells (Prerequisite with GK for G sensing)Glut-3 :Non-insulin mediated G uptake in brain, Sodium dependant.Glut-4 :Insulin mediated G uptake in muscle & adipose tissueGlut5 : Fructose ransporter, very low affinity for glucose, present in Small intestine, brain, muscle

G

Insulin

GLUT-4

Insulin Receptor

Glucose

Blood vessel Peripheral cell

GlycogenI+

I+

Signal Glut-4 Store

LipidsI-FFA

I-

Glucose Metabolism

Glucose

Brain

Adipose Tissue

Skeletal muscle

Liver

Glut-4

Glut-4

I+

I+

Glut-3

NIMGU

G ATP

G Glycerol TG

G G-6P Pyruvate Lactate

Glycogen Co2

I+ I+

I+

NIMGU

NIMGU

I+ Cat + I+

G Glycogen AALactateGlycerol

Glcg+ Glcg,cats

I+

Gluconeogenesis

+ Glcg,cats

I-

Cats- Catecholamine,Cort- Cortisol, I- insulin, NIMGU-Non insulin mediated G uptake

Pathophysiology of Diabetes

Two basics causes of Type 2 Diabetes

1. Insulin Resistance i.e insulin is available in the body but not able to exert it’s biological action

2. Insulin Deficiency i.e inadequate secretion insulin by beta cells of Langerhans

Insulin Resistance

- Insulin Resistance is a condition when insulin does not exert it’s biological effects adequately.

Causes of Insulin Resistance:

1. Genetic component Reduced efficiency of translocation of Glut4 in muscle cells

2. Environmental Componenta. Chronic Hyperglycemia (Glucotoxicity)

Decreased Glut4 translocation in muscle

Reduction in insulin stimulated glucose uptake

b. Elevated plasma FFA levels (Lipotoxicity)

Decreased Glucose transport and inhibition of Glycolysis

Insulin Resistance

Genetic Factor

Insulin Resistance in liver / muscle Increase insulin levels Triglyceride deposition in fati.e. Decrease Lipolysis Increase Lipogenesis Truncal obesity

Insulin Resistance Type 2 Diabetes inWesternized Culturewhere food is available in abundance

* Thrifty Genotype

3 Adrenoreceptor

Metabolic Activity ofVisceral fatInsulin receptor substrate - 1 (IRS -1)Intracellular signals from insulin receptorGlycoprotein (PC - 1) in cell membrane that inhibits the tyrosine kinase activity of insulin receptors

Environmental Factors

-Increase food intake Obesity Increase Fat-Decrease Energy consumption Truncal Secrete Cytokine TNF-

Central Obesity Visceral fat intracellular signaling of undergo Lipolysis the insulin after binding easily to its receptors Increase FA Insulin Resistancelevels in blood (liver and muscle)

Insulin Resistance

Increase glucose levels Increase glucose levels

Increase insulin secretion by - cells B cell fatigue/Failure*

Hyperinsulinaemia Tackle insulin resistance for few days

Hyperglycemia IGT T2D

How does Insulin Resistance leads to Type 2 Diabetes

* IAPP (islet amyloid polypeptide) or Amylin which is co-secreted with insulin by beta cells, polymerizes to form fibrils of amyloid that are deposited around the beta cells in the islets. This may change beta cells & interfere with their function of insulin secretion

Environmental Factors

• Overeating Obesity• Inactivity• Smoking• Diabetogenic Drugs

Genetic Factors

Unknown

GeneticFactors

Unknown

Environment Factors

• Pregnancy• Endocrine Diseases• Diabetogenic drugs• Malnutrition in utero

Insulin Resistance (muscle and liver) - cell defect

Glucose toxicity

Hyperglycaemia

Impaired glucose tolerance

Type 2 Diabetes

Worsening - cell function• ? Amyloid deposition• Malnutrition in utero

Syndrome X

Plasminogenactivator inhibitor-1

Hypertension Triglycerides

Central (android)obesity

HDL-Cholesterol

Impaired glucose tolerance

Type 2 diabetes

Insulinresistance

Hyperinsulinaemia

?

Atheroma

Macrovascular Complications

Diagnosis Of Diabetes

53% Diabetic Symptoms28% Incidental findings16% Infections of Candida2% Complications E.g.. Retinopathy

Stage of diagnosis

Symptoms of Diabetes

There may be no classical symptoms-Polyurea-Polydipsia-Polyphagia-Weight Loss

I DDM (type 1 diabetes) NI DDM (type 2 diabetes)-Sudden onset -Gradual onset-Severe symptoms, includingcoma in some patients

-May be no symptoms

-Recent weight loss -Of ten no weight loss-Usually lean -Usually obese-Spontaneous ketosis -Not ketotic-Absent C peptide -C peptide detectable-Markers of autoimmunitypresent (e.g. islet cellantibodies)

-No markers of autoimmunity

Diagnosis of diabetes considered

With classical symptoms or signs

No classicalsymptoms or signs

Test randomblood glucose

Format 75-g OGTT(WHO criteria)

DIABETES

8-15 mmol/l

IMPAIRED GLUCOSETOLERANCE

>15 mmol/l

NORMAL

Type 1 more likely if :• Severe symptoms• Weight loss • Sustained ketosis or ketonuria• Precoma / coma

Consider C-peptide test

Review and retestperiodically

Assign type of diabetes

144-270mg/dl

>270mg/dl

* As per ADA-97 this has been termed as a ‘IFG’ i.e impaired Fasting glucose

Different Types of Tests

1. Fasting Plasma Glucose (FPG)2. OGTT (Post Prandial Plasma Glucose) 75 mg of Glucose solution is given & blood Glucose is measured after 2 hrs3. Glycosylated Hemoglobin (HbA1c) % of total Hemoglobin bound to glucose in blood : normal is <6-6.5% (Used more commonly in Monitoring of diabetes rather than diagnosis)

Normal range of Blood Glucose = 80-90mg/dl

6.1

6.1- 7

mmol/l

>7

7.8

7.8-11

>11

mmol/l

A. Non-pharmacological approacha. Diet- Energy intake Vs Expenditure- Desirable and target body weight - BMI (<25 kg/m2)- Predict rate of weight loss - Initial weight loss - rapid

- Age over >60 yr., weight loss is slowDeficit Weight Loss 1.4 kg / month - men

0.6 kg / month - woman 500 Kcal / day 0.5 kg / week

Nutrient Components of diet in Type 2 diabetes

High complex carbohydrate (50-60% of total calorie intake)Low Protein (10-15%)Low Fat (< 30%;MUFA are preferred over PUFA)Increase water soluble fiber intake

Current Therapy

Unfortunately Blood glucose levels can be normalized with diet alone in only 15-30% patients

Regular Exercise accelerate weight lossIncrease insulin sensitivityDecrease Glucose output by liverIncrease insulin uptake in liver

Increase number of insulin receptors in MonocytesDecrease Thrombogenic factors like factor VII / PAI - I/ Blood Viscosity

30 min daily walk = Doubling the dose of OHA or 20- 30 U of insulin

Weight loss - Decreased blood pressure - Improves blood lipid profile

B. Exercise

Class 1 : Drugs that reduces Insulin resistanceE.g. Biguanides like Phenformin, Metformin

Class 2 : Drugs that increases Insulin Secretion by Beta cells of pancreas- Sulfonylurias like Glibenclamide, Glipizide, Gliclazide & Glimepiride

- Repaglinide- Insulin injections

Newer Class of Drugs:-Alfa-Glucosidase inhibitor like Acarbose-Thiazolidinedione/Glitazones like

Rosiglitazone & Pioglitazone

Combination of Sulphonylurea + MetforminCombination of Sulphonylurea + insulin + Metformin also can be used.

B. Pharmacological Approach

1.Biguanides ( Phenformin & Metformin)

Introduced in 1950, & Phenformin was first molecule of this class.

Action: Increase peripheral glucose uptakeReduces hepatic glucose productionAlso reduces intestinal glucose absorptionLower blood glucose by avg..2-3mmol/l (36-54mg/dl)

Adv: Very least chances of Hypoglycemia Very useful in Obese type 2 Diabetic Patients because it reduces the weight in obese patients

Disadv: Presence of either Exogenous or endogenous insulin is necessary for their action

Tolerance is poor because of G.I problems like nausea, vomitting, abdominal discomfort,diarrhea etc.

Lactic acidosis was a major side effect with Phenformin because of this it was withdrawn from major markets long back in 1977.

2.Sulphonylureas

1st GenerationTolbutamideChlorpropamideHigher effective doses & more of side effects therefore not used very commonly

2nd GenerationGlibenclamide(Glyburide)GlipizideGliclazideGlimepiride

Action: Increase insulin secretion from beta cells.Reduces hepatic insulin uptake i.e. increased hepatic insulin

clearanceCauses around Lower blood glucose on an avg.. by 3-4 mmol/l (54-72mg/dl)

Sulphonylureas:-

Adv: Very useful in lean type 2 Diabetics where insulin deficiency is a major problem.

Disadv:-•Hypoglycaemia is major side effects especially with longer acting SU like Glibenclamide, Chlorpropamide therefore can’t be used in Elderly

patients & Renally impaired patients•Heamatological complications are more common with 1st generation Su.

•Glibenclamide & Glipizide has higher secondary failures & Specially with Glibenclamide there are higher chances of weight gain.

•There are reports which says that Glibenclamide increase the cardiovascular risk because it closes the K+ dependant ATP

channels in vascular smooth muscle also along that of with B cells.•Glibenclamide acts better on Gluconeogenesis therefore reduces FPG better than Glipizide whereas Glipizide reduces PPG better because of better post-prandial insulin release with Glipizide.

Insulin

ActionInsulin facilities glucose transport into the cell, inhibits gluconeogenesis in the liver, favours triglyceride synthesis. It stimulates glycogen synthesis from glucose in the liver and muscles. Insulin can not be given orally. It has a short plasma half-life and is degraded mainly in the liver, muscle and kidney.

Types of insulin -Short acting insulin's (Neutral insulin injection) - Their duration of action is 7 to 8 hours.-Intermediate acting insulin (Isophane insulin injection) has duration of action of 20 to 24 hours.-Long acting insulin (Ultralente) has duration of action of 25 - 40 hours.

UseIn Diabetes Mellitus it is useful when rapid and intense insulin action is required. In diabetic precoma and coma.Adverse effect: Lipodystrophy at injection site, erythema.

Contraindications : Insulinoma, hypoglycaemia.

3. Newer Drugs:

a. Alfa-Glucosidase Inhibitore.g. Acarbose, miglitol

Action:

Inhibits the Diasaccharidase like Alfa-Glucosidase which are required for the intestinal absorption of glucose.Thereby delays the absorption of Glucose.Normally used as a Co- therapy with SUs in type 2 Diabetes.Recommended dosage is around 50-100 mg with each mealreduces the PPG by 1-2mmol/dl (18-36mg/dl)

Adv:Good for obese patients with ,mild diabetes & poor diet compliance.

Disadv:In high dosage can cause malabsorpton, also causes abdominal bloating, flatulence & diarrhea.

Early diagnosis

UndiagnosedDiet & Exercise

Obese(BMI>27kg/m2) & Syndrome ‘X’

Non-obese(BMI<27kg/m2)

FPG >7m/l (126mg/dl) & HbA1c>6.5%

Low SU Met

Diabetic complications Diet & Exercise

Late Diagnosis

Dose of SU

Met+ low SU

ObeseNon-obese

SU

FPG >9m/l (162mg/dl) & HbA1c >8%

Met+ low SU

SU + Met&/or Acar

SU + Met&/or Insulin

IGT

Mild to Mod.

T2D

Severe, Uncontrolled

T2D

Before Pioglitazone...

SU- Sulfonylurea; Met-Metformin; Acar- Acarbose

An ideal drug...

Insulin Resistance

IGT

Hyperinsulinaemia

Hyperglycemia

Cardiovascular Problems

Gluconeogenesis

Truncal Obesity

Thrifty Genotype

FPG

PPG

Type 2 Diabetes

Atherosclerosis HbA1c

Insulin secretion

FFA

Hypertension

Dyslipidaemia

Txa2 Prostacyclin

Platelet Aggregation Free Radicals

Endothelial Damage

ThromboemboilismRetinopathy Neuropathy Nephropathy

Glibenclamide/Glipizide- Glip ; Rosiglitazone- R; Acarbose-A ; Emnorm- E : Insulin-I ; Piozed-P ; Glycinorm-Gly

Glucose

Diet

Stroke

Glip

R

R

R

A

E

E

E

R

P P

P RP

P

P

Glip

P

P

Gly

Gly

Gly

GlyGly

Gly

Gly

P

Gly

Early diagnosis

UndiagnosedDiet & Exercise

Obese(BMI>27kg/m2) & Syndrome ‘X’

Non-obese(BMI<27kg/m2)

FPG >7m/l (126mg/dl) & HbA1c>6.5%

Low SU Met

Diabetic complications

Lower dose of Sulfonylurea or Metformin

Diet & Exercise

Late Diagnosis

IGT

Mild to Mod.

T2D Dose of SU

Met+ low SU

ObeseNon-obese

SU

FPG >9m/l (162mg/dl) & HbA1c >8%

Met+ low SU

SU + Met&/or Acar

Severe, Uncontrolled

T2D

SU + Met&/or Insulin

Every patient with type 2 Diabetes is the patient for PIOZED

PiozedPiozed

Piozed

PiozedPiozed

Piozed

After Pioglitazone...

Product Profile- Glycinorm

PHARMACODYNAMICS

Gliclazide binds to specific receptors on pancreatic beta cells resulting in release of insulin.

G

G

G

G

ATP

K+Ca2+

Ca2+

Ca2+

Ca2+

EXC

I

SU

GK

GLUT 2

Glucokinase

Insulin

Granule of proinsulin

EXC Exocytosis

SU receptor

GLYCINORM

40 mg BP 80 mg BP 160mg

Each strip contains 10 tablets 10 tablets 10 tablets

Each box contains 10 strips 10 strips 10 strips

Each shipper contains 150 boxes

shelf life 3 years 3 years 3 years

Appearance White scored white scored white scored Tablet Tablet. Tablet

R.P (L.T.E.) 18.50 28.00 45.00

E.S.V. 11.94 18.08 29.05

Antidiabetic-Market

ORAL DIABETIC MARKET

ANTIDIABETIC COMBINATIONS

1%

GLICLAZIDE + METFORMIN

8%

GLIPIZIDE + METFORMIN5%

GLIBENCLAMIDE + METFORMIN

8%

METFORMIN13%

OTHER ANTIDIABETICS8%

REPAGLINIDE1%

ROSIGLITAZONE2%

GLIMEPRIDE5%

GLICLAZIDE 16%

GLIPIZIDE13%

GLIBENCLAMIDE 20%

Total Oral Anti-Diabetic market

Glibenclamide (20%) is the biggest SU followed by Gliclazide(16%)

(Including Pioglitazone)

Total market = 339 CrGrowth rate = 35% ORG-Aug’01

Mar-01 Apr-01 May-01 Jun-01 Jul-01 Aug-01

ORAL ANTIDIABETICS 339 35 - - - - - - -

GLIBENCLAMIDE 113045 56 -4 8804581 9728294 10035722 9321574 9374237 10095955 1291374GLIPIZIDE 43223 39 -5 3037896 3632504 3735478 3661357 3694302 3417764 379868GLICLAZIDE 20614 49 19 1619586 1755604 1826223 1897288 1829273 1846773 227187GLIMEPRIDE 4413 22 207 363577 427623 418533 458556 520289 619349 255772

0ROSIGLITAZONE 3318 12 100 343236 342597 387745 360852 417751 408793 65557REPAGLINIDE 1331 7 100 126223 113039 125729 146743 156078 144756 18533PIOGLITAZONE 2022 9 100 145244 172956 269475 302425 426948 522674 377430

OTHER ANTIDIABETICSMETFORMIN 63531 42 14 5072671 5603451 5489330 5746128 5525098 5293305 220634

GLIBENCLAMIDE + METFORMIN 25 39GLIPIZIDE + METFORMIN 20 80GLICLAZIDE + METFORMIN 10703 32 129 890180 981892 989948 1078973 1200002 1201870 311690

Total market

ORAL ANTIDIABETIC MARKETAUGUST 2001 MAT ORAL ANTIDIABETIC MARKET FOR 6 MONTHS

Aug over MarVALUE

(RS Cr)UNITS (000)

GRR% (units)

All molecules have done well , Pioglitazone has added 3.75 lacks units over last 6 months