Post on 28-Dec-2015
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