DIABETES MELLITUS

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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 bodys need.
Different types of Diabetes Type I Insulin
Dependent Diabetes Mellitus (IDDM) Type II
Non-Insulin Dependent Diabetes Mellitus
(NIDDM) ?Non-obese ?Obese Gestational Diabetes
mellitus
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Prevalence of Type 2 Diabetes
World wide Impact Worldwide 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 Diabetes Peak age
of onset is 60 years Most subjects are diagnosed
at the age of 40 years 5 - 7 of total
population (Western) 50 cases are
undiagnosed Prevalence as high as gt50 in pima
Indians of Arizona Europe / USA - 70 patients
are gt55 years Avg. age is 60 years
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Pancreas
Islets of Langerhans
Alfa cells -Secrete Glucagon Increases glucose in
blood
Beta cells -Secrete Insulin Reduce glucose in
blood
Delta cells -Secrete Somatostatin Hypothalamic
hormone
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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.
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How does insulin get secreted from beta cells
K
DP
I
1st Phase
2nd Phase
At normal glucose level of 80-90mg/dl rate of
insulin secretion is minimal ie - 25mg/min/kg
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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
action
Insulin is taken to Lysosomes for degradation
Insulin receptor is recycled brought back to
cell surface
GLUT-4 mediated Glucose Uptake
Lipogenesis
Glycolysis Glycogenesis
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How does insulin act on peripheral cells
G
G
I
G
G
I
I-
Signal
Glut-4 Store
Glut-1 Basal non-insulin mediated glucose
uptake in many cells like Rbcs, brain Glut-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
tissue Glut5 Fructose ransporter, very low
affinity for glucose, present in Small intestine,
brain, muscle
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Glucose Metabolism
Brain
Glut-3
G ATP
NIMGU
Adipose Tissue
Glut-4
I
G Glycerol TG
Glucose
I
I
NIMGU
Skeletal muscle
Glut-4
I
I
G G-6P Pyruvate Lactate
Glycogen Co2
NIMGU
Cat
I
I
Liver
I
AA Lactate Glycerol
Glcg
G Glycogen
Glcg,cats
Glcg,cats
Gluconeogenesis
I-
Cats- Catecholamine,Cort- Cortisol, I- insulin,
NIMGU-Non insulin mediated G uptake
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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 its biological
action 2. Insulin Deficiency i.e
inadequate secretion insulin by beta cells of
Langerhans
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Insulin Resistance
- Insulin Resistance is a condition when insulin
does not exert its biological effects
adequately. Causes of Insulin
Resistance 1. Genetic component Reduced
efficiency of translocation of Glut4 in muscle
cells 2. Environmental Component a. 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
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Genetic Factor Insulin Resistance in liver /
muscle ? Increase insulin levels
? Triglyceride deposition in fat i.e. Decrease
Lipolysis Increase Lipogenesis
? Truncal obesity Insulin Resistance
? Type 2 Diabetes in Westernized Culture where
food is available in abundance
Thrifty Genotype ? ?3 Adrenoreceptor ? Metabo
lic Activity of Visceral fat Insulin receptor
substrate - 1 (IRS -1) Intracellular signals
from insulin receptor Glycoprotein (PC - 1) in
cell membrane that inhibits the tyrosine kinase
activity of insulin receptors
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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
Resistance levels in blood (liver and
muscle)
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How does Insulin Resistance leads to Type 2
Diabetes
Hyperglycemia IGT T2D
Insulin Resistance ? ? Increase
glucose levels Increase glucose levels ?
? Increase insulin secretion by ? - cells B cell
fatigue/Failure ?
Hyperinsulinaemia ? Tackle insulin resistance
for few days
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
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• Environmental Factors
• Overeating Obesity
• Inactivity
• Smoking
• Diabetogenic Drugs

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

Genetic Factors Unknown
Genetic Factors Unknown
? - cell defect
Insulin Resistance (muscle and liver)
Glucose toxicity
Hyperglycaemia
Impaired glucose tolerance

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

Type 2 Diabetes
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Syndrome X
Plasminogen activator inhibitor-1
Triglycerides
Hypertension
Insulin resistance
Atheroma
Hyperinsulinaemia
?
Macrovascular Complications
Central (android) obesity
HDL-Cholesterol
Impaired glucose tolerance
Type 2 diabetes
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Diagnosis Of Diabetes
Stage of diagnosis
53 ? Diabetic Symptoms 28 ? Incidental
findings 16 ? Infections of Candida 2 ?
Complications E.g.. Retinopathy
Symptoms of Diabetes There may be no classical
symptoms -Polyurea -Polydipsia -Polyphagia -Weight
Loss
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Diagnosis of diabetes considered
With classical symptoms or signs
No classical symptoms or signs
8-15 mmol/l
144-270mg/dl
Test random blood glucose
Format 75-g OGTT (WHO criteria)
gt15 mmol/l
gt270mg/dl
DIABETES
IMPAIRED GLUCOSE TOLERANCE
NORMAL
Review and retest periodically
Assign type of diabetes

• Type 1 more likely if
• Severe symptoms
• Weight loss
• Sustained ketosis or ketonuria
• Precoma / coma
• Consider C-peptide test

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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 hrs 3.
Glycosylated Hemoglobin (HbA1c) of total
Hemoglobin bound to glucose in blood normal is
lt6-6.5 (Used more commonly in Monitoring of
diabetes rather than diagnosis)
mmol/l
mmol/l
Normal range of Blood Glucose 80-90mg/dl
6.1
7.8
6.1- 7
7.8-11
gt7
gt11
As per ADA-97 this has been termed as a IFG
i.e impaired Fasting glucose
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Current Therapy

A. Non-pharmacological approach a. Diet - Energy
intake Vs Expenditure - Desirable and target body
weight - BMI (lt25 kg/m2) - Predict rate of
weight loss - Initial weight loss -
rapid - Age over gt60 yr., weight loss is
slow Deficit 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 (lt
30MUFA are preferred over PUFA) Increase water
soluble fiber intake
Unfortunately Blood glucose levels can be
normalized with diet alone in only 15-30 patients
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B. Exercise
Regular Exercise accelerate weight
loss Increase insulin sensitivity Decrease
Glucose output by liver Increase insulin uptake
in liver Increase number of insulin receptors
in Monocytes Decrease 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
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B. Pharmacological Approach
Class 1 Drugs that reduces Insulin
resistance E.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 Metformin Combination of
Sulphonylurea insulin Metformin also can be
used.
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1.Biguanides ( Phenformin Metformin) Introduced
in 1950, Phenformin was first molecule of this
class. Action Increase peripheral glucose
uptake Reduces hepatic glucose production Also
reduces intestinal glucose absorption Lower
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.
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2.Sulphonylureas 1st Generation Tolbutamide Chlor
propamide Higher effective doses more of side
effects therefore not used very commonly 2nd
Generation Glibenclamide(Glyburide) Glipizide Glic
lazide Glimepiride Action Increase insulin
secretion from beta cells. Reduces hepatic
insulin uptake i.e. increased hepatic insulin
clearance Causes around Lower blood glucose on
an avg.. by 3-4 mmol/l (54-72mg/dl)
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• 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 cant 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.

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Insulin Action Insulin 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. Use In 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.
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3. Newer Drugs a. Alfa-Glucosidase
Inhibitor e.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
meal reduces 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.
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Before Pioglitazone...
SU Met /or Insulin
SU Met /or Acar
FPG gt9m/l (162mg/dl) HbA1c gt8
Met low SU
SU
Met low SU
Non-obese
Obese
Diabetic complications
Diet Exercise
Met
Low SU
Late Diagnosis
Obese (BMIgt27kg/m2) Syndrome X
Non-obese (BMIlt27kg/m2)
FPG gt7m/l (126mg/dl) HbA1cgt6.5
Undiagnosed
Diet Exercise
Early diagnosis
SU- Sulfonylurea Met-Metformin Acar- Acarbose
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An ideal drug...
Thrifty Genotype
Truncal Obesity
Insulin secretion
Diet
Gly
E
Gluconeogenesis
Glip
R
P
Gly
P
R
A
Insulin Resistance
Hyperglycemia
Glucose
P
E
R
R
P
E
P
Hyperinsulinaemia
P
R
Dyslipidaemia
P
P
HbA1c
IGT
Atherosclerosis
Txa2 Prostacyclin
P
Gly
Gly
Glip
Platelet Aggregation
Gly
Free Radicals
Hypertension
Gly
Gly
Thromboemboilism
Retinopathy Neuropathy Nephropathy
Endothelial Damage
Gly
Type 2 Diabetes
Cardiovascular Problems
Stroke
Glibenclamide/Glipizide- Glip Rosiglitazone- R
Acarbose-A Emnorm- E Insulin-I Piozed-P
Glycinorm-Gly
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After Pioglitazone...
Severe, Uncontrolled T2D
Piozed
SU Met /or Insulin
Piozed
Mild to Mod. T2D
SU Met /or Acar
FPG gt9m/l (162mg/dl) HbA1c gt8
Piozed
Piozed
Met low SU
Piozed
Piozed
SU
Met low SU
Non-obese
Obese
Diabetic complications
Diet Exercise
Met
Low SU
Lower dose of Sulfonylurea or Metformin
Late Diagnosis
Obese (BMIgt27kg/m2) Syndrome X
Non-obese (BMIlt27kg/m2)
FPG gt7m/l (126mg/dl) HbA1cgt6.5
IGT
Undiagnosed
Diet Exercise
Early diagnosis
Every patient with type 2 Diabetes is the patient
for PIOZED
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Product Profile- Glycinorm
PHARMACODYNAMICS Gliclazide binds to specific
receptors on pancreatic beta cells resulting in
release of insulin.
K
I
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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
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Antidiabetic-Market
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Total Oral Anti-Diabetic market
Total market 339 Cr Growth rate 35
ORG-Aug01
(Including Pioglitazone)
Glibenclamide (20) is the biggest SU followed by
Gliclazide(16)
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All molecules have done well , Pioglitazone has
added 3.75 lacks units over last 6 months