Presented by Guide

Mr. Gogawale Vinayak G.M.Pharm. (Semester-II)

(Department of Pharmacology)

Dr. U.M.Aswar(Pharmacology)

SINHGAD INSTITUTE OF PHARMACY, NARHE

PATHOBIOLOGY OF DIABETIC COMPLICATIONS

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CONTENTS

• Introduction .

• Complications in diabetes .

• Pathogenesis of complications of diabetes.

• References.

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• Diabetes mellitus is a group of chronic disorders characterize by the hyperglycemia.

• Types of diabetes: 1. Type I diabetes mellitus2. Type II diabetes mellitus3. Gestational diabetes mellitus

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INTRODUCTION

• Type I diabetes mellitus: - It is characterized by the bodies disability to

produce insulin due to autoimmune destruction of beta cells of pancreas.

-It generally occur in the childhood and in adults at late 30s or early 40s.

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Mechanism of type I diabetes mellitus

• Type II diabetes mellitus: -It is caused due to lack of insulin secretion

and insulin resistance action of body which cause hyperglycemia.

-

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Mechanism of type II diabetes mellitus

Complications in diabetes mellitus

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• s complications

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Types of diabetes complications

Eye:• Retinopathy

Heart:• Cardiomyopathy

Kidney:• Nephropathy

Neuropathy

Retinopathy: • Diabetic retinopathy characterized by the growth of

new blood vessels on the retina and posterior surface

of the vitreous.

• It causes the loss of vision of both eyes.

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Eye

Eye

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• Stages of retinopathy:

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Retinopathy

Mild nonproliferative retinopathy

Moderate nonproliferatve retinopathy

Severe nonproliferative retinopathy

Proliferative retinopathy

Cardiomyopathy

• It is a disorder in which the myocardium get affects and

shows left ventricular hypertrophy.

• Diastolic and systolic dysfunction or in combination.

• Patients who suffer from the coronary artery diseases as

well as hypertension they shows synergic adverse effect.

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Heart

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Heart

Heart

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Nephropathy

• Diabetic nephropathy is clinical syndrome characterized

by decreasing glomerular filtration rate, glomerular

hypertrophy, tubulointerstitial fibrosis, decreased

excretion of albumin and decreased creatinine clearance.

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Kidney

• Stages of Nephropathy:

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Nephropathy

Glomerular hypertrophy

Mesangial expansion

Micro albuminuria

Overt-proteinuria Hypertension

End stage renal disease

Neuropathy

Neuropathy

• It is the symptoms of dysfunction of the peripheral

nerve which resembles in pain.

• Changes in the blood vessels supplying the peripheral

nerves underlie the mechanisms involved in micro

vascular damage and hypoxia.4/4/2015 18

Neuropathy

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Pathways causes complications of diabetes• Polyol pathway

• Advanced glycation end product formation

• Protein kinase C

• Hexosamine pathway.

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Pathogenesis of complications of diabetes

Increased polyol pathway flux

• Aldose reductase is the enzyme in the polyol pathway.

• It is cytosolic, monomeric oxidoreductase that catalyses

the NADPH dependent reduction of wide variety of

carbonyl compounds including glucose.

• The metabolism of the glucose from this pathway is in

small percentage than the total glucose use.4/4/2015 21

• The polyol pathway involves two enzymatic reactions

the first is the reduction of glucose to sorbitol by the

action of aldose reductase and the second oxidation of

sorbitol to fructose by the action of sorbitol

dehydrogenase.

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Increased polyol pathway flux

Increased polyol pathway flux

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Advanced glycation end product formation

• It is a non enzymatic reaction in free amino acids and

carbonyl compounds or carbonyl groups of reducing

sugar called as Millard reaction.

• It is three stage reaction as follows:1. Early stage2. Intermediate stage3. Late stage

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Advanced glycation end product formation

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Protein Kinase C

• Diacylglycerol is produced as well as inosytol

triphosphate whenever receptor induced phosphotidyl

inositol hydrolysis occurs.

• The main effect of diacylglycerol is to activate

memabrane bound protein kinase which catalyses the

phosphorylation of intracellular proteins 4/4/2015 26

Protein Kinase C

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Hexosamine pathway

• Fructose 6 phosphate is converted glucosamine 6

phosphate,catalysed by first and end relating enzyme

glutamine fructose 6 phosphate amidotransferase

(GFAT). The major end product is UDP N

acetylglucosamine (UDP-GlcNAc) require to

formation of O- linked glycoprotein4/4/2015 28

Hexosamine pathway

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References

• Schalkwijk C. G., Stehouwer C. D., “Vascular Complications In Diabetes

Mellitus: The Role Of Endothelial Dysfunction”, Clinical Science (2005) 109,

143–159.

• Sharma V., Sharma P.L., “Role of Different Molecular Pathways in the

Development of Diabetes-Induced Nephropathy” ISSN(2013) 2155-6156 JDM.

• Zychowska M.,et al. “Mechanisms And Pharmacology Of Diabeticneuropathy –

Experimental And Clinical Studies.”ISSN(2013)1601-1610.

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References

• Singh V. P. et al., “Advanced Glycation End Products and

Diabetic Complications” , Korean J Physiol Pharmacol(2014)

vol 18,1-14.

• Brownlee M., “Biochemistry and molecular cell biology of

diabetic complications”, Nature (2001) vol 414, 813-820.

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