The age of Diabetes and AGE

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The Age of Diabetes and AGE

• Presented by
• Ashwini Kumar
• Doctoral Research Scholar
• Department of Biotechnology
• National Institute of Technology Raipur
• C.G

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Diabetes..

• Hyperglycemia
• IDDM (Type 1 Diabetes or T1D)
• NIDDM (Type 2 Diabetes or T2D)
• Maturity Onset of Diabetes in Youngs (MODY)
• Latent Autoimmune Diabetes in Adults (LADA) or
  Slow Onset T1D
• Gestational Diabetes
• PCOS

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Diabetes Outcome

• Cardiovascular Disorders CVD
• Diabetic Neuropathy
• Diabetic Nephropathy
• Diabetic Retinopathy
• Diabetic Foot
• Pulmonary Disorders
• Impaired wound healing

• Source Kumar A et al. Type 2 Diabetes Mellitus
  The Concerned Complications and Target Organs.
  Apollo Medicine 201411(3)161-166.

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Type 2 Diabetes

• Most common form of diabetes.
• Obesity, Diet, Environmental factors, Oxidative
  stress
• Insulin resistance
• Hereditary, TCF7L2 gene
• Polyphagia, Polydipsia and Polyuria
• AGEs

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Advanced Glycation End Products (AGEs)

• Major result of uncontrolled hyperglycemia.
• Glycation Non-enzymatic addition of a reducing
  sugar
• Protein glycation Reaction between free amino
  group of the protein and a carbonyl group from a
  reducing sugar to form a freely reversible Schiff
  base.
• Unstable shiffs base undergoes Amadori
  rearrangement to form stable amadori product.
• Affects both intracellular and extracellular
  proteins.

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Source Ahmed N. Advanced glycation end
productsrole in pathology of diabetic
complications. Diab Res Clin Pract 2005 673-21
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Supporting content..
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Effects of AGEs

• Lipid peroxidation
• Modify proteins
• AGE-Immune Complex
• Amino groups of purines in DNA susceptible to
  glycation
• Alter enzyme activity
• Protein fragmentation
• Alter immunogenecity
• Decrease ligand binding

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AGEs Receptors

• AGEs interact with their cellular receptors.
• Macrophage Scavenger Receptor Type 1 and 2
• Galectin-3 (AGE-R3)
• RAGE (Receptors for AGE)

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RAGE

• Multi-ligand receptor on cell surface
• 35 kDa protein
• Immunoglobulin superfamily
• Macrophages, endothelial cells, smooth muscle,
  astrocytes
• Expression increases in diabetes
• AGE interaction with macrophage RAGE induces
  oxidative stress.
• Mammalian, CAMs

Neeper M et al. Cloning and Expression of a
Cell Surface Receptor for Advanced Glycosylation
End Products of Protein. J Biol Chem 1992
267(21) 14998-15004. Sessa L et al. The
Receptor for Advanced Glycation End-Products
(RAGE) Is Only Present in Mammals, and Belongs to
a Family of Cell Adhesion Molecules (CAMs). Plos
One 2014 9(1) e86903.
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Effects of AGE RAGE
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AGEs and Inflammations

• Expression increases in inflammation increased
  expression leads to inflammation.
• Found on immune cells like Macrophages,
  Neutrophills, T B cells, Dendritic cells.
• Triggered by many ligands involved in
  inflammation.
• Expression in endothelial cells leukocyte
  adhesion.
• Activation of NF-kB

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AGEs and CVDs

• Most frequent effect of diabetes mellitus
• Targets vasculature and myocardium.
• Atherosclerosis
• Thickening of tunica intima arterial occlusion
• Increased oxidation and glycation of LDL
• ? Increased plasminogen activator
  inhibitor-1
• ? Decreased TPA
• Glycated HDL Less clearance of oxidized LDL,
  less ability to prevent monocyte-endothelial
  adhesion.
• Arteriosclerosis
• ? Collagen damage
• ? ECM Damage

AGEs
LDL
Glycoxidized LDL
Atherosclerosis Thrombosis Embolism
Arteriosclerosis Hypertension Vascular
Damage Decreased NO
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AGEs and Neuro-ailments

• Peripheral Neuropathy
• ? Sensory Motor Nerves
• ? Nerve fiber degeneration
• ? Endoneurial microangiopathy
• ? Microvascular injury
• ? Reduced myelination
• ? Axonal cytoskeleton glycated
• ? AGEs in every component of nerve
  tissue
• ? AGEs induced inflammation

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Contd..

• Alzheimers disease
• ? ß-amyloid (Aß) deposition as
  extra-neural plaques
• ? Aß as ligand for neural and microglial
  RAGE
• ? Cell death in RAGE expressing cells
• ? AGE accumulation in AD
• ? RAGE activation BACE1 activity
  increases
• ? Mitochondrial dysfunction in neurons
• ? RAGE Transports Aß across BBB
• ? AGE RAGE Decreased cerebral blood
  flow.

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AGE and Diabetic Retinopathy

• Major cause of blindness in diabetic population.
• Loss of pericytes, micro-aneurysm, vessel
  thickening, increased leakyness..leading to
  macular oedema and macular damage
• Higher AGE (NCML) in retina and serum of DR
  patients.
• Muller cells are greatly damaged.
• RAGE expression increased in diabetic muller
  cells.
• AGE modified albumin was higher in retinal
  capillary of IDDM patients.
• AGE destroys Pigment Epithelium Derived Factor
  (PEDF) which protects against DR.
• AGE RAGE Retinal neuron death.

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Sources of External - AGEs

• Obtained through food.
• Longer or intense heating or cooking
• Food with high carbohydrate, fats and (carb
  protein)
• High food AGE consumption greater serum AGE
• Milk tea, bakery, potato, white rice, meat
  products

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References

• Peppa M et al. The Role of Advanced Glycation
  End Products in the Development of
  Atherosclerosis. Curr Diab Rep. 2004 4(1)
  31-36.
• Chuah Y. K. et al. Receptor for Advanced
  Glycation End Products and Its Involvement in
  Inflammatory Diseases. Int J Inflam. 2013 2013
  1-15.
• Goldin A et al. Advanced Glycation End Products
  Sparking the Development of Diabetic Vascular
  Injury. Circulation 2006 114(6) 597-605.
• Yagihashi S et al. Mechanism of diabetic
  neuropathy Where are we now and where to go? J
  Diabetes Invest 2011 2(1) 18-32.
• Sparvero L. J. et al. RAGE (Receptor for
  Advanced Glycation Endproducts), RAGE Ligands,
  and their role in Cancer and Inflammation. J
  Transl Med 2009 7(17).
• Schmidt A. M et al. The biology of the receptor
  for advanced glycation end products and its
  ligands. Biochem Biophys Acta 2000 1498 99-111.
  
• Milne R et al. Advanced glycation end products
  and diabetic retinopathy. Amino Acids 2013 44
  1397-1407.

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• Zong H et al. AGEs, RAGE, and Diabetic
  Retinopathy. Curr Diab Rep 2011 11 244-252.
• Boehm B. O. Elevated serum levels of
  Ne-carboxymethyl-lysine, an advanced glycation
  end product, are associated with proliferative
  diabetic retinopathy and macular oedema.
  Diabetologia 2004 47 1376-1379.
• Poulsen M. W. Advanced glycation endproducts in
  food and their effects on health. Food Chem Tox
  2013 60 10-37.

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