• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. Which are the primary pathways implicated in hyperglycemia-induced microvascular damage?

  • Accumulation of Advanced Glycation End Products (AGEs)
  • Accumulation of sorbitol  (Polyol flux pathway)
  • Hexosamine flux pathway
  • Increase protein kinase C

• **Polyol flux pathway **

• Q. Describe the sorbitol pathway?

  • Glucose is converted by Aldose reductase into sorbitol

• Q. What are the consequence of sorbitol accumulation?

  • Depletion of NADPH
  • Increased cell osmolality
  • Decrease in intracellular myoinositol

• Q. Why is depletion of NADPH critical?

  • NADPH is required for scavenging of radical oxygen species
  • Reduction of NADPH reduces the ability of the cell to scavenge reactive oxygen species

• Q. Summarize the polyol flux pathway with a diagram

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• Advanced Glycation End Products (AGEs)

• Q. Give the sequence of formation of AGE?

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• Q. Which are the three precursors of AGE?

  • Glyoxal
  • Methylglyoxal
  • 3-Deoxyglucosone

• Q. What are RAGE?

  • Receptor for AGE

• Q. Describe the consequences of AGE?

  • Glucose binds to protein  formation of AGE:
  • Crosslinking of AGE
  • AGE binding with RAGE → proinflammatory pathway activated

• **Hexosamine pathway **

• Q. Describe the Hexosamine flux pathway?

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• Q. What does UDP N glucosamine do ?

  • UDP N- glucosamine glycosylates transcription factors leading to increased transcription of certain proteins like TGF-beta, PAI-1, etc

• Q. What happens to the hexosamine pathway?

  • Increase in glucose leads to increase flux through the hexosamine pathway
  • This leads to increase in the formation of ROS and disruption of various cell transcription factor

• Q. Which drug reduces the flux of glucose via the hexosamine pathway?

  • Benfotiamine

• **Protein kinase c **

• Q. What is the importance of protein kinase C?

  • Increase glucose  increase diacylglycerol → increase protein kinase C

• Q. What are the consequences of protein Kinase C activation?

  • Increase VEGF
  • Increase TGF beta
  • Increase NAPH oxidases  increase ROS
  • Increase PAI-1 → increase thrombosis
  • Increase Nk-kb → increase proinflammatory cytokines
  • increased endothelin 1 →vasoconstriction

• Q. Which is the protein kinase C inhibitor?

  • Ruboxistaurin

• Q. Does the protein kinase C pathway affect microvascular complications only?

  • No
  • It can lead to both microvascular and macrovascular complications

• Q. What isoforms of PKC produce what in diabetic nephropathy?

  • PKC alpha- albuminuria
  • PKC beta – glomerular hypertrophy and mesangial expansion
  • Both increase reactive oxygen species

• Q. Describe the IP3 /DAG pathway?

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  • DAG is increased in Diabetes and hence more production of Protein Kinase C

• **Oxidative stress **

• Q. What is the role of oxidative stress in the whole process?

  • Oxidative stress in the final common pathway for all the metabolic processes described above

• PARP (Poly-ADP ribose polymerase)

• Q. What is PARP?

  • Poly-ADP ribose polymerase

• Q. What is the role of PARP in diabetic neuropathy?

  • Increased glucose  activates PARP
  • PARP destroys NAD+
  • This leads to increase free radicals and disruption of the DNA transcription process
  • It also reduced G6PDH, which is a critical pathogenic factor

• Q. What is the importance of G6PDH?

  • Glyceraldehyde 6 phosphate dehydrogenase is a crucial enzyme in the glucose metabolism
  • This is inhibited by PARP
  • This leads to the accumulation of Glyceraldehyde 6 phosphate, which is shunted to produce DAG (Protein kinase C) and Methylglycoxal (which produces AGE)

• Q. Describe some charts showing unifying pathways for diabetic microvascular complications and the role of G6PDH?

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