Complications in Type 1 Diabetes: Nephropathy

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Complications in Type 1 Diabetes Nephropathy
Peter A. Gottlieb, MD Barbara Davis
Center University of Colorado Health Sciences
Center Denver, CO
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Why do complications occur?

• Insulin hypothesis
• Glucose hypothesis
• DCCT and many other studies support glucose
  hypothesis

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EDIC Long Term Benefit of Intensive Treatment

• The Diabetes Control and Complications
  Trial/Epidemiology of Diabetes Interventions
• and Complications Research Group. N Engl J Med
  2000342381-9.

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EDIC Long Term Benefit of Intensive Treatment

• The Diabetes Control and Complications
  Trial/Epidemiology of Diabetes Interventions
• and Complications Research Group. N Engl J Med
  2000342381-9.

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EDIC Long Term Benefit of Intensive Treatment
- The Diabetes Control and Complications
Trial/Epidemiology of Diabetes Interventions
and Complications Research Group. N Engl J Med
2000342381-9.
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• Transient hyperglycemia leads to oxidative stress
  which increases complications
• Testing of this hypothesis is needed to determine
  if this is indeed true

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Diabetic Nephropathy Pathogenesis

• Increased intraglomerular pressure
• Mesangial cell expansion
• Reactive Oxygen Species (ROS)
• Endothelial cell dysfunction
• Increased Glomerular Basement Membrane Thickness
  and Interstitial Fibrosis

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DETAIL Study Head to Head Comparison of ACE vs.
ARB in Type 2 DN

• 5 yr, prospective, multicenter, randomized study
  in T2DM with HTN and early DN
• 120 subjects onTelmisartan 40-80 mg/day vs. 130
  subjects on Enalapril 10-20 mg/day
• Primary endpoint Change in GFR
• Secondary endpoints Change in albuminuria, BP,
  CR, other CV outcome measures

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DETAILBaseline Characteristics
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DETAIL Equivalent Protection from ACE and ARB in
Change GFR
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DETAIL Key Points

• Use of ACE or ARB slows down loss of GFR in T2DM
  with nephropathy
• Confirms previous shorter term studies
• Additional protection seen for CV complications

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ACE and ARB Lower Proteinuria better than ACE
alone in T2DM

• Small 24 week study with 26 pts demonstrated that
  combination therapy of Losartan with Enalapril
  reduced proteinura greater than increased dose of
  Enalapril alone
• Blood pressure was similarly lowered in both
  groups
• CRP levels were lowered in combined treatment
  group, unchanged in ACE alone
• Other parameters measured were not significantly
  different between groups

Igarashi, et al, Endocrine Journal, 2006, epub
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Prevention and Treatment of Diabetic Nephropathy
in T1DM

• Periodic screening for microalbuminuria timed
  overnight samples beginning at 5 years from
  diagnosis
• Treatment of either microalbuminuria or HTN (to
  120/80 or age-matched target) with ACE or ARB
• Use ACE or ARB, ACE with ARB and Diuretics, then
  consider other therapies based on clinical
  considerations

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How do complications occur?

• Activation of Polyol Pathway
• Accumulation of Advanced Glycosylation End
  Products
• Protein Kinase C Pathway
• Flux Through the Hexosamine Pathway
• Oxygen Radicals and Enhanced Oxidative Stress
• Altered Expression of Growth Factors and
  Vasoactive Mediators

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Aldose Reductase and Polyol Pathway
- Brownlee, M. Nature 2001 41413 813-820.
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AGE Pathway
- Brownlee, M. Nature 2001 41413 813-820.
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How can we intervene?

• Polyol Pathway Sorbinil, Zenarestat
• Advanced Glycosylation End Products
  Aminoguanidine, sR RAGE
• Protein Kinase C Pathway Selective PKC
  inhibitors such as LY333531
• Flux through Hexamine ?
• Oxidative Stress Vitamin C, Vitamin E, a lipoic
  acid
• Altered Expression of Growth Factors VEGF
  inhibitors

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Effect of a-lipoic acid on experiemental diabetic
retinopathy
Lin, et al, Diabetologia, 2006, 491089-1096
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Do they work?

• Sorbinil, Zenarestat - Toxicity, Ineffective
• Aminoguanidine, sR RAGE - ?
• PKC inhibitors - LY333531 - Maybe
• Flux through Hexamine ?
• Oxidative Stress Vitamin C, Vitamin E, a lipoic
  acid Small effect?
• Altered Expression of Growth Factors VEGF
  inhibitors - Unknown

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Why have our best efforts not succeeded?

• Toxicity
• Drug Development Efficacy
• Need to target multiple pathways at once
• Or something else?

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PKC Pathway
- Brownlee, M. Nature 2001 41413 813-820.
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Unified Theory of Complications
- Brownlee, M. Nature 2001 41413 813-820.
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Inhibition of GAPDH Affects Multiple Complication
Pathways
- Du X, et al. J. Clin. Invest. 11210491057
(2003).
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New Therapeutic Approaches

• Glyceraldehyde-3-phosphate and fructose-6-phosphat
  e are major substrates for complication pathways
• Benfotiamine, is a derivative of the B vitamin
  thiamine
• Activates the thiamine dependent pentose
  phosphate enzyme transketolase which converts
  these compounds away from these pathways
• Affecting this pathway changes substrate
  availability for polyol, hexosamine,
  diacylglycerol (PKC), AGE pathway and NF-kB
  signaling

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MMF and ACE synergize to Reverse Experimental DN
Wu, et al. Inflamm res. 2006. 192-199
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MMF and ACE synergize to Reverse Experimental DN
TGFb
ED1
MCP-1
Wu, et al. Inflamm res. 2006. 192-199
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Unified Theory of Complications
Benfotiamine
PARP inhibitors
- Brownlee, M. Nature 2001 41413 813-820.
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New Therapeutic Approaches

• Molecules which can affect GAPDH activity
• Superoxide Dismutase
• Poly(ADPribose)polymerase (PARP) inhibitors, PJ34

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Summary

• Tight control of blood sugars is the best means
  to prevent and reverse complications of diabetes
• Reducing glycemic variability may also contribute
  to the development of complications and can be
  achieved with CGMS
• Therapies such as PKC inhibitors which attack
  single pathways may be of benefit
• New therapeutic approaches which can target
  multiple pathways simultaneously may offer the
  best chance to prevent complications

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Thank you