Complications in Type 1 Diabetes: Complications in Type 1 Diabetes:

NephropathyNephropathy

Peter A. Gottlieb, MDPeter A. Gottlieb, MDBarbara Davis CenterBarbara Davis Center

University of Colorado Health Sciences Center University of Colorado Health Sciences Center Denver, CODenver, CO

Why do complications occur?Why do complications occur?

• Insulin hypothesisInsulin hypothesis

• Glucose hypothesisGlucose hypothesis

• DCCT and many other studies support DCCT and many other studies support glucose hypothesisglucose hypothesis

EDIC: Long Term Benefit of EDIC: Long Term Benefit of Intensive TreatmentIntensive Treatment

-The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-9.

EDIC: Long Term Benefit of EDIC: Long Term Benefit of Intensive TreatmentIntensive Treatment

-The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-9.

EDIC: Long Term Benefit of EDIC: Long Term Benefit of Intensive TreatmentIntensive Treatment

- The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-9.

• Transient hyperglycemia leads to oxidative stress which increases complications

• Testing of this hypothesis is needed to determine if this is indeed true

Diabetic Nephropathy: Diabetic Nephropathy: PathogenesisPathogenesis

• Increased intraglomerular pressure

• Mesangial cell expansion• Reactive Oxygen Species (ROS)• Endothelial cell dysfunction• Increased Glomerular Basement

Membrane Thickness and Interstitial Fibrosis

DETAIL Study: Head to Head DETAIL Study: Head to Head Comparison of ACE vs. ARB in Comparison of ACE vs. ARB in

Type 2 DNType 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

DETAIL:DETAIL:Baseline CharacteristicsBaseline Characteristics

DETAIL: Equivalent Protection from DETAIL: Equivalent Protection from ACE and ARB in Change GFRACE and ARB in Change GFR

DETAIL: Key PointsDETAIL: 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

ACE and ARB Lower Proteinuria ACE and ARB Lower Proteinuria better than ACE alone in T2DMbetter 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

Prevention and Treatment of Prevention and Treatment of Diabetic Nephropathy in T1DMDiabetic 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

How do complications occur?How do complications occur?

• Activation of Polyol PathwayActivation of Polyol Pathway• Accumulation of Advanced Glycosylation Accumulation of Advanced Glycosylation

End ProductsEnd Products• Protein Kinase C PathwayProtein Kinase C Pathway• Flux Through the Hexosamine PathwayFlux Through the Hexosamine Pathway• Oxygen Radicals and Enhanced Oxidative Oxygen Radicals and Enhanced Oxidative

StressStress• Altered Expression of Growth Factors and Altered Expression of Growth Factors and

Vasoactive Mediators Vasoactive Mediators

Aldose Reductase and Aldose Reductase and Polyol PathwayPolyol Pathway

- Brownlee, M. Nature 2001 414:13 813-820.

AGE PathwayAGE Pathway

- Brownlee, M. Nature 2001 414:13 813-820.

How can we intervene?How can we intervene?• Polyol Pathway – Sorbinil, ZenarestatPolyol Pathway – Sorbinil, Zenarestat • Advanced Glycosylation End Products – Advanced Glycosylation End Products –

Aminoguanidine, sR RAGEAminoguanidine, sR RAGE• Protein Kinase C Pathway – Selective PKC Protein Kinase C Pathway – Selective PKC

inhibitors such as LY333531inhibitors such as LY333531• Flux through Hexamine – ?Flux through Hexamine – ?• Oxidative Stress – Vitamin C, Vitamin E, Oxidative Stress – Vitamin C, Vitamin E,

lipoic acidlipoic acid• Altered Expression of Growth Factors – Altered Expression of Growth Factors –

VEGF inhibitorsVEGF inhibitors

Effect of Effect of -lipoic acid on -lipoic acid on experiemental diabetic retinopathyexperiemental diabetic retinopathy

Lin, et al, Diabetologia, 2006, 49:1089-1096

Do they work?Do they work?

• Sorbinil, Zenarestat - Sorbinil, Zenarestat - Toxicity, IneffectiveToxicity, Ineffective • Aminoguanidine, sR RAGE - Aminoguanidine, sR RAGE - ??• PKC inhibitors - LY333531 - PKC inhibitors - LY333531 - MaybeMaybe• Flux through Hexamine – Flux through Hexamine – ??• Oxidative Stress – Vitamin C, Vitamin E, Oxidative Stress – Vitamin C, Vitamin E,

lipoic acid – lipoic acid – Small effect?Small effect?• Altered Expression of Growth Factors – Altered Expression of Growth Factors –

VEGF inhibitors - VEGF inhibitors - UnknownUnknown

Why have our best efforts not Why have our best efforts not succeeded?succeeded?

• ToxicityToxicity• Drug Development – EfficacyDrug Development – Efficacy• Need to target multiple pathways at Need to target multiple pathways at

onceonce• Or something else?Or something else?

Unified Theory of Unified Theory of ComplicationsComplications

- Brownlee, M. Nature 2001 414:13 813-820.

Inhibition of GAPDH Affects Inhibition of GAPDH Affects Multiple Complication PathwaysMultiple Complication Pathways

- Du X, et al. J. Clin. Invest. 112:1049–1057 (2003).

New Therapeutic ApproachesNew Therapeutic Approaches

• Glyceraldehyde-3-phosphate and fructose-6-Glyceraldehyde-3-phosphate and fructose-6-phosphate are major substrates for phosphate are major substrates for complication pathwayscomplication pathways

• Benfotiamine, is a derivative of the B vitamin Benfotiamine, is a derivative of the B vitamin thiaminethiamine

• Activates the thiamine dependent pentose Activates the thiamine dependent pentose phosphate enzyme transketolase which phosphate enzyme transketolase which converts these compounds away from these converts these compounds away from these pathwayspathways

• Affecting this pathway changes substrate Affecting this pathway changes substrate availability for polyol, hexosamine, availability for polyol, hexosamine, diacylglycerol (PKC), AGE pathway and NF-diacylglycerol (PKC), AGE pathway and NF-B signalingB signaling

MMF and ACE synergize to MMF and ACE synergize to Reverse Experimental DNReverse Experimental DN

Wu, et al. Inflamm res. 2006. 192-199

MMF and ACE synergize to MMF and ACE synergize to Reverse Experimental DNReverse Experimental DN

Wu, et al. Inflamm res. 2006. 192-199

TGFTGF

ED1ED1 MCP-1MCP-1

Unified Theory of Unified Theory of ComplicationsComplications

- Brownlee, M. Nature 2001 414:13 813-820.

Benfotiamine

PARP inhibitors

New Therapeutic ApproachesNew Therapeutic Approaches

• Molecules which can affect GAPDH activity

• Superoxide Dismutase

• Poly(ADPribose)polymerase (PARP) inhibitors, PJ34

SummarySummary

• Tight control of blood sugars is the best Tight control of blood sugars is the best means to prevent and reverse complications means to prevent and reverse complications of diabetesof diabetes

• Reducing glycemic variability may also Reducing glycemic variability may also contribute to the development of contribute to the development of complications and can be achieved with complications and can be achieved with CGMSCGMS

• Therapies such as PKC inhibitors which Therapies such as PKC inhibitors which attack single pathways may be of benefitattack single pathways may be of benefit

• New therapeutic approaches which can target New therapeutic approaches which can target multiple pathways simultaneously may offer multiple pathways simultaneously may offer the best chance to prevent complicationsthe best chance to prevent complications

Thank youThank you