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Tel Aviv, Israel – February 22 nd 2005

Department of Pediatrics University of Chieti, Italy. Diabetic complications in children: Molecular biology driving future treatment Francesco Chiarelli Department of Paediatrics, University of Chieti, Italy. Tel Aviv, Israel – February 22 nd 2005. 2- to 4- fold increase in

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Tel Aviv, Israel – February 22 nd 2005

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  1. Department of Pediatrics University of Chieti, Italy Diabetic complications in children: Molecular biology driving future treatmentFrancesco ChiarelliDepartment of Paediatrics, University of Chieti, Italy Tel Aviv, Israel – February 22nd 2005

  2. 2- to 4- fold increase in cardiovascular mortality and stroke2 Leading cause of blindness in working age adults1 Stroke DiabeticRetinopathy CardiovascularDisease Diabetic Nephropathy Leading cause of end-stage renal disease3 DiabeticNeuropathy Leading cause of non-traumatic lower extremity amputations4 Diabetes: A Systemic Disease National Diabetes Information Clearinghouse. Diabetes Statistics–Complications of Diabetes.(website)http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp.

  3. RISK FACTORS FOR DIABETIC ANGIOPATHY • Disease duration • Poor metabolic control-high hemoglobin A1c • Hypertension • Hyperlipidemia • Smoking • Puberty • Genes?

  4. Diabetes (Systemic) Hyperglycemia (Systemic) Glycation, Oxidants, Lipids(Systemic and Local) Alter Cell Signaling (PKC, MAPK, JNK Others) Alter Cytokine Signaling (Insulin, Angiotensin) (Local) Vascular/Endothelial/Monocyte Dysfunctions Micro- and Cardiovascular Diseases

  5. Questions : What Molecular Mechanisms Are Mediating Hyperglycemia’s Adverse Effects ?

  6. Sheetz MJ, King GL, JAMA 27: 2579-88, 2002

  7. Chiarelli F et al., J Pediatr, 1999

  8. Role of growth factors in the pathogenesis of diabetic nephropathy • GH bFGF • IGF-1 EGF • VEGF PDGF • TGF-beta IGF-2 • aFGF IGFBPs Chiarelli F et al., Horm Res, 2000

  9. VEGF • Vascular Endothelial Growth Factor

  10. Vascular Endothelial Growth Factor • Protein • Increased by lack of oxygen • Causes new retinal vessel growth • Causes retinal vessel leakage • High in diabetic patients with new retinal vessel growth • High in diabetic patients with macular edema

  11. – VEGF NO + VEGF Ecs SMCs Functionally intact (NO up-regulated) VEGF up-regulated Dysfunctional (NO down-regulated) VEGF down-regulated

  12. VEGF in Human Ocular Fluids VEGF (ng/ml) 30 25 =aqueous fluid =vitreous fluid 20 =mean 15 10 5 0 No Proliferative Diabetes, Diabetes, Diabetes, active PDR Diseases without PDR quiescent PDR Aiello LP et al. N. Engl. J. Med. 1994;331:1480-7

  13. VE GF PLCg PI3 Kinase PLCg-P PKB/Akt PIP2 DAG&IP3 Anti-apoptosis HIF-1 PKCa,b,d Protein Synthesis (eg. eNOS) b b Permeability Neovascularization Mechanism of VEGF Action KDR Fibrosis

  14. Serum levels of VEGF (pg/ml) Age Chiarelli F et al., Diabetic Med, 2001

  15. VEGF concentrations and later development of microalbuminuria • Serum VEGF levels higher than 150 pg/ml are able to predict later development of persistent microalbuminuria in patients with onset of diabetes during childhood in a period of life when AER is still in normal range Santilli F, Chiarelli F, J Clin Endocrinol Metab, 2001

  16. Group 1 Group 2 Santilli F, Chiarelli F, J Clin Endocrinol Metab, 2001

  17. Development of persistent or intermittent microalbuminuria in group 1 and group 2 P value NS p<0.01 NS Group 1 8.3 (8.1-8.9) 10/52 4/52 Group 2 8.4 (8.1-9.0) 1/49 3/49 Duration of follow-up (years) Persistent microalbuminuria Intermittent microalbuminuria Santilli F, Chiarelli F, J Clin Endocrinol Metab, 2001

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