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UPDATE ON RESEARCH BETA CELLS

UPDATE ON RESEARCH BETA CELLS.  IN VITRO AND ANIMAL MODELS Erol CERASI  HUMAN STUDIES Stephano DEL PRATO. Brea, Cimez, Nice. autoantibodies DNA. DNA pancreatic imaging hormones biological scan. TYPE 2 DIABETES. DIABETES. TYPE 1 DIABETES. O T H E R S.

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UPDATE ON RESEARCH BETA CELLS

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  1. UPDATE ON RESEARCHBETA CELLS  IN VITRO AND ANIMAL MODELS Erol CERASI  HUMAN STUDIES Stephano DEL PRATO Brea, Cimez, Nice

  2. autoantibodies DNA DNA pancreatic imaging hormones biological scan TYPE 2 DIABETES DIABETES TYPE 1 DIABETES O T H E R S • monogenic forms of diabetes • complex genetic disorders • pancreatic diseases • iatrogenic diabetes • diabetes associated with endocrinopathies

  3. islet of Langerhans insulin ß-CELL

  4. TYPE 1 DIABETES: A MULTIGENIC DISEASE MHC class II chr 6 CTLA-4 ICOS1 2q33 5 ’ VNTR insulin gene 11p15 10q 6q27 6q21 10p11 11q13 6q24 IDDM 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 AIRE APECED FOXP3 IPEX

  5. MODY Glucokinase HNF1-a HNF1-b HNF4-a IPF-1 TYPE 2 DIABETES: A MULTIGENIC DISEASE Calpain10 2p37 12q15 NIDDM 1 2 3 4 5 6 7 8 9 10 - - - - - - - - - - - - - - - - - MUTATIONS Insulin receptor Insulin Trypsinogen Frataxine CFTR Mitochondrial DNA HFE

  6. Rab27a-granulophiline Syntaxine 1a, Munc 18.1 ß-CELL Jing X et al., J Clin Invest, 2005 :146 Kasai K et al. J Clin Invest, 2005 : 388

  7. INSULIN SECRETORY DEFECTS IN TYPE 2 • Reduced early insulin secretory response to oral glucose • Reduced first phase insulin response to i.v. glucose • Reduced ability of b cells to compensate for insulin-resistance • Decreased glucose sensing ability of the b cell • Shift in the dose response curve relating glucose and insulin secretion • Alterations in oscillations of insulin secretion Hyperglycemic glucose clamp Response to oscillatory glucose infusion

  8. 5 ’ VNTR insulin gene 11p15 IDDM12 3 …. **association studies  linkage studies UKPDS Lancet, 1998 KEY ISSUES • role of b cells in type 1 diabetes immune failure ? • a decreased b cell mass in type 2 diabetes ? • a unique functional defect of b cells in type 2 diabetes ? • biological diagnostic parameters in type 2 diabetes ? • clinical tests to evaluate b cell function in clinic ?

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