1. Studies on Islet Hormone Secretion in MODY1: RW Pedigree with Q268X Mutation in HNF-4  Gene  Three groups of 4 to 7 subjects each:  No mutation identified, not diabetic: ND (–)  Mutation identified, not diabetic: ND (+)  Mutation identified, diabetic: D (+)

2. MODY1 (RW Pedigree): Plasma C-Peptide Levels in Response to L-Arginine Infused IV Alone and Again During Hyperglycemic Clamp

3. MODY1 (RW Pedigree): Insulin Secretion Rates (ISR) by Deconvolution of Plasma C-Peptide Levels During IV L-Arginine Infusion

4. MODY1 (RW Pedigree): Plasma Amylin Levels in Response to L-Arginine Infused IV Alone and Again During Hyperglycemic Clamp

5. MODY1 (RW Pedigree): Plasma Glucagon Response Areas (AUC) During IV Infusion of L-Arginine

6. MODY1 (RW Pedigree): Plasma Pancreatic Polypeptide Response Areas (AUC) to Insulin-Induced Hypoglycemia

7. Conclusions Regarding Pancreatic Islet Function in MODY1 (HNF-4  Mutation) [1/2]  Nondiabetic as well as diabetic subjects have a defect in  insulin secretion in response to administered arginine as well as to glucose  glucagon secretion in response to administered arginine  pancreatic polypeptide (PP) secretion in response to insulin-induced hypoglycemia

8. Conclusions Regarding Pancreatic Islet Function in MODY1 (HNF-4  Mutation) [2/2]  The secretory defect in the three islet- cell types (  -,  - and PP-cells) may be  at a common step in signal transduction, or  due to a decrease in the mass of the respective cell type, or  signal transduction and cell mass defects

9. Course of the Insulin-Secretory Defect in MODY1 (HNF-4  Mutation   Progressive decrease in insulin secretion at a rate of 1-4% per year over a period of 3 decades (observed in the RW Pedigree)

10. Pathogenesis of MODY1 (HNF-4  Mutation   HNF-4  protein  is a member of the steroid hormone receptor superfamily of nuclear transcription factors  plays a role in tissue-specific regulation of expression of multiple genes in the liver, pancreas, kidney, intestine, including the genes that regulate glucose transport and glycolysis (Stoffel & Duncan)

11. Pathogenesis of  -cell Dysfunction in MODY1 (HNF-4  Mutation   Defective insulin secretion associated with HNF-4  mutation is linked to impaired mitochondrial oxidation (Wang et al)  HNF-4  regulates gene expression in islet  -cells by influencing the function of the HNF-1  protein (Wang et al), and vice versa (Thomas et al; Hanson et al)

12. The  -Cell & MODY-Related Proteins

13. Hepatocyte Dysfunction Causing Plasma Lipid Changes in MODY1 (HNF-4  Mutation   HNF-4  is essential in controlling transcription of many genes involved in lipoprotein metabolism in the liver  In prediabetic and diabetic MODY1 subjects, HNF-4  mutation leads to hepatocyte secretory defects in lipoproteins, resulting in decreased serum levels of triglycerides, lipoprotein (a), and apolipoproteins A-II and C-III

14. Serum Levels of Lipoprotein (a) and Triglycerides in Subjects with HNF-4  (RW) and other (MODY-X) Mutations

15. Clinical Implications of Genetic Heterogeneity of MODY [1/2]  MODY1 and MODY3  Progressive clinical course in terms of hyperglycemia, with increasing treatment requirements  Development of microvascular, macrovascular and neuropathic complications of diabetes in a frequency similar to that seen in type 2 diabetes

16. Clinical Implications of Genetic Heterogeneity of MODY [2/2]  MODY2  Mild to moderate elevation in plasma glucose levels  Not progressive  Complications rare  Molecular-genetic diagnosis has important implications for clinical management of all MODY subtypes

17. Differences in Clinical Parameters Among Diabetic MODY Subtypes [1/2] Parameter MODY1 MODY2 MODY3  Plasma glucose  FastingNormal toMildly  Normal to severely  severely   Post-prandial Greatly  Mildly  Greatly   Progression of hyperglycemiaSevere None or mildSevere  Microvascular complicationsCommonRareCommon  Renal threshold for glucose NormalNormal Low

18. Differences in Clinical Parameters Among Diabetic MODY Subtypes [2/2] ParameterMODY1MODY2MODY3  Sensitivity to sulfonylurea Normal NormalIncreased  Treatment Progressive RareProgressive requirements 1/3 oral agent 1/3 oral agent 1/3 insulin1/3 insulin  PlasmaTriglycerides  Apo M  lipoproteinsLp (a)  Apo AII  Apo CIII   MODY5 is associated with congenital glomerulocystic, uterine and genital developmental disorders.

19. Chronic Complications of Diabetes in MODY  Microvascular and neuropathic complications as common in MODY1 and MODY3 as in Type 2 diabetes  matched for duration and degree of hyperglycemia  most likely determined by the degree of glycemic control

20. MODY: Clinical Strategies  Molecular-genetic screening and diagnosis are feasible for young subjects at risk for MODY, and have important prognostic implications.  Genetically susceptible subjects can be counseled to have periodic evaluation of glucose tolerance beginning at a young age.  Attainment of normoglycemia beginning at time of appearance of metabolic abnormalities can prevent vascular and neuropathic complications.

21. Estimated Worldwide Prevalence of MODY  2 to 5 % of all diabetic patients

22. Distribution of MODY Subtypes MODY SubtypeUnited France Kingdom MODY1 5%0% MODY2 12% 63% MODY3 64% 21% MODY4 2%0% MODY5 1%0% MODY“X” (unknown) 16% 16%

23. MODY: Expectations for the Future  Understanding of the pathophysiology of MODY emerging from molecular- biological and physiological studies will lead to new therapeutic approaches that delay, prevent or correct the decline in pancreatic islet  -cell function.  MODY could serve as a paradigm for similar studies in genetically more complex forms of diabetes.

24. Potential Future Development of Drugs That Target HNF-4  Haplo-Insufficiency  In MODY1: Agonist agents specifically acting on the islet  -cell, to increase HNF-4  activity, and improve insulin secretion  In MODY3: Similar agonist agents to increase HNF-1  activity  In non-MODY subjects with dyslipoproteinemia: Antagonist agents selectively acting on the liver and intestine, to improve lipoprotein metabolism

25. MODY: Extension to Type 2 Diabetes [1/2]  Recent evidence suggests that misregulation of the HNF transcription factor network in pancreatic islets and liver, and particularly HNF-4 , may contribute to Type 2 diabetes. (Odom DT et al. Science 2004;303:1378-81; Kulkarni RN, Kahn CR. Science 2004;303:1311-2.)

26. MODY: Extension to Type 2 Diabetes [2/2]  Genetic studies in an Ashkenazi-Jewish population (1), and in families resident in Finland (2) revealed significant haplotype- tag single nucleotide polymorphisms (htSNPs) in the HNF-4  region of chromosome 20q, which increase susceptibility to Type 2 diabetes. (1) Love-Gregory LD, et al. Diabetes 2004;53:1134-40. (2) Silander K, et al. Diabetes 2004;53:1141-49.

27. Collaborators in Investigations on the RW Pedigree (MODY1; HNF-4  ) [1/3]  1960s and 1970s:  John C Floyd, Jr  Sumer B Pek  1973-1974 in clinical genetics:  Robert B Tattersall

28. Collaborators in Investigations on the RW Pedigree (MODY1; HNF-4  ) [2/3]  1980s and 1990s in molecular genetics:  M A Permutt (Washington U)  S C Elbein (U Utah)  G I Bell (U Chicago)  D W Bowden (Bowman Gray U)  M Stoffel (Rockefeller U)

29. Collaborators in Investigations on the RW (MODY1, HNF-4  ) & P (MODY3, HNF-1  ) Pedigrees [3/3]  1990s in pathogenesis, insulin secretion/action, etc:  W H Herman (U Michigan)  J B Halter (U Michigan)  M J Smith (U Michigan)  L L Ilag (U Michigan  J Sturis (U Chicago)  M M Byrne (U Chicago)  K S Polonsky (U Chicago)