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Studies on Islet Hormone Secretion in MODY1: RW Pedigree with Q268X Mutation in HNF-4 a Gene

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

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Studies on Islet Hormone Secretion in MODY1: RW Pedigree with Q268X Mutation in HNF-4 a Gene

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  1. Studies on Islet Hormone Secretion in MODY1: RW Pedigree with Q268X Mutation in HNF-4a 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-4a 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-4a Mutation) [2/2] • The secretory defect in the three islet-cell types (b-, a- 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-4a 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-4a Mutation) • HNF-4a 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 b-cell Dysfunction in MODY1 (HNF-4a Mutation) • Defective insulin secretion associated with HNF-4a mutation is linked to impaired mitochondrial oxidation (Wang et al) • HNF-4a regulates gene expression in islet b-cells by influencing the function of the HNF-1a protein (Wang et al),and vice versa(Thomas et al; Hanson et al)

  12. The b-Cell & MODY-Related Proteins

  13. Hepatocyte Dysfunction Causing Plasma Lipid Changes in MODY1 (HNF-4a Mutation) • HNF-4a is essential in controlling transcription of many genes involved in lipoprotein metabolism in the liver • In prediabetic and diabetic MODY1 subjects, HNF-4a 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-4a (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 MODY2MODY3 • Plasma glucose • Fasting Normal toMildly Normal toseverely severely  • Post-prandial Greatly Mildly Greatly  • Progression ofhyperglycemia Severe None or mildSevere • Microvascularcomplications CommonRareCommon • Renal thresholdfor glucose Normal Normal Low

  18. Differences in Clinical Parameters Among Diabetic MODY Subtypes [2/2] Parameter MODY1MODY2MODY3 • Sensitivity tosulfonylurea Normal NormalIncreased • TreatmentProgressive RareProgressiverequirements 1/3 oral agent 1/3 oral agent1/3 insulin 1/3 insulin • PlasmaTriglycerides Apo M lipoproteinsLp (a) Apo AII Apo CIII  • MODY5 is associated with congenital glomerulocystic, uterine and genitaldevelopmental 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 Subtype United 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 b-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-4a Haplo-Insufficiency • In MODY1: Agonist agents specifically acting on the islet b-cell, to increase HNF-4a activity, and improve insulin secretion • In MODY3: Similar agonist agents to increase HNF-1a 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-4a, 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-4a 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-4a) [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-4a) [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-4a) & P (MODY3, HNF-1a) 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)

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