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MODY: MATURITY-ONSET DIABETES OF THE YOUNG

MODY: MATURITY-ONSET DIABETES OF THE YOUNG. Stefan S. Fajans, MD University of Michigan May 2004. Maturity-Onset Diabetes of the Young (MODY) 1975 Definition. Type-2 diabetes mellitus in the young plus Autosomal dominant inheritance. Current Definition of MODY.

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MODY: MATURITY-ONSET DIABETES OF THE YOUNG

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  1. MODY: MATURITY-ONSET DIABETESOF THE YOUNG Stefan S. Fajans, MD University of Michigan May 2004

  2. Maturity-Onset Diabetes of the Young (MODY)1975 Definition • Type-2 diabetes mellitus in the young plus • Autosomal dominant inheritance

  3. Current Definition of MODY • A heterogeneous disorder due to heterozygous monogenic mutations in one of at least 6 different genes • Onset of diabetes early in life: childhood, adolescence, young adulthood • Autosomal dominant inheritance • Primary defect in insulin secretion

  4. Heterozygous Gene Mutations Identified in MODY Name (Year) Gene Chromosome MODY1 (1991) HNF-4a 20q MODY2 (1993) Glucokinase 7p MODY3 (1996) HNF-1a 12q MODY4 (1997) IPF-1 (PDX-1) 13q MODY5 (1997) HNF-1b 17q MODY6 (1999) Neuro-D1 / BETA-2 2q HNF = Hepatocyte nuclear factor IPF = Insulin promoter factor PDX-1 = Pancreatic duodenal homeobox-1

  5. Homozygous Mutations of MODY-Related Genes • Permanent neonatal diabetes (PND) results from homozygous mutations of • Glucokinase gene • Insulin promoter factor (IPF-1) gene

  6. MODY-Related Proteins [1/4] • Glucokinase • Expressed in b-cells and liver • Catalyzes transfer of phosphate from ATP to glucose, generating glucose-6-phosphate, a rate-limiting step in glucose metabolism • “Glucose sensor” in b-cells • Facilitates glycogen synthesis in the liver

  7. MODY-Related Proteins [2/4] • Liver-enriched transcription factors HNF-1a, HNF-1b, and HNF-4a • Expressed in liver and other organs, including pancreatic islets, kidneys and genitalia • Part of a network of transcription factors that function together to control expression of multiple genes • Regulate expression of the insulin gene, and genes of proteins involved in glucose transport and metabolism, and mitochondrial metabolism

  8. MODY-Related Proteins [3/4] • Transcription factor IPF-1 • Expressed in pancreatic islets • Regulates transcription of a variety of genes, including genes for insulin, somatostatin, islet amyloid polypeptide, glucokinase, and GLUT-2 • Mediates glucose-induced stimulation of insulin-gene transcription

  9. MODY-Related Proteins [4/4] • Transcription factor Neuro-D1 (BETA2) • Expressed in pancreatic islets • Activates the transcription of the insulin gene • Required for normal development of the pancreatic islets

  10. Distinguishing Clinical Characteristics ofMODY and Type 2 Diabetes (DM2)[1/2] • Mode of inheritance • MODY: Monogenic, autosomal dominant • DM2: Polygenic • Age of onset • MODY: Childhood, adolescence, usually <25 years • DM2: Usually 40-60 years; occasionally in obese adolescents • Pedigree • MODY: Multi-generational • DM2: Rarely multi-generational

  11. Distinguishing Clinical Characteristics ofMODY and Type 2 Diabetes[2/2] • Penetrance • MODY: 80-95 % • DM2: Variable (10-40 %) • Body habitus • MODY: Not obese • DM2: Usually obese • Dysmetabolic syndrome • MODY: Absent • DM2: Usually present

  12. MODY1 (HNF-4a Mutation): Pedigree RW, Branch W, Offspring of II-5 III V IV II G 2 1 9 6 5 3 7 8 4 170 I I 39 40 50 60 – V IV II R-B PVD-A MI PVD-A N, Np, R-B, MI PVD-A-G PVD-A R MI 3 1 4 2 6 5 + – + 11 9 13 ? 43 42 41 52 14 + + I + – 10 135 III – + + 9 16 11 + 12 + – + 30 R + – 9 22 + 29 + + 1 + 21 N – N 14 III – – – + + 29 – – + 27 25 – 144 146 147 141 IV 5 7 – 17 – – + – – + 14 17 13 + 5vv +presence (NM), or –absence (NN) of gene mutation. 161 – V I Type 1 diabetes + 8 + – 10 18 9 + + 13 17 + 10 + + Tested and normal Multiple offspring 5 5

  13. MODY1 (HNF-4a Mutation): Pedigree RW, Branch W, Offspring of II-2 MI PVD-A 2 II 43 R N PVD 4 3 1 2 5 6 7 8 9 III 22 61 48 – – + + – + – 32 57 IV 24 19 27 + – 23 19 + + 24 + – + – – 26 + + + V 12 14 13 12 14 – – 10 7 5 1 11 4 5 – 1 + – – + – – – + + + +presence (NM) or– absence (NN) of genemutation Tested and normal Type 2 diabetes

  14. Phenotypic Expression and Natural History of MODY • Recognition at young age • Under age 25 years • 7-13 years or younger, if sought by glucose testing in younger generations • Not progressive, or slowly progressive • Hyperglycemia responsive to diet and/or oral anti-hyperglycemic agents for years to decades • May progress to insulin-requiring diabetes (not insulin-dependent or ketosis-prone) • May progress rapidly from young age onward

  15. MODY1 (HNF-4a Mutation):Plasma Glucose & Insulin Levels During OGTT (0.75 g/kg BW) in Groups of RW Pedigree

  16. MODY1 (HNF-4a Mutation): Possible Early Defects in Insulin Secretion & Action in RW Pedigree • Methods: • Bergman’s minimal model: Frequently sampled IV GTT • Polonsky’s low-dose glucose infusion to measure insulin secretion rate (ISR) & pulse analysis • Conclusions: • Non-diabetic members: Deranged and deficient insulin secretion; no insulin resistance. Apparently the primary inherited abnormality causing susceptibility to diabetes. • Diabetic members: Deranged and deficient insulin secretion; any decrease in insulin action is secondary to hyperglycemia

  17. Frequently Sampled IVGTT in Nondiabetic (–) & Diabetic (+) Marker Members of R-W Pedigree (MODY1; HNF-4a)

  18. Pulsatile Insulin Secretion & Fluctuations in Plasma Glucose During Constant Glucose Infusion in 3 Members of the R-W Pedigree

  19. Protocol for the Stepped Glucose Infusion Method to Determine Insulin Secretion Rate Time (Minutes)

  20. Insulin Secretion Rate (ISR) in MODY1 (HNF-4a Mutation); RW Pedigree GLUCOSE (mmol/L)

  21. Insulin Secretion Rate (ISR) in MODY2 Subjects (Glucokinase Mutations) N= 6

  22. Insulin Secretion Rate in Nondiabetic MODY3 Subjects (HNF-1a Mutation)

  23. Insulin Secretion Rate in Diabetic & Nondiabetic MODY3 (HNF-1a Mutation) and Control Subjects

  24. Insulin Secretion Rate in MODY1, MODY2 & MODY3, and Control Subjects

  25. Comparison of Insulin Secretion Dynamics in Three MODY Subtypes MODY1 MODY2 MODY3 Prediabetic Mildly diabetic Prediabetic • Plasma glucose concentration, at which insulin secretion rate (ISR) is reduced: >7 mM <7 mM >8 mM • Glucose priming of insulin secretion rate (ISR) : Absent Normal Normal

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