1. MODY: MATURITY-ONSET DIABETES OF 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) GeneChromosome Name (Year) GeneChromosome MODY1 (1991) HNF-4  20q MODY2 (1993) Glucokinase 7p MODY3 (1996) HNF-1  12q MODY4 (1997) IPF-1 (PDX-1) 13q MODY5 (1997) HNF-1  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  -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  -cells  Facilitates glycogen synthesis in the liver

7. MODY-Related Proteins [2/4]  Liver-enriched transcription factors HNF-1 , HNF-1 , and HNF-4   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 of MODY 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 of MODY 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-4  Mutation): Pedigree RW, Branch W, Offspring of II-5 – + 141 135 144 III IV V IV V V IV 147 II – – + 13 9 14 12 9 + + + – – 30 + 29 14 13 + + +17 10 10 9 8 18– + + + + + 17 + 17 + 13 – – – – –– + 27 25 + 29 + – + 21 16 + 22 11 + +– – 39 170 161 14 + 1 + 10 9 + + – – – 11 + – Tested and normal Type 1 diabetes 146 5vv 5 7 N N R + presence (NM), or – absence (NN) of gene mutation. ? 43 42 9 87 6 5 4 3 1 1 2 3 4 5 6 5060 40 41 MIPVD-A N, Np, R-B, MI PVD-A-G PVD-AR 2 MI 52 – I III I G 5 5 Multiple offspring R-BPVD-A III II I I

13. MODY1 (HNF-4  Mutation): Pedigree RW, Branch W, Offspring of II-2 2 III IV V II 12 3 4 5678 9 Tested and normal 14 10 11 1312 5 1 75 4 1 43 48 32 57 22 61 19 24 19 27 26 23 24 + – – – – – + + + –+ + +– – – + + +– + + + ––++––+ PVD MIPVD-A + presence (NM) or – absence (NN) of gene mutation Type 2 diabetes RN 14 12 ––

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-4  Mutation): Plasma Glucose & Insulin Levels During OGTT (0.75 g/kg BW) in Groups of RW Pedigree

16. MODY1 (HNF-4  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-4  )

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-4  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-1  Mutation)

23. Insulin Secretion Rate in Diabetic & Nondiabetic MODY3 (HNF-1  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 8 mM  Glucose priming of insulin secretion rate (ISR) : Absent Normal Normal