MODY: MODY: MATURITY-ONSET DIABETESMATURITY-ONSET DIABETES

OF THE YOUNGOF THE YOUNG

Stefan S. Fajans, MDStefan S. Fajans, MD

University of MichiganUniversity of MichiganMay 2004May 2004

Maturity-Onset Diabetes of the Maturity-Onset Diabetes of the Young (MODY)Young (MODY)

1975 Definition1975 Definition

Type-2 diabetes mellitus in the youngType-2 diabetes mellitus in the young

plus plus

Autosomal dominant inheritanceAutosomal dominant inheritance

Current Definition of MODYCurrent Definition of MODY

A heterogeneous disorder due to A heterogeneous disorder due to heterozygous monogenic mutations heterozygous monogenic mutations in one of at least 6 different genesin one of at least 6 different genes

Onset of diabetes early in life: Onset of diabetes early in life: childhood, adolescence, young childhood, adolescence, young adulthoodadulthood

Autosomal dominant inheritanceAutosomal dominant inheritance

Primary defect in insulin secretionPrimary defect in insulin secretion

Heterozygous Gene Mutations Heterozygous Gene Mutations Identified in MODYIdentified in MODY

Name Name (Year)(Year) Gene Gene ChromosomeChromosome

MODY1 MODY1 (1991)(1991) HNF-4HNF-4 20q 20q

MODY2 MODY2 (1993)(1993) GlucokinaseGlucokinase 7p 7p

MODY3 MODY3 (1996)(1996) HNF-1HNF-1 12q 12q

MODY4 MODY4 (1997)(1997) IPF-1 (PDX-1)IPF-1 (PDX-1) 13q 13q

MODY5 MODY5 (1997)(1997) HNF-1HNF-1 17q 17q

MODY6 MODY6 (1999)(1999) Neuro-D1 / BETA-2 2qNeuro-D1 / BETA-2 2q

HNF = Hepatocyte nuclear factorHNF = Hepatocyte nuclear factor

IPF = Insulin promoter factorIPF = Insulin promoter factor

PDX-1 = Pancreatic duodenal homeobox-1PDX-1 = Pancreatic duodenal homeobox-1

Homozygous Mutations of Homozygous Mutations of MODY-Related GenesMODY-Related Genes

Permanent neonatal diabetes (PND) Permanent neonatal diabetes (PND) results from homozygous mutations results from homozygous mutations ofofGlucokinase geneGlucokinase gene

Insulin promoter factor (IPF-1) geneInsulin promoter factor (IPF-1) gene

MODY-Related Proteins MODY-Related Proteins [1/4][1/4]

GlucokinaseGlucokinase

Expressed in Expressed in -cells and liver-cells and liver

Catalyzes transfer of phosphate from Catalyzes transfer of phosphate from ATP to glucose, generating glucose-6-ATP to glucose, generating glucose-6-phosphate, a rate-limiting step in glucose phosphate, a rate-limiting step in glucose metabolismmetabolism

““Glucose sensor” in Glucose sensor” in -cells-cells

Facilitates glycogen synthesis in the liverFacilitates glycogen synthesis in the liver

MODY-Related Proteins MODY-Related Proteins [2/4][2/4]

Liver-enriched transcription factors Liver-enriched transcription factors HNF-1HNF-1, HNF-1, HNF-1, and HNF-4, and HNF-4Expressed in liver and other organs, including Expressed in liver and other organs, including

pancreatic islets, kidneys and genitaliapancreatic islets, kidneys and genitalia

Part of a network of transcription factors that Part of a network of transcription factors that function together to control expression of function together to control expression of multiple genesmultiple genes

Regulate expression of the insulin gene, and Regulate expression of the insulin gene, and genes of proteins involved in glucose genes of proteins involved in glucose transport and metabolism, and mitochondrial transport and metabolism, and mitochondrial metabolismmetabolism

MODY-Related Proteins MODY-Related Proteins [3/4][3/4]

Transcription factor IPF-1Transcription factor IPF-1Expressed in pancreatic isletsExpressed in pancreatic islets

Regulates transcription of a variety of Regulates transcription of a variety of genes, including genes for insulin, genes, including genes for insulin, somatostatin, islet amyloid polypeptide, somatostatin, islet amyloid polypeptide, glucokinase, and GLUT-2glucokinase, and GLUT-2

Mediates glucose-induced stimulation Mediates glucose-induced stimulation of insulin-gene transcriptionof insulin-gene transcription

MODY-Related Proteins MODY-Related Proteins [4/4][4/4]

Transcription factor Neuro-D1 Transcription factor Neuro-D1 (BETA2)(BETA2)Expressed in pancreatic isletsExpressed in pancreatic islets

Activates the transcription of the Activates the transcription of the insulin geneinsulin gene

Required for normal development of the Required for normal development of the pancreatic isletspancreatic islets

Distinguishing Clinical Characteristics ofDistinguishing Clinical Characteristics ofMODY and Type 2 Diabetes (DM2)MODY and Type 2 Diabetes (DM2) [1/2][1/2]

Mode of inheritanceMode of inheritance

MODY: Monogenic, autosomal dominantMODY: Monogenic, autosomal dominant

DM2: PolygenicDM2: Polygenic

Age of onsetAge of onsetMODY: Childhood, adolescence, MODY: Childhood, adolescence, usually <25 yearsusually <25 years

DM2: Usually 40-60 years; DM2: Usually 40-60 years; occasionally in obese adolescentsoccasionally in obese adolescents

PedigreePedigree

MODY: Multi-generationalMODY: Multi-generational

DM2: Rarely multi-generationalDM2: Rarely multi-generational

Distinguishing Clinical Characteristics ofDistinguishing Clinical Characteristics ofMODY and Type 2 DiabetesMODY and Type 2 Diabetes [2/2][2/2]

PenetrancePenetranceMODY: 80-95 %MODY: 80-95 %

DM2: Variable (10-40 %)DM2: Variable (10-40 %)

Body habitusBody habitusMODY: Not obeseMODY: Not obese

DM2: Usually obeseDM2: Usually obese

Dysmetabolic syndromeDysmetabolic syndromeMODY: AbsentMODY: Absent

DM2: Usually presentDM2: Usually present

MODY1 (HNF-4MODY1 (HNF-4 Mutation): Mutation): Pedigree RW, Branch W, Offspring of II-5Pedigree RW, Branch W, Offspring of II-5

––

++

141141

135135

144144

IIIIII

IVIVVV

IVIV VV

VV

IVIV147147

IIII

––

––

++

1313

99

1414

1212

99

++

++

++

––

––

3030++

2929

1414

1313

++

++ ++1717 1010 1010 99 881818–– ++ ++ ++ ++ ++

1717 ++ 1717 ++ 1313 –– –––– ––

––––++2727 2525 ++2929 ++ ––

++2121

1616++

2222

1111++

++––

––3939

170170

161161

1414++ 11

++

1010

99++

++

––

––

––

1111++

––

Tested and normalTested and normal

Type 1 diabetesType 1 diabetes

146146

5vv

77

NNNN

RR

++ presence (NM), or presence (NM), or –– absence absence (NN) (NN) of gene mutation.of gene mutation.

?? 4343 4242

9988776655443311

11 22 33 44 55 66

5050 60604040

4141

MIMIPVD-APVD-A

N, Np, R-B, MIN, Np, R-B, MIPVD-A-GPVD-A-G

PVD-APVD-ARR

22

MIMI

5252

––

II

IIIIII

IIGG

55

Multiple offspringMultiple offspring

R-BR-BPVD-APVD-A

IIIIII

II

I

I

MODY1 (HNF-4MODY1 (HNF-4 Mutation): Mutation): Pedigree RW, Branch W, Offspring of II-2Pedigree RW, Branch W, Offspring of II-2

22

IIIIII

IVIV

VV

IIII

11 22 33 44 55 66 77 88 99

Tested and normalTested and normal

1414 1010 1111 1313 1212 55 11 77 55 44 11

4343

4848 3232 57572222 6161

1919 2424 1919 2727 2626 2323 2424

++ –– –– –– –– –– ++ ++ ++–– ++

++++ –– –– –– ++ ++ ++ –– ++ ++ ++

–– –– ++ ++ –– ––++

PVDPVD

MIMIPVD-APVD-A

++ presence (NM) orpresence (NM) or – – absence (NN) of geneabsence (NN) of gene mutationmutation

Type 2 diabetesType 2 diabetes

RRNN

1414 1212 ––––

Phenotypic Expression and Phenotypic Expression and Natural History of MODYNatural History of MODY

Recognition at young ageRecognition at young ageUnder age 25 yearsUnder age 25 years

7-13 years or younger, if sought by glucose testing 7-13 years or younger, if sought by glucose testing in younger generationsin younger generations

Not progressive, or slowly progressiveNot progressive, or slowly progressiveHyperglycemia responsive to diet and/or oral Hyperglycemia responsive to diet and/or oral

anti-hyperglycemic agents for years to decadesanti-hyperglycemic agents for years to decades

May progress to insulin-requiring diabetes May progress to insulin-requiring diabetes (not insulin-dependent or ketosis-prone)(not insulin-dependent or ketosis-prone)

May progress rapidly from young age onwardMay progress rapidly from young age onward

MODY1 (HNF-4MODY1 (HNF-4 Mutation): Mutation): Plasma Glucose & Insulin Levels During OGTT Plasma Glucose & Insulin Levels During OGTT

(0.75 g/kg BW) in Groups of RW Pedigree(0.75 g/kg BW) in Groups of RW Pedigree

MODY1 (HNF-4MODY1 (HNF-4Mutation): Mutation): Possible Early Defects in Insulin Secretion Possible Early Defects in Insulin Secretion

& Action in RW Pedigree& Action in RW Pedigree Methods:Methods:

Bergman’s minimal model: Frequently sampled IV GTT Bergman’s minimal model: Frequently sampled IV GTT

Polonsky’s low-dose glucose infusion to measure insulin Polonsky’s low-dose glucose infusion to measure insulin secretion rate (ISR) & pulse analysissecretion rate (ISR) & pulse analysis

Conclusions:Conclusions: Non-diabetic members: Deranged and deficient insulin Non-diabetic members: Deranged and deficient insulin

secretion; no insulin resistance. Apparently the primary secretion; no insulin resistance. Apparently the primary inherited abnormality causing susceptibility to diabetes.inherited abnormality causing susceptibility to diabetes.

Diabetic members: Deranged and deficient insulin Diabetic members: Deranged and deficient insulin secretion; any decrease in insulin action is secondary to secretion; any decrease in insulin action is secondary to hyperglycemiahyperglycemia

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

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

Protocol for the Stepped Glucose Infusion Protocol for the Stepped Glucose Infusion Method to Determine Insulin Secretion RateMethod to Determine Insulin Secretion Rate

Time (Minutes)Time (Minutes)

Insulin Secretion Rate (ISR) in MODY1 Insulin Secretion Rate (ISR) in MODY1 (HNF-4 (HNF-4Mutation); RW PedigreeMutation); RW Pedigree

GLUCOSE (mmol/L)GLUCOSE (mmol/L)

Insulin Secretion Rate (ISR) in MODY2 Insulin Secretion Rate (ISR) in MODY2 Subjects (Glucokinase Mutations)Subjects (Glucokinase Mutations)

N= 6N= 6

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

Insulin Secretion Rate in Diabetic & Nondiabetic Insulin Secretion Rate in Diabetic & Nondiabetic MODY3 (HNF-1MODY3 (HNF-1 Mutation) Mutation)

and Control Subjects and Control Subjects

Insulin Secretion Rate in MODY1, MODY2 & Insulin Secretion Rate in MODY1, MODY2 & MODY3, and Control SubjectsMODY3, and Control Subjects

Comparison of Insulin Secretion Comparison of Insulin Secretion Dynamics in Three MODY SubtypesDynamics in Three MODY Subtypes

MODY1MODY1 MODY2 MODY2 MODY3 MODY3

Prediabetic Mildly diabetic Prediabetic Mildly diabetic PrediabeticPrediabetic

Plasma glucose Plasma glucose concentration, at concentration, at which insulin which insulin secretion rate secretion rate

(ISR) is reduced: (ISR) is reduced: >7 mM>7 mM <7 mM <7 mM >8 mM >8 mM

Glucose priming Glucose priming of insulin secretion of insulin secretion

rate (ISR) :rate (ISR) : AbsentAbsent Normal Normal Normal Normal