Download MODY: Maturity-Onset Diabetes Of The Young. Part I

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
 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
Heterozygous Gene Mutations
Identified in MODY
Name
(Year)
Gene
Chromosome
MODY1 (1991)
HNF-4a
MODY2 (1993)
Glucokinase
MODY3 (1996)
HNF-1a
12q
MODY4 (1997)
IPF-1 (PDX-1)
13q
MODY5 (1997)
HNF-1b
17q
MODY6 (1999)
Neuro-D1 / BETA-2
20q
7p
2q
HNF
= Hepatocyte nuclear factor
IPF
= Insulin promoter factor
PDX-1 = Pancreatic duodenal homeobox-1
Homozygous Mutations of
MODY-Related Genes
 Permanent neonatal diabetes (PND)
results from homozygous mutations
of
 Glucokinase gene
 Insulin promoter factor (IPF-1) gene
MODY-Related Proteins [1/4]
 Glucokinase
 Expressed in b-cells and liver
 Catalyzes transfer of phosphate from
ATP to glucose, generating glucose-6phosphate, a rate-limiting step in glucose
metabolism
 “Glucose sensor” in b-cells
 Facilitates glycogen synthesis in the liver
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
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
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
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
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
MODY1 (HNF-4a Mutation):
Pedigree RW, Branch W, Offspring of II-5
II
G
2
1
3
6
5
4
7
I
I
40
V
IV
–
III
9
8
MI
1
MI
PVD-A
PVD-A
R
2
50
3
4
60
R-B
PVD-A
5
N, Np, R-B, MI
PVD-A-G
6
IV V
170
39
–
II
+
+
11
13
14
+
+
?
43
42
41
52
III
9
+
12
–
9
30
+
+
–
29
29
+
–
27
144
17
17 +
+
–
13 –
+
–
10
+
10 + 18
–
–
147
5
7
+
9
+8+
–
5vv
of gene mutation.
–
+
14
–
+ presence (NM), or – absence (NN)
I
13 + 17
–
25 +
+
146
–
+
+
21
N
141
V
+
22
III
+
11
–
N
–
14
+
+
R
+
10
16
+
IV
I
–
135
–
9
161
Type 1 diabetes
Tested and normal
Multiple offspring
–
1
MODY1 (HNF-4a Mutation):
Pedigree RW, Branch W, Offspring of II-2
MI
PVD-A
II
43
2 PVD 3
1
III
V
48
–
IV
19
2
–
+
14
–
12
–
24
14
–
–
+
+
10
+ presence (NM) or –
–
32
4
+
19
–
+
11
–
27
–
+
+
13
–
Type 2 diabetes
6
12
–
7
22
–
57 +
absence (NN) of gene mutation
Tested and normal
5
R
N
26
+
5
–
23
1
+
7
8
9
61
+
24
+
+
5
–
4
–
+
+
1
+
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
MODY1 (HNF-4a Mutation):
Plasma Glucose & Insulin Levels During OGTT
(0.75 g/kg BW) in Groups of RW Pedigree
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
Frequently Sampled IVGTT in Nondiabetic (–) &
Diabetic (+) Marker Members of
R-W Pedigree (MODY1; HNF-4a)
Pulsatile Insulin Secretion & Fluctuations in
Plasma Glucose During Constant Glucose
Infusion in 3 Members of the R-W Pedigree
Protocol for the Stepped Glucose Infusion
Method to Determine Insulin Secretion Rate
Time (Minutes)
Insulin Secretion Rate (ISR) in MODY1
(HNF-4a Mutation); RW Pedigree
GLUCOSE (mmol/L)
Insulin Secretion Rate (ISR) in MODY2
Subjects (Glucokinase Mutations)
N= 6
Insulin Secretion Rate in Nondiabetic
MODY3 Subjects (HNF-1a Mutation)
Insulin Secretion Rate in Diabetic & Nondiabetic
MODY3 (HNF-1a Mutation)
and Control Subjects
Insulin Secretion Rate in MODY1, MODY2 &
MODY3, and Control Subjects
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
Normal
Normal
 Glucose priming
of insulin secretion
rate (ISR) :
Absent