Transcript MODY: Maturity-Onset Diabetes of the Young. Part II.

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 (+)
MODY1 (RW Pedigree): Plasma C-Peptide Levels
in Response to L-Arginine Infused IV Alone and
Again During Hyperglycemic Clamp
MODY1 (RW Pedigree): Insulin Secretion Rates
(ISR) by Deconvolution of Plasma
C-Peptide Levels During IV L-Arginine Infusion
MODY1 (RW Pedigree): Plasma Amylin Levels in
Response to L-Arginine Infused IV Alone and
Again During Hyperglycemic Clamp
MODY1 (RW Pedigree): Plasma Glucagon Response
Areas (AUC) During IV Infusion of L-Arginine
MODY1 (RW Pedigree):
Plasma Pancreatic Polypeptide Response Areas
(AUC) to Insulin-Induced Hypoglycemia
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
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
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)
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)
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)
The b-Cell & MODY-Related Proteins
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
Serum Levels of Lipoprotein (a) and
Triglycerides in Subjects with HNF-4a (RW) and
other (MODY-X) Mutations
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
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
Differences in Clinical Parameters
Among Diabetic MODY Subtypes [1/2]
Parameter
MODY1
MODY2
MODY3
Normal to
severely 
Mildly 
Normal to
severely 
 Post-prandial Greatly 
Mildly 
Greatly 
 Plasma glucose
 Fasting
 Progression of
hyperglycemia Severe
None or mild
Severe
 Microvascular
complications
Common
Rare
Common
 Renal threshold
for glucose
Normal
Normal
Low
Differences in Clinical Parameters
Among Diabetic MODY Subtypes [2/2]
Parameter
MODY1
MODY2
MODY3
Normal
Normal
Increased
 Sensitivity to
sulfonylurea
 Treatment
Progressive
Rare
requirements 1/3 oral agent
1/3 insulin
 Plasma
lipoproteins
Triglycerides 
Lp (a) 
Apo AII 
Apo CIII 
Progressive
1/3 oral agent
1/3 insulin
Apo M 
 MODY5 is associated with congenital
glomerulocystic, uterine and genital
developmental disorders.
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
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.
Estimated Worldwide Prevalence
of MODY
2 to 5 % of all diabetic patients
Distribution of MODY Subtypes
MODY Subtype
United
Kingdom
France
MODY1
5%
0%
MODY2
12%
63%
MODY3
64%
21%
MODY4
2%
0%
MODY5
1%
0%
16%
16%
MODY“X” (unknown)
MODY: Expectations for the Future
 Understanding of the pathophysiology
of MODY emerging from molecularbiological 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.
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
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.)
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 haplotypetag 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.
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
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)
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)