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

Maturity-Onset Diabetes
of the Young (MODY):
MONOGENIC DIABETES
Sumer Belbez Pek, MD
University of Michigan
April 2016
“MODY”
Hikayesi ve Tarihi
TAKIM:
Sumer Pek + Stefan Fajans + John Floyd
Başlangıç: Diabetes Teşhisinde, Kan
Glukos Düzeyini Daha Güvenililir Kılmak
 1940’larda, Jerome Conn ve Stefan Fajans
“Glucose Tolerance Test”i kullanarak, ve buna
ek “Cortisone Glucose Tolerance Test”i de
geliştirerek, diabetes teşhisinde şimdi
kullanılmakta olan kriterleri kesinleştirdiler.
 Stefan Fajans, bu iki diagnostik testi, NIH
tarafından desteklenen yeni bir çalışmada
kullanmaya karar verdi:
“Natural history of diabetes”
University of Michigan Study:
“NATURAL HISTORY of DIABETES” (1/4)
 Project started in 1950s at the University of
Michigan in Ann Arbor, under the leadership of
Stefan Fajans.
 Aim: “Prospective, long-term study involving
first-degree relatives of patients with maturityonset diabetes mellitus” (later called “Type 2”),
including children and young adults, who were
considered to be in good health.
 Protocol: Oral glucose tolerance tests, and
“cortisone glucose tolerance tests” (C-GTT) to
unmask early and latent stages of diabetes.
University of Michigan Study:
“NATURAL HISTORY of DIABETES” (2/4)
 Among the non-diabetic relatives of diabetic
patients with a family history of diabetes, 26%
had abnormal C-GTTs, versus only 4%
without a family history.
 Some of the relatives with abnormal C-GTT
were nonobese children as young as 7 years
old, who ultimately developed overt diabetes.
 The term “maturity onset diabetes of the
young” was used for the first time in 1964 by
Fajans.
University of Michigan Study:
“NATURAL HISTORY of DIABETES” (3/4)
 Insulin immunoassay became available in mid-
1960s; plasma levels revealed that the relatives
with abnormal C-GTT had low insulin responses
to glucose.
 The autosomal pattern of inheritance emerged in
the 1970s, based on data collected on several
families, largest being the “RW Family”
(360 members spanning 6 generations;
74 members with diabetes).
 The abbreviation “MODY” was first introduced in
1975 at the University of Michigan (Tattersall &
Fajans).
Example of the Inheritance Pattern of
Diabetes in the Pedigree RW, Branch W
Generation
II
43
III
IV
19
V
+
48
–
–
+
14
–
12
–
24
14
–
–
+
+
10
–
32
19
–
+
11
27
–
Presence, or – absence of gene mutation
Tested and normal
Type 2 diabetes
–
+
+
13
–
22
–
57 +
+
12
–
26
+
5
–
_ 23
1
+
7
61
+
24
+
+
5
–
4
–
+
+
1
Numbers designate age at time of study
Gene mutation subsequently confirmed
+
University of Michigan Study:
“NATURAL HISTORY of DIABETES” (4/4)
 As an inherited health problem, MODY
attracted the attention of geneticists.
Donald Steiner’s group at University of
Chicago offered collaboration.
 Blood samples from the large “RW” family
were delivered from Ann Arbor to Chicago.
“MODY”nin Gen Bozukluğundan
Ötürü Geliştiğinin Keşfi ve Tarifi:
Monogenic Diabetes
“SINGLE-GENE POLYMORPHISM”
Autosomal Dominant
Heterozygous
Discovery of “Monogenic Diabetes”
 At University of Chicago, working on the blood
samples of the RW Family, Graeme Bell reported in
1991 a DNA polymorphism on Chromosome 20q,
initially identified as adenosine deaminase gene
(ADA).
 In 1996, Graeme Bell’s group revised the gene
abnormality in Chromosome 20q as a
Q268X nonsense mutation in the gene of
HNF4a, a “nuclear transcription factor”.
 As other monogenic forms of diabetes were
identified, HNF4a-defective form was named
“MODY1”.
Gene Transcription Process
in the Cell Nucleus
Gene
DNA helix
Transcription
(RNA synthesis)
Nuclear RNA
RNA Splicing
Protein synthesis
Messenger RNA
Pancreatic Islet Function Abnormalities
Caused by HNF4a Gene Mutation
in MODY1 (RW Pedigree)
[Clinical Studies at the University of Michigan]
 b-Cell: Decreased Insulin, C-Peptide, Amylin
 a-Cell: Decreased Glucagon
 ∂-Cell: Decreased Pancreatic Polypeptide
ß-Cell Function in MODY1 (HNF4a Mutation):
High Plasma Glucose & Low Insulin Levels During
Oral Glucose Tolerance Test
ß-Cell Function in MODY1 (HNF4a Mutation):
Low Plasma C-Peptide Levels in Response to
L-Arginine Infused Intravenously
ß-Cell Function in MODY1 (HNF4a Mutation):
Low Plasma Amylin Levels in Response to
L-Arginine Infused Intravenously
a-Cell Function in MODY1 (HNF4a Mutation):
Low Plasma Glucagon Levels in Response to
L-Arginine Infused Intravenously
∂-Cell Function in MODY1 (HNF4a Mutation):
Low Plasma Pancreatic Polypeptide in
Response to Insulin-Induced Hypoglycemia
Hepatocyte Dysfunction
in MODY1 (HNF4a Mutation)
 Because transcription factor HNF4a is
expressed also in hepatocytes,
dyslipidemia occurs in diabetic as well as
prediabetic MODY1 subjects as a
“primary defect in lipoprotein synthesis”,
even before the onset of diabetes
Özet (1/2): MODY1’in Tarifi
 Soydan geçen “autosomal dominant” ve
“heterozygous” tek gen bozukluğu (monogenik)
 Tek gen bozukluğu, tüm pankreas adacık
hücreleri, ve karaciğer hücreleri üzerinde etken
 Azalmış insulin salgılanması en baştaki sorun
 Diabetes, çoğunlukla çocukluk ve gençlik
süresinde gelişir, yanlışlıkla Tip-1 DM sanılabilir,
ve sulfonilüre yerine insulin’e başlatılabilir
 Diabetes yeni tanılan çocuğun/gencin soy
kuşaklarında diabetes yaygınlığı araştırılmalı
Özet
: MODY1 ile Tip-2 Diabetes’in
Karşılaştırılması
(2/2)
MODY1
 Tek gen bozuk, ve tek
Tip-2 DM
 Karışık genlerin etkisi belirsiz
başına etken
 Çocuk, veya genç (<25 y)
 Gelişkin (40-60 y), şişmansa
daha erken
 Çok aile kuşağında rastlanır  Kuşaklarda çok seyrek
 Genetik etki oranı %80-95
 Genetik etki %10-40
arasında
 Beden gelişimi obes değil
 Çoğunlukla obese yakın
veya obes
 Metabolik sindrom gelişmez  Metabolik sindrom sık gelişir
Sonuç
 MODY hikayesi, hızla gelişmekte olan
teknolojilerin sebatla etkilenmesi sonucu, çok az
rastlanan bir hastalığın mekanizmasının keşfi ile,
o hastalığın çok daha sık rastlanan formlarının da
gelişme yollarının kanıta bağlı açıklanması
kolaylaşacak (şimdiye kadar 30 tip MODY!)
 MODY çalışmaları sonucu şimdiye kadar ele
geçen bilginin, MODY tiplerinin ve geç gelişen
klasik Tip-2 diabetes çeşitlerinin engellenmesi ve
tedavisi yönünde yeni girişimlere yol açacağına
inanıyoruz.
MODY’nin ß-Hücresine Etkisi
2010:
Sumer Pek +++ Stefan Fajans