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 maturity-onset 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).

III

IV

V

II

Tested and normal

14 10 11 13 12 5 1 7 5 4 1

43

48 32 57 22 61

19 24 19 27 26 23 24

+ – – – – – + + + – +

+ + – – – + + + – + + +

– – + + – – +

+ Presence, or – absence of gene mutation

Type 2 diabetes

14 12 – –

Example of the Inheritance Pattern of

Diabetes in the Pedigree RW, Branch W

Numbers designate age at time of study

Gene mutation subsequently confirmed

Generation

_

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

RNA Splicing

Messenger RNA

Gene

DNA helix

Transcription

(RNA synthesis)

Nuclear RNA

Protein synthesis

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 (2/2): MODY1 ile Tip-2 Diabetes’in

Karşılaştırılması

Tek gen bozuk, ve tek

başına etken

Çocuk, veya genç (<25 y)

Çok aile kuşağında rastlanır

Genetik etki oranı %80-95

Beden gelişimi obes değil

Metabolik sindrom gelişmez

Karışık genlerin etkisi belirsiz

Gelişkin (40-60 y), şişmansa

daha erken

Kuşaklarda çok seyrek

Genetik etki %10-40

arasında

Çoğunlukla obese yakın

veya obes

Metabolik sindrom sık gelişir

MODY1 Tip-2 DM

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