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

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1 Maturity-Onset Diabetes of the Young (MODY): MONOGENIC DIABETES Sumer Belbez Pek, MD University of Michigan April 2016

2 MODY Hikayesi ve Tarihi

3 TAKIM: Sumer Pek + Stefan Fajans + John Floyd

4 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

5 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%

6 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.

7 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).

8 Example of the Inheritance Pattern of Diabetes in the Pedigree RW, Branch W Generation II 43 III IV _ V Presence, or absence of gene mutation Tested and normal Type 2 diabetes Numbers designate age at time of study Gene mutation subsequently confirmed

9 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.

10 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

11 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.

12 Gene Transcription Process in the Cell Nucleus Gene DNA helix Transcription (RNA synthesis) RNA Splicing Nuclear RNA Protein synthesis Messenger RNA

13 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

14 ß-Cell Function in MODY1 (HNF4a Mutation): High Plasma Glucose & Low Insulin Levels During Oral Glucose Tolerance Test

15 ß-Cell Function in MODY1 (HNF4a Mutation): Low Plasma C-Peptide Levels in Response to L-Arginine Infused Intravenously

16 ß-Cell Function in MODY1 (HNF4a Mutation): Low Plasma Amylin Levels in Response to L-Arginine Infused Intravenously

17 a-cell Function in MODY1 (HNF4a Mutation): Low Plasma Glucagon Levels in Response to L-Arginine Infused Intravenously

18 -Cell Function in MODY1 (HNF4a Mutation): Low Plasma Pancreatic Polypeptide in Response to Insulin-Induced Hypoglycemia

19 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

20 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

21 Özet (2/2): MODY1 ile Tip-2 Diabetes in Karşılaştırılması MODY1 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 Tip-2 DM 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

22 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.

23 MODY nin ß-Hücresine Etkisi

24 2010: Sumer Pek +++ Stefan Fajans

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