Illinois AACE Annual Meeting October 13, 2018

Transcription

1 Illinois AACE Annual Meeting October 13, 2018 The Importance of Making a Diagnosis: The case for Monogenic Diabetes Louis H. Philipson MD, PhD Director, Kovler Diabetes Center Professor of Medicine and Pediatrics James C. Tyree Professor of Diabetes Research and Care Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism University of Chicago Medicine

2 Presenter Disclosure Research Funding Louis Philipson MD PhD NIH/NIDDK/NHLBI American Diabetes Association, JDRF, Helmsley Kovler Family Foundation Novo Nordisk Royalties The University of Chicago received royalties from Athena Diagnostics for genetic testing for mutations in GCK, HNF1A, HNF1B and HNF4A I will be discussing the off-label use of generic glyburide

3 The Team

4 Monogenic Diabetes: What It Teaches Us about the Common Forms of Diabetes Type 1 Diabetes Monogenic Diabetes Polymorphisms in genes involved in monogenic forms of diabetes also play a role in polygenic T2D Type 2 Diabetes Yang Y, Chan L. Monogenic Diabetes: What It Teaches Us on the Common Forms of Type 1 and Type 2 Diabetes. Endocr Rev Jun;37(3):

5 And so. It remains a challenge to translate our knowledge from research in the monogenic diabetes genes into effective forms of treatment. Because many of these have been shown to occur in T1D or T2D, we are hopeful that future research into these genes will provide new insights into disease pathogenesis and treatment target identification, not only for the rare monogenic disorders, but also for the worldwide epidemic of T1D and T2D. Yang Y, Chan L. Monogenic Diabetes: What It Teaches Us on the Common Forms of Type 1 and Type 2 Diabetes. Endocr Rev Jun;37(3):

6 The first step in wisdom is to know the things themselves; this notion consists in having a true idea of the objects; objects are distinguished and known by classifying them methodically and giving them appropriate names. Therefore, classification and name-giving will be the foundation of our science Carolus Linnaeus Systema Naturae (1735)

7 KCNJ11, ABCC8, INS GCK, HNF1A, HNF4A, HNF1B Diabetes Mellitus Polygenic Forms Monogenic Forms T1 Diabetes T2 Diabetes Syndromic Non-syndromic Account for 1-5% of cases? Autoimmune form, autoantibody positive Account for 95% of cases Obesity, insulin resistance Neonatal Diabetes Most common: MODY Most common:

8 University of Chicago and University of Michigan Pioneered the Genetic Studies of Diabetes The R-W Pedigree Stefan S. Fajans University of Michigan HNF4A-MODY (MODY1)

9 Case 1 58 year old female initially found to be hyperglycemic at age 19 with fasting blood glucose of 130 mg/dl. BMI was 19 kg/m 2. BG retested at age 23 during pregnancy, and was diagnosed as having gestational diabetes and then type 2 diabetes mellitus. Initially diet-controlled, but transitioned between oral agents (including metformin and troglitazone) and insulin due to fluctuating diagnoses of gestational, type 1 and T2DM Presented to a new endocrinologist s office at age 58. Mild-moderate insulin resistance: 0.87 units insulin/kg; using 90 units/day via insulin pump Current weight 230 pounds and BMI 40.7kg/m 2 9

10 Genetic diagnosis identified a HNF1A Mutation: c.1053delg p.ser352profs12x 1. Obesity doesn t always mean T2D 2.Inquire about your patient s family history 3. Genetic testing to confirm 10

11 Monogenic Forms of Diabetes 1.Understand the phenotype-genotype connection 2.Take a careful family history 3.Identify those who should have cost-effective genetic testing 4.Decide how those genes should be evaluated 5.Realize that not all phenotypes will have a known genetic cause 6.Recognize that therapy may be directed by the specific mutation 7.Act on the implications for the other family members 11

12 Maturity Onset Diabetes of the Young: MODY A heterogeneous metabolic disorder due to heterozygous monogenic mutations in one of at least 13 different genes Onset of diabetes early in life: childhood, adolescence, young adulthood (but may be discovered at any age) Autosomal dominant inheritance (usually) Non-obese (usually) No islet autoimmunity (usually) Primarily due to gene defects in insulin secretion (usually) Neonatal diabetes is caused by an overlapping set of genes

13 R171X Florez et al., 2014

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15 HNF1A and Renal Glucosuria MODY3 patients are characterized by reduced tubular reabsorption of glucose. The renal defect is due to reduced expression of the SGLT2 (2000) HNF1A directly controls SGLT2 gene expression. Pontoglio M, et al

16 Vaxilliare et al., 2016

17 Case 2: Diabetes or hyperglycemia? Dx age 26 FBG mildly elevated: 124 mg/dl during routine physical HbA1c ranges between 5.6% and 6.2% BMI: 23.0 kg/m 2 Diabetes autoantibody tests: negative On insulin for 13 years, ~20 units per day (0.26 u/kg/day Genetic testing revealed GCK- MODY2: Thr168Asn

18 Glucokinase: the pancreatic/liver glucose sensor Glucokinase Bell et al., 2001

19 Mutations in the Glucokinase Gene Reduce Glucose Phosphorylating Capacity and Result in Diabetes Normal MODY2 Neonatal DM Glucose-stimulated insulin response William Winter/ Mark Sperling

20 GCK: no treatment in required* After 13 years, patient unplugged his insulin pump *Usually

21 GCK-No vascular complications Despite a median duration of 48.6 years of hyperglycemia, patients with a GCK mutation had an extremely low prevalence of microvascular and macrovascular complications. These findings may provide insights into the risks associated with isolated, mild hyperglycemia. A1c tends to be 6-7.5%, and rises with age as it does in unaffected family members Steele AM. Hattersley AT. JAMA (3):

22 GCK: What you need to know GCK-MODY2 continues to be misdiagnosed and improperly treated, unnecessarily driving up the costs and complications of diabetes care GCK-MODY2 can be accurately identified based on simple clinical criteria: Stable elevated fasting glucose and A1c Usually a family history that could include either type 1 or type 2 diagnoses Autoantibody negative, usually non-obese Clinical genetic testing should be more readily available for the 1 in 1,000 individuals affected by GCK-MODY2

23 Case 3: The T-Pedigree Proband - 44 year-old woman with onset of diabetes at 3 months of age. Treated since then as T1D on MDI, pump. N/A N/A WT HbA1c >9%. Dx 11 mo Dx infancy Dx 50 yr She was a member of the local JDRF board, heard the Lilly Jaffe story and contacted us soon thereafter. She, her brother and her son all are somewhat resistant to insulin, on about 75 U/day. WT Dx 24 yr INS: G32S Dx 5 mo INS: G32S Dx 8 mo F1 INS: G32S Dx 12 mo S1 INS: G32S PGM1 INS: G32S Dx 2 mo S2 INS: G32S Dx 4 mo Dx 1 mo

24 Glycine is Conserved at Position B8 Among Insulin Sequences and Also IGFs

25 Insulin and the pancreatic beta cell Insulin is the major biosynthetic and secretory product Insulin mrna - 20% of total mrna ( ,000 insulin mrna molecules/cell. Insulin - 10% of the total protein. Insulin - 50% or more of the total protein synthesis when maximally stimulated x 10 6 molecules of insulin/min (and 3.9 million molecules of reactive oxygen species/h 2 O 2 generated in the formation of the three disulfide bonds in proinsulin). Insulin biosynthesis by its very nature induces ER stress which is aggravated by increasing demand.

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27 B8 Gly>Ser Mutation Prevents Formation of the A7-B7 Disulfide Bond Dr. G. Lipkind

28 Genetic Variation in the Insulin Gene: Coding Variants

29 Insulin Gene Mutations Insulin is critically and uniquely important for the beta cell (Pro)insulin gene mutations cause a variety of diabetes phenotypes with variable age of onset Experiments of nature contribute to understanding structure-function aspects of folding requirements and insulin receptor binding Mutations can be in coding or non-coding regions, de novo, dominant or recessive Early recognition may preserve islet structure for some time; rodent and fish models may be useful for treatment strategies and islet cell plasticity Treatments in the future might target chaperones or allele specific knockdowns

30 Case 5: Syndromic diabetes 3 siblings from Guatemala came to the US All three had increased thirst, urination and weight loss prior to diagnosis and had been treated with a daily injection of glargine in Guatemala At the border: the children were not on insulin and were not on insulin for over a week. The children were hyperglycemic but were not in DKA All three children were slim, had high blood sugars and mild to moderate blood beta-hydroxybutyrate levels (tested in the office). Their HbA1C levels (done in the emergency room) were 8.1%, 7.5% and 6.4%. In all three siblings, their insulin, GAD, islet cell and IA2 antibodies are negative. Dx at 5 Dx at 4 Dx at 3

31 WFS1 Homozygous Mutation: c.409_424dup p.val142glyfs*110 The 70 predicted pathogenic mutations are highlighted with green/red coloured circles compared to normal sequence with blue circles Qian et al., 2015

32 WFS1 Homozygous Mutation: WFS1p.R558C The 70 predicted pathogenic mutations are highlighted with green/red coloured circles compared to normal sequence with blue circles Qian et al., 2015

33 Wolfram Syndrome: DIDMOAD Wolfram syndrome, also known as DIDMOAD (diabetes insipidus, insulin-deficient diabetes mellitus, optic atrophy and deafness), is a rare neurodegenerative disorder of autosomal recessive inheritance Links ER Calcium, IP3, mitochondria to regulate mitophagy (mito movement and fission-fusion) linking in turn to aspects of ER stress leading to cell death In the brain now linked to the Pink1-Parkin mitophagy pathway DI, DM, optic atrophy, deafness, psychiatric illness Can present early with DM or deafness alone

34 28 Proband Dx: age 21 Polyuria, weight loss, fatigue (195#, 5 11 BMI: 27.2 kg/m 2 ) Advancing deafness BG: 280 mg/dl after 12-hr fast Ab negative Rx: Insulin, oral medications (metformin - nausea) 2-3 years A1c in 6% range

35 rd Generation T1D 4 th Generation T1D T1D Autism Spectrum

36 56 2 nd Generation Kidney transplant for FSGS Advancing deafness Insulin resistance U-500 insulin via pump Myopathy (untreatable) rd Generation 4 th Generation

37 nd Generation Estranged relationship Overweight Borderline DM Hole in heart Severe development delay CHF Psychiatric symptoms 3 rd Generation th Generation

38 2007 colon cancer Borderline DM Overweight Italian immigrant st Generation 2 nd Generation 3 rd Generation th

39 Felczak et al. Pathology of mitochondria in MELAS syndrome: an ultrastructural study Pol J Pathol 2017; 68 (2):

40 Organs affected in MIDD R. Murphy, D. M. Turnbull, M. Walker and A. T. Hattersley Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabetic Medicine 25,

41 Monogenic Diabetes: Mostly Beta-cell Dysfunction Gene expression HNF1A, HNF1B, HNF4A, PDX1, NEUROD1, GLIS3 PAX4, PAX6, NEUROG3, PTF1A, RFX6, GATA6, MNX1, NKX2-2, GATA4, PCBD1 Neonatal Diabetes: >70% due to four causes: Glucose metabolism GCK Disorder of autoimmunity FOXP3, AIRE, STAT3, IL2RA ER stress EIF2AK3, WFS1, WFS2/ CISD2, IER3IP1, DNAJC3 Insulin synthesis INS Epigenetic disorder of the beta cell 6q24, ZFP57 Glucose transport SLC2A2 (GLUT2) KCNJ11 INS ABCC8 6q24 Testing of neonates MUST include these 4 loci at the very least Exocrine pancreas CEL, CFTR, HFE Ion channel dysfunction KCNJ11, ABCC8 Insulin secretion SLC19A2 (Thiamine transporter-1) trna methyl-transferase TRMT10A

42 Uncertainty Over Which Genes To Test Comprehensive monogenic diabetes gene panel now available for US clinicians

43 GCK HNF1A KCNJ11 INS HNF4A ABCC8 6q24 PDX1 FOXP3 HNF1B GATA6 EIF2AK3 WFS1 INSR RFX6 STAT3 IER3IP1 CFTR IGF2 IL2RA PAX4 Number of participants Participants with known monogenic cause 900 Participants KCNJ11: 47% INS: 22% ABCC8: 18% 6q24: 13% GCK: 61% HNF1A: 30% HNF4A: 8% HNF1B: 1% Gene

44 Monogenic Diabetes: What It Teaches Us about the Common Forms of Diabetes Type 1 Diabetes Monogenic Diabetes Type 2 Diabetes Polymorphisms in genes involved in monogenic forms of diabetes also play a role in polygenic T2D Yang et al., 2016

45 NIDDK U54: Atypical Diabetes External Scientific Panel Steering Committee PIs, NIDDK Coordinating Unit Single IRB Data and Biorepository Core Database and Repository WG Database Core Biorepository Discovery and Analysis Core Data Discovery WG Patient Discovery WG Genetics WG Phenotyping WG

46 Personalized Medicine: Learning from Monogenic Forms of Diabetes 1. Understand the phenotype-genotype connection 2. Take a careful family history 3. Identify those who should have cost-effective genetic testing 4. Decide how those genes should be evaluated 5. Realize that not all phenotypes will have a known genetic cause 6. Recognize that therapy may be directed by the specific mutation 7. Act on the implications for the other family members

47 If I have seen a little further it is by standing on the shoulders of giants -Issac Newton in a letter to Robert Hooke, February 5, 1676 Jim Tyree Stefan S. Fajans Richard Landau Donald F. Steiner

48 Thanks to all the participants, patients and their families

49 Acknowledgements Funding Sources NIH/NIDDK JDRF Jaffe Family Lewis Sebring Foundation Kovler Diabetes Center American Diabetes Association Helmsley Trust Novo Nordisk Jansen Medtronic

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51 No Not yet.. However.