Professor Andrew Hattersley University of Exeter

Transcription

1 Professor Andrew Hattersley University of Exeter

2 Special considerations for MODY and Neonatal Diabetes: Pregnancy, Cardiovascular and Complication risk Professor Andrew Hattersley University of Exeter Medical School, Exeter, UK

3 The challenges of monogenic diabetes once diagnosed What is the complication risk? Appropriate treatment of the mother with monogenic diabetes in pregnancy?

4 Maturity-onset diabetes of the young (MODY): in the pre-genetic era: described as a single mild disease Early diagnosis of diabetes (<25) Non insulin-dependent diabetes Complications rare mild Autosomal dominant inheritance Tattersall (QJM 1974)

5 Maturity-onset diabetes of the young (MODY): in the post genetic era MODY 22% Glucokinase 66% Transcription factors <1% Insulin <1% SUR1 11% MODY x 61% HNF1A 4% HNF4A 2% HNF1B <1% IPF1 <1% CEL

6 Complication risk differs by genetic subtype Scientific insights Clinical insights Gene discovery Clinical features Allows patient diagnosis Specific beta-cell defect Pathophysiology Complication risk Treatment Response

7 Genetic subtype determines Complication Risk MODY 22% Glucokinase 66% Transcription factors <1% CEL <1% Insulin 11% MODY x 61% HNF1A 4% HNF4A 2% HNF1B <1% IPF1 <1% NeuroD1 Microvascular V. low High Mod? High??too rare Macrovascular low V High Mod? High??too rare

8 Glucokinase - all patient have similar mildly raised HbA1c Life long HbA1c Median 6.8% (95% CI %) GCK patients Family controls Steele et al JAMA 2014

9 GCK patients untreated for 50 yrs have no significant microvascular complications Nephropathy 31% Proteinuria 70% GCK n=98 Retinopathy 1% other cause 1% 2% 24% 5% Control n=89 86% 14% 37% YT2D n=80 16% 4% 10% 8% Maculopathy 0% Maculopathy 0% Maculopathy 8% 25% Microalbuminuria Advanced eye disease Proliferative Pre- proliferative <5 MAs Background 5 MAs No retinopathy Steele, Shields et al JAMA 2014

10 Hepatic Nuclear factor 1 Alpha (HNF1A) diabetes deteriorating glycaemia with age hence increased complication risk Transcription factor 20 (HNF1A,HNF4A 300mg/dl - HNF1B) 16 Glucose (mmol/l) mg/dl - 4. Glucokinase Normal Age (yr) Stride & Hattersley Annals of Medicine 2002

11 Hepatic Nuclear Factor I alpha (HNF1A) MODY not mild High Prevalence of Complications Young slim severe hyperglycaemia Like T1D Not mild Severe micro-vascular complications if poor glycaemia Early cardiovascular disease Steele et al Diab Med 2010

12 HNF1A MODY patients die earlier from cardiovascular disease All cause mortality (n=394) (sex and smoking corrected) p < Cardiovascular mortality (n=394) (sex and smoking corrected) HNF1A-MODY HNF1A-MODY Unaffected family members Unaffected family members Hazard ratio 1.9 ( ) Males median age death 69 v 83 yrs Hazard ratio 2.6 ( ) Males 3.4 (1,5-7.7) Steele, Diabetic Med, 2010

13 Cardiovascular Risk high despite HNF1A MODY slim & high HDL HNF1A MODY have high HDL, & low TG compared to T2D Consider statins for all patients with HNF1A Definitely >age 40 Case-by-case basis in younger males McDonald TJ et al Clin Chim Acta 2012

14 In Neonatal diabetes identifying potassium channel mutations led to excellent control on high dose sulphonylureas Kir6.2 Glucose K ATP Channel Sulphonylureas depolarisation Ca 2+ Voltage dependent Ca 2+ Channel L type 90% can stop insulin injections and get better control on SU tablets Pearson et al NEJM 06 Insulin pump GLUT 2 K + Glucose 6 P ATP MgADP [Ca 2+ ]i Insulin Metabolism Nucleus Glibenclamide tablets 50% neonatal diabetes have potassium channel mutations Gloyn et al NEJM 04

15 Excellent long-term control on SU & very low Complication rates 10 year follow-up data (n=81) HbA1c (%) Pre SU transfer HbA1c SU dose Year of follow-up 94% Insulin Free, >800 years of FU: no hypos with L o C or seizures 8% complications: retinopathy & MA older & transferred late 20 v 4 yr Glyburide dose mg/kg/day Pam Bowman Pål Njølstad Fabrizio Barbetti Michel Polak Bowman et al Lancet Diabetes & Endo (2018)

16 The challenges of monogenic diabetes once diagnosed What is the complication risk? Appropriate treatment of the mother with monogenic diabetes in pregnancy? How treatment should vary according to whether monogenic diabetes gene inherited by the fetus?

17 Birth weight in MODY and neonatal diabetes subtypes alters with whether fetus inherits mutation Centile birth weight Glucokinase Decrease 550g ` HNF1A No change ` HNF4A Increase 800g ` HNF1B Decrease 900g ` KCNJ11 Decrease 900g ` mutation no mutation Fetus 0 mutation Fetus no mutation 0 mutation Fetus no mutation 0 mutation Fetus no mutation 0 mutation Fetus no mutation Hattersley et al Nature Genetics 1998 Pearson et al PLoS Medicine 2007 Pearson et al PLoS Medicine 2007 Edghill et al Diabetic Medicine 2006 Slingerland et al JCEM 2006 Modified from McCarthy & Hattersley Diabetes 2008

18 Sarah: Slim Gestational diabetes first pregnancy 21 yr BMI 19.7 kgm -2 pre pregnancy Universal Screening in 1 st Pregnancy OGTT 28 wks fpg 6.8 mmol/l 2hr 8.0 mmol/l Fasting glucose remained > 6mmol/l despite 160U insulin >3U/kg/day Avoided carbohydrate & ate mainly salad Felt awful, consistently sweaty changed clothes 2-3x/day Stopped work after massive hypo, lost consciousness > 20 mins, Induced 39 weeks son 3200g Glucokinase MODY

19 Glucokinase mutations cause MODY (Froguel et al Nature 1992; Hattersley et al Lancet 1992) GLUT 2 Glucose K ATP Channel Glucose 6 P Glucokinase sulphonylureas K + Metabolism ATP MgADP Glucokinase the pancreatic glucose sensor depolarisation Ca 2+ [Ca 2+ ]i Nucleus Recognition in pregnancy Voltage dependent Ca 2+ Channel L type Insulin Fasting 10 plasma glucose 8 (mmol/l) 6 200mg/dl - 100mg/dl - Prevalence 1 in 1000 population 2% GDM, Not a/w obesity 37% GDM FPG > 5.5 mol/l, BMI < 25kg/m 2 (Chakera, Hattersley, Dunn et al Diabetes Care 2014) Consistently raised fasting glucose > 5.5 mmol/l Gestational diabetes c Age (years) European MODY Consortium (n =242) Stride et al Diabetologia 2002 Glucokinase Normal

20 The impact of Maternal and Fetal Glucokinase mutations on birth weight Fetal Glucokinase mutation Maternal Glucose Maternal Glucokinase mutation Glucose sensing by fetal pancreas Insulin secretion by fetal pancreas Insulin mediated growth of fetus Birth weight Hattersley Nature Genetics 1998

21 Centile birth weight according to maternal and fetal genotype 100 Centile birth weight % ` Mother Fetus 0 mutation no mutation no mutation no mutation mutation mutation no mutation mutation Hattersley et al Nature Genetics 1998

22 Glucose threshold mmol/l Glucose threshold Glucose threshold (mmol/l) Glucose is regulated at higher fasting glucose in Glucokinase patients Therefore very hard to alter fasting glucose with treatment Glucose 8 (mmol/l) 6 Glucose challenge Time (mins) European MODY Consortium (n =245) Stride et al Diabetologia 2002 GCK Controls Hypoglycaemic clamp with insulin Symptoms 2.6 CONTROL P=0.002 GCK Adrenali Adrenaline ne CONTROL 2.9 TGCK Glucagon CONTROL 2.6 p= GCK P=0.001 GCK 3.7 Spyer, et al unpublished

23 Fetal mutation not insulin treatment determines fetal outcome in GCK pregnancy 4.2 no fetal mutation 4.1 kg 4.1 kg Mean corrected birth weight (kg) fetal mutation 3.5 kg 3.3 kg DIET INS 1 DIET INS Diet Insulin Diet Insulin Mutation Mutation No mutation No mutation Spyer et at Diabetic Medicine, 2009

24 Management of GCK-MODY in pregnancy Pregnant woman with glucokinase-mody Fetus does not inherit mutation Measure directly if CVS or Amnio sample Assess indirectly by US A/C > 75 th centile CF DNA soon (Exeter) Fetus inherits mutation?insulin to prevent macrosomia in last trimester Deliver 38 weeks No treatment needed?deliver 40 weeks Chakera Hattersley et al. Diabetes Care 2015

25 Sarah: Slim Glucokinase diabetes second pregnancy 25 yr BMI 22.4 kgm -2 pre pregnancy Early OGTT 8 weeks FPG 6.5 and 2 hr 10.2 Diagnosed Glucokinase No treatment in first 2 trimesters Did not monitor glucose Healthy diet Regular scans from 28 weeks Normal fetal growth (fetal AC - < 75 Th Centile) Induced 39.5 weeks son 3560g

26 Claire Diagnosed diabetes aged 23yr BMI 25 kg/m 2 Treated with qds insulin initially HNF1A MODY diagnosed aged 32 yr - transferred to Gliclazide 80mg od HbA1c 6.8% (improved on insulin) Attends pre-pregnancy counseling when 33 yrs

27 Considerations in HNF1A pregnancy birth weight centile No fetal mutation effect on birth weight HNF1A ` mutation no mutation Fetus Pearson et al PLoS Medicine 2007 Best treated with low dose sulfonylureas outside pregnancy Used to transfer to Glibenclamide but now clear evidence crosses placenta & results in increased birth weight and neonatal complications (e.g. Balsells M, BMJ 2015)

28 Management of HNF1A/4A- MODY in pregnancy Not considering pregnancy SU Continue SU pre- conception SU 1 st tri Switch to insulin in 2 nd /3 rd tri Switch to insulin pre-conception Continue insulin all pregnancy Pro: maintain good control in 1 st tri Con: risk deterioration of control in pregnancy Pro: safe for all pregnancy Con: risk of deterioration of control at conception (Shepherd M et al.. Diabetic Medicine 2017)

29 The Biggest Baby in Bradford HNF4A mutation identified Mother Pre-gestational diabetes Diabetes diet diag 25 yr Father and 1 brother early-onset diabetes Pregnancy First pregnancy aged 26 Treated with insulin in pregnancy HbA1c 6.5% last trimester Son: Macrosomia Birth weight 5.9 kg hypoglycaemia glucose 1.2 mmol/l persisted- treated Diazoxide 6/12 Patient, Father and Brother All had diabetes all macrosomic >4.3Kg

30 Birth weight is increased by 800g with fetal mutations in HNF4A Father affected Birth weight centile g p<0.001 Mother affected g p< ` 3540g ` 3780g 0 mutation no mutation Fetus 0 mutation no mutation Fetus Pearson et al PLoS Medicine 2007

31 Neonatal Transient Hypoglycaemia in HNF4A mutation carriers Family members with documented hypoglycaemia P<0.003 ` Neonatal Hypoglycaemia (<2.0 mmol/l >48 hrs) common (~20%) in HNF4 mutation carriers Typically treated for c 6 months with diazoxide 2 0 mutation no mutation Pearson et al PLoS Medicine 2007

32 Managing HNF4A in pregnancy Difficult: Hyperinsulinaemia in utero leading to macrosomia and hypoglycaemia as neonate/infant Need very strict control of maternal glycaemia Insulin (?Sulphonylureas in first trimester) Even if normoglycaemic high risk of macrosomia. Fetal scanning and early delivery (Consider < 38 weeks) Fetus inheriting a paternal mutation has as a greater risk of macrosomia than typical GDM therefore normoglycaemic mother needs same monitoring Offspring will develop neonatal hypoglycaemia at birth if inherit mutation need paediatrician at delivery Pearson et al PLoS Medicine 2007

33 Desiring pregnancy with potentially dominantly inherited neonatal diabetes Type 1 Diagnosed aged 3/12 DKA C peptide negative Insulin treated 0.6-1U/kg 23yr KCNJ11 Neonatal diabetes diagnosed Transferred SU age 23 Excellent control 6.1% ( % on insulin) Desires Pregnancy aged 28 yrs Desires Pregnancy KCNJ11 neonatal diabetes How should pregnancy be managed?

34 Glibenclamide in neonatal diabetes pregnancy Glibenclamide treatment may be beneficial or detrimental depending on whether or not the fetus is affected Mother KCNJ11 TNDM 60mg/day glibenclamide HbA 1c 5.2% - second and third trimesters. Baby Inherited the mutation Caesarean at 38 weeks. Birth weight 3010g (48 th centile) Has not developed NDM at 18 months Mother KCNJ11 PNDM 85mg/day glibenclamide HbA 1c 6.1% - second and third trimesters. Baby Did NOT inherit the mutation Delivery at 33 weeks. Birth weight 3600g (>97 th centile) Glibenclamide detected in cord and in baby Gaal et al. Diabetes Care 2012 Myngheer et al. Diabetes Care 2014

35 Possible management of Kir6.2 neonatal diabetes in pregnancy During Pregnancy Glibenclamide in first trimester Consider CVS for fetal genotyping Fetal ultrasound scans from 26 weeks Decreased growth Normal / increased growth Continue glibenclamide Switch to insulin (Shepherd M et al.. Diabetic Medicine 2017)

36 Conclusions Complications in monogenic diabetes follow glycaemia except for HNF1A increased CVD risk Treatment in pregnancy of monogenic diabetes differs from GDM, T1D and T2D In pregnancy treatment of maternal hyperglycaemia needs to consider the fetal impact of treatment esp SUs as well as the major impact of monogenic diabetes genes on fetal growth Future for fetal genetic determination: Cell Free DNA Can do paternal now (Exeter offers this now) Maternal to alter pregnancy management in GCK pregnancy within 6 months

37 The Exeter Diabetes Research Team Gene discovery: Sian Ellard, Sarah Flanagan, Mike Weedon, Elisa De Franco, Anna Gloyn Hana Lango-Allen, Kevin Colclough, Richard Caswell, Jayne Houghton, Anne-Marie Patch Tim Frayling, Mike Bulman Annet Damhuis, Andrew Parrish Clinical and post gene discovery: Ali Chakera, Maggie Shepherd, Ewan Pearson, Gill Spyer, Adam Brooke, Tim McDonald, Richard Oram, Angus Jones, Bev Shields, Pam Bowman, Nick Thomas,, Ewan Pearson, Oscar Rubio-Cabezas, Rachel Besser, Katherine Owen, Anna Steele, Susie Hammersley, Kash Patel, Noel Morgan, Sarah Parish, John Dennis, Lauren Rodgers, William Henley, Willie Hamilton, Chris Hyde,

38 Resources to help the difficult decisions in monogenic diabetes Web: diabetesgenes.org M. Shepherd et al Diabetic Medicine 2017 A J Chakera et al Diabetes Care 2015 Diabetes Diagnostics App for Apple phones and Android