1. 1 WHO Classification of Diabetes (1999) Type 1 Insulin-dependent Absolute insulin deficiency Autoimmune destruction of B-cells Islet cell antibodies Type 2 Non-insulin dependent Both decreased insulin secretion and insulin resistance

2. 2 “Other specific sub-types” Diabetes Primary Feature Diabetes Secondary Feature Genetic MODY Mitochondrial diabetes Partial Lipodystrophy Insulin receptor defects Genetic Haemochromatosis Cystic fibrosis Downs Syndrome Friedrichs Ataxia Myotonic Dystrophy Non-Genetic Exocrine disease Endocrinopathies Drugs

3. 3 Pt 1: Age 45yrs 1983  Diabetes Mellitus (aged 16) No ketones/no wt loss Mother had type 2 diabetes Initially given Sulphonylurea - stopped because of recurrent hypos and wt gain Switched to twice daily insulin

4. 4 1986-2002 Very poor blood glucose control (HbA1c averaged 14%) Admitted that she did not take insulin because of weight-but no episodes of ketoacidosis Pt 1: Age 45yrs

5. 5 2002 C-peptide positive and GAD Ab negative Not Type 1 DM Developed diabetic retinopathy 2006 ? Maturity onset diabetes of the Young Genetic screen – heterozygous for a point mutation in the HNF1a gene (S608fsdelAG)

6. 6 Pt 1 Family MT + Pt 1 MT + N

7. 7 2009 Proliferative diabetic retinopathy Bilateral laser treatment Raised BP and Cholesterol 2012 Diabetic Kidney disease eGFR 22 Pt 1: Age 45yrs

8. 8 “Other specific sub-types” Diabetes Primary Feature Diabetes Secondary Feature Genetic MODY Mitochondrial diabetes Partial Lipodystrophy Insulin receptor defects Genetic Haemochromatosis Cystic fibrosis Downs Syndrome Friedrichs Ataxia Myotonic Dystrophy Non-Genetic Exocrine disease Endocrinopathies Drugs

9. 9 Maturity Onset Diabetes of the Young: MODY Early onset non-insulin dependent diabetes before the age 25 yrs autosomal dominant pattern of inheritance rare (1-3% of Type 2 diabetes) initially assumed to be single condition

10. Hattersley et al, 1992

11. 11 MODY: Genetic heterogeneity

12. 12 Pt 2: Age 35yrs 2006 Left lower lobe pneumonia HbA1c 6.6% and RBG 10mmol/l FBG 7.2 mmol/l and GAD Ab negative Diagnosed DM FHx DM

13. 13 Pt 2: Family Pt 2Tablet Treated GDM x 4 Insulin 3 sibs positive for the N254H mutation in Glucokinase Diagnosis: MODY 2

14. 14 Pt 2: Age 35yrs HbA1c 2007 6.6% 2008 6.8% 2009 6.8% 2010 6.8% 2011 6.8% Remains on diet treatment alone Sisters stopped their medications

15. Pancreatic beta-cell Glut 2 Mitochondria  ATP/ADP K+K+ Glucose Insulin Secretion Ca 2+ K ATP Channel Calcium Influx  [Ca 2+ ] i + + + + +++ | | | | X Glucokinase

16. 16 Age (years) 01020304050+60 Fasting Blood Glucose Glucokinase HNF1 

17. 17 Feature HNF1  (MODY 3) Glucokinase (MODY 2) Fasting hyperglycaemia+++ Diabetes progressionYesNo Small vessel complications CommonRare Sulphonylurea sensitivity YesNo MODY: Clinical heterogeneity

18. 18 MODY summary points: Gene mutations have high penetrance but are uncommon Genetic heterogeneity contributes to clinical heterogeneity Gene identification influences clinical management (pharmocogenetics)

19. 19 Pt 3 1980  Type 2 Diabetes aged 42 yrs FH X T2DM Hypertension and Mixed dyslipidaemia HbA 1 8.0%(BMI 28)78 kg 1990 HbA 1 8.5%77 kg Max dose SU + metformin

20. 20 Pt 3 1991 HbA 1c 10.6%79 kg SU stopped BD insulin + metformin 1994 HbA 1c 7.7%80 kg 58 units insulin/day + metformin

21. 21 Pt 3 1997 HbA 1c 10.6%84 kg 96 units insulin/day Renal impairment (metformin stopped) Ischaemic heart disease Diabetic retinopathy Hypertension and dyslipidaemia ?taking insulin

22. 22 Pt 3 1999 Accelerated hypertension  admission Abd U/S: fatty infiltration of liver, but normal kidneys Renal Angiogram: normal BP controlled with 4 agents HbA 1c 10.9%87 kg DESPITE 144 units/day, BMs 10-15 mmol/l

23. 23 Pt 3 2001 HbA 1c 12.2%88 kg Proliferative retinopathy  laser therapy Add Rosiglitazone to insulin therapy No Heart Failure LFTs:Alk Phosph  170 ALT normal

24. 24 Pt 3 2002 HbA 1c 7.2%(best since 1992!)94 kg BP check

25. 25 Partial Lipodystrophy   subcutaneous fat and  central and ectopic fat deposition  Metabolic Syndrome: Severe insulin resistance Type 2 diabetes Hypertension Dyslipidaemia Fatty infiltration of the liver and non- alcoholic steatohepatits (NASH)

26. 26 Pt 3 2002 (cont:)  Abnormal LFTs: Alk Phosph:  143  GT:  173 ALT: 40 (ULN)  Referred to Chris Day  Liver biopsy: steatohepatitis and evidence of micronodular cirrhosis!  Family history-mother had cirrhosis and diabetes

27. 27 Pt 3 2011 HbA1c 11.2% 92 units/day 81kg Eye disease  partially sighted Poorly controlled BP Chronic renal impairment IHD Cirrhosis and portal hypertension

28. 28 Pt 3 Summary:  Partial lipodystrophy  Familial T2DM and cirrhosis  Type 2 diabetes – difficult to manage  Metabolic Syndrome  Small and large vessel complications of diabetes  Cirrhosis and portal hypertension

29. 29 “Other specific sub-types” Diabetes Primary Feature Diabetes Secondary Feature Genetic MODY Mitochondrial diabetes Partial Lipodystrophy Insulin receptor defects Genetic Haemochromatosis Cystic fibrosis Downs Syndrome Friedrichs Ataxia Myotonic Dystrophy Non-Genetic Exocrine disease Endocrinopathies Drugs

30. 30 Familial Partial Lipodystrophy: FPLD2 (Dunnigan Lipodystrophy)  Abnormal fat distribution develops after puberty  More marked phenotype in women  Autosomal dominant  Failure of subcutaneous adipocytes to differentiate  compensatory expansion of central fat stores (including liver)  Mutations in the lamin A/C gene (LMNA)

31. LMNA gene mutation R644C American Journal of Medical Genetics Part A Volume 146A, Issue 12, pages 1530-1542, 13 MAY 2008 DOI: 10.1002/ajmg.a.32331 http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.32331/full#fig1 Volume 146A, Issue 12, http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.32331/full#fig1

32. The laminopathies: a clinical review Clinical Genetics Volume 70, Issue 4, pages 261-274, 17 AUG 2006 DOI: 10.1111/j.1399-0004.2006.00677.x http://onlinelibrary.wiley.com/doi/10.1111/j.1399-0004.2006.00677.x/full#f1 Volume 70, Issue 4, http://onlinelibrary.wiley.com/doi/10.1111/j.1399-0004.2006.00677.x/full#f1

33. Summary: approach to patient < 25yrs with newly diagnosed diabetes  Is it Type 1 diabetes?-if not, could it be:  A genetic subtype – more likely if not overweight and strong family history of diabetes  Type 2 diabetes-more likely if both parents have T2DM and /or patient is markedly overweight 33