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Download No Slide Title - Diabetes UK Newcastle Support Group
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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 “Other specific sub-types” Diabetes Primary Feature Genetic MODY Mitochondrial diabetes Partial Lipodystrophy Insulin receptor defects Diabetes Secondary Feature Genetic Haemochromatosis Cystic fibrosis Downs Syndrome Friedrichs Ataxia Myotonic Dystrophy Non-Genetic Exocrine disease Endocrinopathies Drugs 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 Pt 1: Age 45yrs 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 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 Pt 1 Family MT + MT + MT + Pt 1 MT + N MT + 7 Pt 1: Age 45yrs 2009 Proliferative diabetic retinopathy Bilateral laser treatment Raised BP and Cholesterol 2012 Diabetic Kidney disease eGFR 22 8 “Other specific sub-types” Diabetes Primary Feature Genetic MODY Mitochondrial diabetes Partial Lipodystrophy Insulin receptor defects Diabetes Secondary Feature Genetic Haemochromatosis Cystic fibrosis Downs Syndrome Friedrichs Ataxia Myotonic Dystrophy Non-Genetic Exocrine disease Endocrinopathies Drugs 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 Hattersley et al, 1992 11 MODY: Genetic heterogeneity Type Gene Chr. Frequency Penetrance at 40yrs 5% >80% MODY 1 HNF-4 20q MODY 2 Glucokinase 7p 22% 95% MODY 3 HNF-1 12q 58% >90% MODY 4 IPF-1 13q <1% ? MODY 5 HNF-1 17q 1% ? 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 Pt 2: Family GDM x 4 Insulin Tablet Treated Pt 2 3 sibs positive for the N254H mutation in Glucokinase Diagnosis: MODY 2 14 Pt 2: Age 35yrs 2007 2008 2009 2010 2011 HbA1c 6.6% 6.8% 6.8% 6.8% 6.8% Remains on diet treatment alone Sisters stopped their medications Pancreatic beta-cell Glucose Insulin Secretion Glut 2 + Glucokinase + | + | Mitochondria +| | ATP/ADP K+ KATP Channel X +++ +++ [Ca2+]i Ca2+ Calcium Influx 16 HNF1 Fasting Blood Glucose Glucokinase 0 10 20 30 40 Age (years) 50 +60 17 MODY: Clinical heterogeneity Feature HNF1 (MODY 3) Glucokinase (MODY 2) Fasting hyperglycaemia ++ + Diabetes progression Yes No Small vessel complications Common Rare Sulphonylurea sensitivity Yes No 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 Pt 3 1980 Type 2 Diabetes aged 42 yrs FHX T2DM Hypertension and Mixed dyslipidaemia HbA1 8.0% (BMI 28) 1990 HbA1 8.5% Max dose SU + metformin 78 kg 77 kg 20 Pt 3 1991 HbA1c 10.6% SU stopped BD insulin + metformin 1994 HbA1c 7.7% 58 units insulin/day + metformin 79 kg 80 kg 21 Pt 3 1997 HbA1c 10.6% 84 kg 96 units insulin/day Renal impairment (metformin stopped) Ischaemic heart disease Diabetic retinopathy Hypertension and dyslipidaemia ?taking insulin 22 Pt 3 1999 Accelerated hypertensionadmission Abd U/S: fatty infiltration of liver, but normal kidneys Renal Angiogram: normal BP controlled with 4 agents HbA1c 10.9% 87 kg DESPITE 144 units/day, BMs 10-15 mmol/l 23 Pt 3 2001 HbA1c 12.2% 88 kg Proliferative retinopathy laser therapy Add Rosiglitazone to insulin therapy No Heart Failure LFTs: Alk Phosph 170 ALT normal 24 Pt 3 2002 HbA1c 7.2% BP check (best since 1992!) 94 kg 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 nonalcoholic steatohepatits (NASH) 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 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 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 “Other specific sub-types” Diabetes Primary Feature Genetic MODY Mitochondrial diabetes Partial Lipodystrophy Insulin receptor defects Diabetes Secondary Feature Genetic Haemochromatosis Cystic fibrosis Downs Syndrome Friedrichs Ataxia Myotonic Dystrophy Non-Genetic Exocrine disease Endocrinopathies Drugs Familial Partial Lipodystrophy: FPLD2 (Dunnigan Lipodystrophy) Abnormal fat distribution develops after puberty More marked phenotype in women Autosomal dominant Failure of subcutaneous adipocytes to differentiatecompensatory expansion of central fat stores (including liver) Mutations in the lamin A/C gene (LMNA) 30 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 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 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
