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WHO Classification of Diabetes (1999)

Type 1Insulin-dependent Absolute insulin deficiencyAutoimmune destruction of B-cellsIslet cell antibodies

Type 2 Non-insulin dependentBoth decreased insulin secretion and insulin resistance

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“Other specific sub-types”

Diabetes Primary Feature

Diabetes Secondary Feature

GeneticMODYMitochondrial diabetesPartial LipodystrophyInsulin receptor defects

GeneticHaemochromatosisCystic fibrosisDowns SyndromeFriedrichs AtaxiaMyotonic Dystrophy

Non-GeneticExocrine diseaseEndocrinopathiesDrugs

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Pt 1: Age 45yrs1983

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

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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

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2002C-peptide positive and GAD Ab negativeNot 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)

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Pt 1 Family

MT +

MT +

Pt 1MT +

MT +

MT +

N

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2009Proliferative diabetic retinopathy Bilateral laser treatment

Raised BP and Cholesterol

2012Diabetic Kidney disease eGFR 22

Pt 1: Age 45yrs

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“Other specific sub-types”

Diabetes Primary Feature

Diabetes Secondary Feature

GeneticMODYMitochondrial diabetesPartial LipodystrophyInsulin receptor defects

GeneticHaemochromatosisCystic fibrosisDowns SyndromeFriedrichs AtaxiaMyotonic Dystrophy

Non-GeneticExocrine diseaseEndocrinopathiesDrugs

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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

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MODY: Genetic heterogeneity

Type Gene Chr. Frequency Penetrance at 40yrs

MODY 1 HNF-4 20q 5% >80%

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% ?

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Pt 2: Age 35yrs2006

Left lower lobe pneumoniaHbA1c 6.6% and RBG 10mmol/l

FBG 7.2 mmol/l and GAD Ab negative

Diagnosed DM

FHx DM

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Pt 2: Family

Pt 2 Tablet Treated

GDM x 4Insulin

3 sibs positive for the N254H mutation in Glucokinase Diagnosis: MODY 2

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Pt 2: Age 35yrsHbA1c

2007 6.6%2008 6.8%2009 6.8%2010 6.8%2011 6.8%

Remains on diet treatment aloneSisters stopped their medications

Pancreatic beta-cell

Glut 2

Mitochondria

ATP/ADP K+

GlucoseInsulin Secretion

Ca2+

KATP Channel

Calcium Influx

[Ca2+]i

++

++

+++ +++

|

|

|

|

X

Glucokinase

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Age (years)

0 10 20 30 40 50 +60

FastingBlood Glucose Glucokinase

HNF1

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Feature HNF1

(MODY 3)

Glucokinase

(MODY 2)

Fasting hyperglycaemia ++ +

Diabetes progression Yes No

Small vessel complications

Common Rare

Sulphonylurea

sensitivity

Yes No

MODY: Clinical heterogeneity

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MODY summary points:

Gene mutations have high penetrance but are uncommon

Genetic heterogeneity contributes to clinical heterogeneity

Gene identification influences clinical management (pharmocogenetics)

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Pt 31980

Type 2 Diabetes aged 42 yrs

FHX T2DMHypertension and Mixed dyslipidaemia

HbA1 8.0% (BMI 28) 78 kg

1990

HbA1 8.5% 77 kg Max dose SU + metformin

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Pt 31991

HbA1c 10.6% 79 kg

SU stoppedBD insulin + metformin

1994

HbA1c 7.7% 80 kg58 units insulin/day + metformin

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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

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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

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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

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Pt 32002

HbA1c 7.2% (best since 1992!) 94 kg

BP check

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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)

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Pt 32002 (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

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Pt 3

2011HbA1c 11.2% 92 units/day 81kgEye disease partially sightedPoorly controlled BPChronic renal impairmentIHDCirrhosis and portal hypertension

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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

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“Other specific sub-types”

Diabetes Primary Feature

Diabetes Secondary Feature

GeneticMODYMitochondrial diabetesPartial LipodystrophyInsulin receptor defects

GeneticHaemochromatosisCystic fibrosisDowns SyndromeFriedrichs AtaxiaMyotonic Dystrophy

Non-GeneticExocrine diseaseEndocrinopathiesDrugs

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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)

LMNA gene mutation R644C

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

The laminopathies: a clinical review

Clinical GeneticsVolume 70, Issue 4, pages 261-274, 17 AUG 2006 DOI: 10.1111/j.1399-0004.2006.00677.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1399-0004.2006.00677.x/full#f1

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

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