Male , 36 years of age

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Male , 36 years of age

• Impaired fasting glucose since 1988 (21 years of
  age)
• R/ diet alone
• Lean, 177cm and 57,2 kg, was never obese
• No complaints, coincidental finding during check
  up
• Medical history negative
• Family history mother ( age of 50) and sister
  (after corticosteroids) have diabetes.
• 2 healthy children

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Lab results

• HbA1C 6,6 (4-6)
• C-Peptide 2,25 ng/ml (0,8-4,2)
• Normal liver function and renal function
• No microalbuminuria
• Low cholesterol(154 mg/dl), high HDL (50 mg/dl)
  and low triglycerides
• ICA 12 JDF Units (lt12)
• GAD65 AB 0,6 (lt2,6)
• Insulin antibodies 0,5 (lt0,6)

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Medical therapy

• 05/04 Glargine 6 units, Repaglinide 3x2mg /d
• 09/04 HbA1C 7,3
• Glargine 8U, lispro with every meal, repaglinide
  stopped

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Maturity-Onset Diabetes of the Young (MODY)

• 2-5 of diabetics
• autosomal dominant inheritance
• onset usually before age 25
• impaired ?-cell function
• normal weight, no islet cell
  autoantibodies
• no insulin resistance

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MODY Types

• MODY 1 mutations in hepatocyte nuclear
  transcription factor-4?
• (HNF-4?) ? severe ?-cell secretory defect
• MODY 2 mutations in glucokinase ? mild
  hyperglycemia
• due to ? ?-cell reponsiveness to glucose
• MODY 3 mutations in hepatocyte nuclear
  transcription factor-1?
• (HNF-1?) ? severe ?-cell secretory defect
• MODY 4 mutations in insulin promoter factor
  (IPF-1 gene)
• MODY 5 mutations in hepatocyte nuclear factor
  1? (HNF-1?)
• ? severe ?-cell secretory
  defect
• MODY 6 mutations in neurogenic differentiation
  factor 1
• (Neuro D1)

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Clinical entity of MODY

• Early onset, non insulin-dependent diabetes
• Insulin treatment not a requisite 5 years
  following diagnosis and no significant C-peptide
  deficit
• Autosomal dominant inheritance at least 2
  generations (diagnosis before 25 years)
• No acanthosis nigricans, no obesity
• No pancreatic auto-antibodies(especially GAD)

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Diabetes in Young Adults (15-30 years)
Type 2
Type 1
MODY
MIDD
5 10 15 20 25 30 35 40 45
50 55 60 65 70 75 80 85 90
Age of diagnosis
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Diagnostic criteria for MODY

• Early-onset diabetes
• Not insulin-dependent diabetes
• Autosomal dominant inheritance
• Caused by a single gene defect altering beta-cell
  function, obesity unusual

Tattersall (QJM 1974)
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The Genetic Causes of MODY
MODY
11MODY x
75Transcription factors
14Glucokinase(MODY2)
3HNF1?
3HNF4?
lt1IPF1
lt1NeuroD1
69HNF1?(MODY3)
Frayling, et al Diabetes 2001
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Two subtypes of MODY Glucokinase and
Transcription factor
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16
12
Glucose
(mmol/l)
8
.
.
4
0
0
20
40
60
80
100
Age (yr..)
Pearson, et al Diabetes 2001
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Glucokinase (MODY 2)

• Glucokinase central role in insuline secretion
• Glucose-gtglucose-6-phosphate-gtinsuline secretion
• Expressed in beta cells and hepatocytes
• Pancreatic glucose sensor

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Glucokinase (MODY2)
Rare in hospital diabetic clinicsIncidental
hyperglycaemia in childrenCommon in gestational
diabetesPersistent raised fasting
glucose(99-162 mg/dl) from birth Little rise (54
mg/dl) in OGTT No extra-pancreatic featuresNot
obese (usually) Often asymptomatic TEST PARENTS!
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Transcription factor MODY

• Transcription factors key role in the regulation
  of gene expression in development of adult tissue
• Reduced maximal insulin secretion
• Hepatocyte nuclear factors play a key role in
  beta-cell development, regulation of
  proliferation of beta-cells and metabolism in the
  mature beta cell
• Progressive beta cell dysfunction

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HNF1a (MODY3)
Commonest cause of MODY May be misdiagnosed as
type 1 Typically develop 12-30 yr FPG maybe
normal initially Large rise (90 mg/dl) in
OGTTWorsening glycaemia with age Low renal
threshold (glycosuria)Not obese
(usually) Parents and grandparents usually
diabetic
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HNF1a (MODY3) and treatment

• Low dose sulfonylureas, first - line medication
• Marked sensitivity, should be introduced with
  caution.
• Hypersecretion of insulin, increased sensitivity
  to the insulin secreted
• Metformin not as effective

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OGTT Results GCK and HNFEuropean MODY
Consortium (n 364) - Stride et al Diabetologia 02
Differentiating between HNF1a (MODY3) and
Glucokinase (MODY 2) based on moderate
hyperglycaemia following glucose challenge
Plasma Glucose mmol/l

HNF1

GCK
p lt 0.001
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Summary Glucokinase and Transcription factor
diabetes rather than MODY MODY
Transcription factormutations
Glucokinasemutations
(HNF-1?, HNF-1b, HNF-4?)

Onset at birthStable hyperglycaemiaDiet
treatmentComplications rare
Adolescence/young adult onsetProgressive
hyperglycaemia1/3 diet, 1/3 OHA, 1/3
InsulinComplications frequent
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HNF-1? (MODY 5) Renal Cysts and Diabetes (RCAD)

• Renal cysts
• Often seen on anti-natal scanning - variable
• Renal function variable - mild impairment -
  endstage renal failure 50 require dialysis
• Different renal histology
• Diabetes
• Diagnosis 22 (10 - 47) yr., often on insulin
• Other extra-pancreatic features uterine
  abnormalities, insulin resistance and gout

Nishigori et al Diabetes 1998, Lindner et al 1999
Hum Mol Gen Bingham et al 2000 Kidney Int,
Bingham et al 2001 AmJ Hum Gen, Bingham et al
2002 Kidney Int,
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Young adult diabetes diagnosis distinction from
type 1 and type 2 NOT on a single clinical
criteriaor a single investigationmulti -
facetted approach needed
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MODY Type1 Non insulin
dependent Yes No Parents
affected 1 0-1 Age of onset lt 25yr Yes
YesMODY diagnostic criteria separate well
from Type 1
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MODY Type 2 Type1 Non insulin
dependent Yes Yes No Parents
affected 1 1-2 0-1 Age of onset lt
25yr Yes unusual Yes MODY diagnostic
criteria do not separate well from early-onset
Type 2
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MODY Type 2 Type1 Non insulin
dependent Yes Yes No Parents
affected 1 1-2 0-1 Age of onset lt
25yr Yes unusual YesObesity /-
/-Acanthosis - -NigricansRacia
l groups low high low(Type 2 prevalence)
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Clinical Assessment of Non-Type 1Young Adult
Diabetes

• Clinical Assessment
• - Diabetes characteristics
• - Non-pancreatic manifestations
• - Family History
• Investigations
• - General Specific Diagnostic Tests

Key for diabetes syndromes
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Diabetes
Neurological
Obesity
Deafness
Acanthosis nigricans
DIDMOAD MIDD
Type A IRLipodystrophy
Retinitis pigmentosa

OtherCystic fibrosisRenal cysts Diabetes
Prader-Willi
AlstromBardet-BiedlLawrence-Moon
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Non genetic Investigations

• MODY
• Variable
• Not present
• Usually detectable(0-1 nmol/l)
• normal (HDLgt1.2 MODY3)

• Type 1
• Variable
• gt95 diagnosis
• not measurable
• gt 3-5 years
• (lt0.33nmol/l)
• normal

Glycaemia Autoantibodies ICA, IA2 or GAD C
peptide Lipids
Type 2 Variable unusual detectable may be
high (gt1nmol/l) HDL low TG high
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Criteria distinguishing HNF1a (MODY3) from Type 1
are useless for differentiating from Type 2
young adults!

• Familial 2 generations 96 HNF1a 80 Type
  2
• 3 generations 74 HNF1a 50 Type 2

• C peptide present or not insulin 100 HNF1a
  100 Type 2 treated 3 yrs post diagnosis

• Pancreatic Auto - antibody -ve 98 HNF1a
  90 Type 2

• So use different data for answering different
  questions!

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Distinguishing HNF1a (MODY3) from Type 2
Consider in type 2 diabetic young adults when.

• Not obese 86 HNF1a 25 Type 2
• Not over weight 64 HNF1a 4 Type 2

• Not acanthosis nigricans 100 HNF1a 20 Type
  2
• HDL gt 1.2 mmol/l 83 HNF1a lt8 Type 2

• Caucasian 94 HNF1a 30 Type 2

• Consider HNF1a testing in any Type 2 young
  adult who is not obese, does not have AN, or low
  HDL especially if CaucasianUK Data on
  HNF1a/Type 2 Hattersley, Barrett, Ehtisham, Owen,
  Pearson unpublished

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Genetic Testing why do it?

• Makes diagnosis defines monogenic and subtype
• Differentiates from type 1
• Helps define prognosis
• Helps family counselling
• Helps treatment decisions
• - Glucokinase safely leave children
  off treatment
• - HNF1a very sensitive to
  sulfonylureas

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MODY conclusion

• Use both diagnostic criteria and clinical
  information and non-genetic investigation to
  suggest a diagnosis
• Genetic testing makes diagnosis defines MODY,
  defines subtype helps with counselling, prognosis
  and treatment
• BUT .Expensive 1-400- - only do if alter
  management
• Test ordered guided by clinical criteria as to
  likely gene. Discuss each case before testing