1

CSIM2.26
DIABETES

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PITUITARY

F(X):

UNUSUAL

MONOGENIC DIABETES
MATURITY ONSET DIABETES OF THE YOUNG AGE (MODY)
1. Maturity onset diabetes of the young (MODY) refers to any of several hereditary forms of
diabetes caused by mutations in an autosomal dominant gene disrupting insulin production.
2. MODY is often referred to as "monogenic diabetes" to distinguish it from the more common
types of diabetes (especially type 1 and type 2), which involve more complex combinations of
causes involving multiple genes (i.e., "polygenic") and environmental factors.
3. MODY 2 and MODY 3 are the most common forms. " MODY should not be confused with latent
autoimmune diabetes of adults (LADA) a form of type 1 DM, with slower progression to insulin
dependence in later life
4. MODY is caused by a mutation (or change) in a single gene. If a parent has this gene

mutation, any child they have, has a 50% chance of inheriting it from them.

5. Diagnosis/clinical features

a. Residual insulin secretion at least 3 years after diagnosis of type 1 DM

b. Young age of onset
c. Lack of metabolic syndrome in those presumed to have type 2 DM
6. Different type of MODY
a. Glucokinase MODY (32%)
b. Transcription factor MODY (68%)
c. MODYx
7. Beta cell physiology is key to pathophysiology. Glucokinase vs non-glucokinase
GLUCOKINASE MODY
1. Loss of function impairs glucose sensing.
2. It make 30% of MODY cases in UK and most common form of MODY in children.
3. Pathophysiology:
mutations in glycolytic site of GK
o >130 different mutations found to date
increased threshold for glucose-stimulated insulin secretion
insulin secretion remains regulated
microvascular complications not observed
pharmacological interventions not recommended
mild hyperglycaemia discordant with key role of GK in beta cell
o suggests degree of physiological adaptation
4. What does it looks like?
Presentation
- common in gestational diabetes
- rare in hospital diabetes clinics
- incidental
hyperglycaemia
children

in

Clinical features
- persistent, raised fasting glucose
- no extra-pancreatic features
- usually non-obese
- often asymptomatic
- parents & family: consider testing to support
dx.

TRANSCRIPTION FACTOR MODY

NF-IA & HNF-4A MODY
1. Clinical features
a. similar for HNF-Ia & HNF-4a
b. normoglycaemic in childhood
i. typically develop DM 12-30 years
ii. worsening glycaemia with age

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iii. may be misdiagnosed as type I DM
c. low renal threshold for glucose seen in HNF-Ia
d. poor control does lead to complications
e. parents & grandparents may have DM
f. HNF-1a
i. the most common form of MODY
2. Treatment
a. Sensitive to low dose sulphonylureas
i. low dose sulphonylureas are first line treatment
gliclazide
glibenclamide
ii. prandial secretogogues
b. In those diagnosed as type I DM
i. insulin can be stopped
HNF-IB MODY
1. HNF-1b function
o closely related to HNF-1a
o distinct DM phenotype
o pancreatic and genitourinary anomalies
2. Epidemiology
o 5-10% of MODY in UK
3. Clinical features
o RCAD: renal cysts & diabetes syndrome
o renal function variable: mild and RRT in up to 50%
o DM alone unusual
o patients not sensitive to sulphonylureas
o usually require insulin

NEONATES DIABETES
1. permanent neonatal diabetes
2. It is VERY RARE
3. Mechanism
a. GOF mutations KCNJII or ABCC8 genes in 40-50%
i. Kir6.2 & SURI subunits of K+ATP channel
ii. K+ channel cannot respond to ATP & permanently open
iii. no beta cell depolarisation
iv. failure of insulin release
b. insulin gene mutation 10%
i. require insulin therapy
4. Presentation & clinical features
a. neurological involvement in 20%
5.