neonates diabetes

2

CSIM2.26 PITUITARY F(X): Unusual DiabetesMonogenic 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

>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

suggests degree of physiological adaptation

4. What does it looks like?

Presentation

Clinical features

common in gestational diabetes

rare in hospital diabetes clinics

incidental hyperglycaemia in children

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

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

closely related to HNF-1a

distinct DM phenotype

pancreatic and genitourinary anomalies

2. Epidemiology

5-10% of MODY in UK

3. Clinical features

RCAD: renal cysts & diabetes syndrome

renal function variable: mild and RRT in up to 50%

DM alone unusual

patients not sensitive to sulphonylureas

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.