Clinical Science & Investigative Medicine 2015

Endocrine & Metabolic Disease

unusual diabetes

Dr Stuart Little
Newcastle upon Tyne Hospitals NHS Foundation Trust

371 million
world diabetes day
92 million
14 November
63 million
22.9%

Unusual diabetes
objectives
Recognise specific forms of diabetes

monogenic
congenital
syndromic
secondary diabetes

Review molecular & cellular pathophysiology of

specific forms of diabetes
Be able to plan & interpret investigations to establish a
diagnosis of specific forms of diabetes

MODY
maturity onset diabetes of the young
17 years

26 years

Insulin
stopped

Diagnosed type 1 diabetes aged 18

lean, keen sportsman
treated with insulin
problems with hypoglycaemia

26 years old

specialist sports clinic

noted not using any basal insulin
fasting glucose 5 mmol/L & HbA1c 39 mmol/mol

Insulin stopped & gliclazide commenced

HbA1c 42 mmol/mol
no problems with hypoglycaemia

MODY
what is it & how do we make a diagnosis?
Different types of MODY
glucokinase MODY
transcription factor MODY

Differentiating from other forms of DM

type I
type 2
genetic syndromes

Investigations for MODY

Diabetes in young adults 15-30

diabetes is a diagnostic specialty

Type 1

Type 2

Genetic Syndromes
MODY

MODY
clinical features
Residual insulin secretion at least 3 years after
diagnosis of type 1 DM
Young age of onset
Lack of metabolic syndrome in those presumed
to have type 2 DM

The genetics of MODY

12 genes identified to date
Glucokinase
32%

Transcription factors
68%

HNF-Ia 52%
HNF-4a 10%
HNF-1b 6%
IPF-I
Neuro-DI

MODYx

MODY
beta cell physiology is key to pathophysiology

Beta cell insulin secretion

the critical role of glucokinase
Ca2+

Glucose

K+
K+
Ca2+

K+

Glucose

K+

K+

Ca2+
Ca2+

K+

K+

K+
K+

insulin

Ca2+

Glu
Glu

ADP

ATP

Ca2+

insulin

insulin

Glucokinase
G6P
G6P

G6P

insulin

Glucokinase MODY
loss of function impairs glucose sensing
Epidemiology
30 % of MODY cases in UK
most common form of MODY in children

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

Glucokinase MODY
what does it look like?
Presentation
rare in hospital diabetes clinics
incidental hyperglycaemia in children
common in gestational diabetes

Clinical features

persistent, raised fasting glucose

no extra-pancreatic features
usually non-obese
often asymptomatic
parents & family
consider testing to support diagnosis

MODY
beta cell development is key to pathophysiology too

Transcription factor MODY

the role of beta cell development genes

Primitive gut
endoderm

Primitive gut
endoderm
Hnf6
HnfIb
Foxa2
Hnf4a
Hex
Gata4
Gata6

beta cell in Islet

Pancreatic
endoderm
Hnf6
HnfIb
Foxa2
Hnf4a
Hex
Gata4
Gata6
Hlxb9
PaxI
PtfIa

Pancreatic
progenitor
Hnf6
HnfIb
Foxa2
Hnf4a
Hex
Gata4
Gata6
Hlxb9
PdxI
PtfIa
Nkx6.I
Nkx2.2

Early endocrine Endocrine

progenitor
progenitor

Immature -cell Mature -cell

Foxa2
Hnf4a
Hex
Gata6
PdxI
Nkx6.I
Nkx2.2
Pax6
Isl1
NeuroD
MafA

Transcription factor MODY

beta cell development & diabetes

Transcription factors in pancreas development

endoderm migration
cell differentiation
cell mass
cell function

HNF-1a

visceral endoderm differentiation

pancreas & islet development

HNF-1b

activation of NHF4A & HNF1A

regulatory relationships

HNF-4a

beta cell differentiation

Transcription factor MODY

HNF-Ia & HNF-4a MODY
Clinical picture
similar for HNF-Ia & HNF-4a
normoglycaemic in childhood
typically develop DM 12-30 years
worsening glycaemia with age
may be misdiagnosed as type I DM

low renal threshold for glucose seen in HNF-Ia

poor control does lead to complications
parents & grandparents may have DM
HNF-1a
the most common form of MODY

HNF-Ia & HNF-4a MODY

treatment
Sensitive to low dose sulphonylureas
low dose sulphonylureas are first line treatment
gliclazide
glibenclamide

prandial secretogogues

In those diagnosed as type I DM

insulin can be stopped

Transcription factor MODY

HNF-Ib MODY
HNF-1b function
closely related to HNF-1a
distinct DM phenotype
pancreatic and genitourinary anomalies

Epidemiology

5-10% of MODY in UK

Clinical features
RCAD

renal cysts & diabetes syndrome

renal function variable

mild
RRT in up to 50%

DM alone unusual
patients not sensitive to sulphonylureas
usually require insulin

Diagnostic testing in MODY

why do genetic testing?
Makes a diagnosis

defines monogenic DM & subtype

Differentiates from type 1 DM

Helps define prognosis
Helps family counselling
Helps guide treatment decisions

Diagnostic testing in MODY

why do testing at all?
Glucokinase MODY
safely leave children off treatment

HNF-Ia MODY

very sensitive to sulphonylureas

Unusual diabetes
diagnosing MODY.conclusions
Use a balanced approach
diagnostic criteria
clinical information
non-genetic investigation

Genetic testing

defines MODY
defines subtype
cost is high
350 per gene in UK
access may be limited
justification if alters management?
guided by clinical criteria

Unusual diabetes
neonatal diabetes
Epidemiology
rare
1:100,000 live births affected

Mechanism

some 15 gene disorders identified to date

GOF mutation in beta cell K+-ATP channel in majority of cases

Presentation & clinical features

presentation birth to six months
high glucose levels or DKA
low birth weight
IUGR

C-peptide very low

low insulin release

DM may be transient or permanent

Unusual diabetes
permanent neonatal diabetes
Epidemiology
very rare

Mechanism
GOF mutations KCNJII or ABCC8 genes in 40-50%

Kir6.2 & SURI subunits of K+ATP channel

K+ channel cannot respond to ATP & permanently open
no beta cell depolarisation
failure of insulin release

insulin gene mutation 10%

require insulin therapy

Presentation & clinical features

neurological involvement in 20%

Unusual diabetes
genetic syndromes & diabetes
Name of syndrome

Diabetes Mellitus associations

Downs syndrome

Autoimmunity main factor

Excess cases presenting < 3 compared
sporadic type 1 DM

DIDMOAD (Wolframs syndrome)

Diabetes Insipidus, Diabetes
Mellitus, Optic Atrophy, Deafness

AR inheritance.
Mutation WFS1
Reduced insulin production

Turners syndrome

Autoimmune type 1 DM

Prader Willi Syndrome

Obesity & insatiable craving for food

Lawrence-Moon & Bardet-Biedl

Syndromes

Obesity and insulin resistance

Klinefelters Syndrome

High truncal fat & insulin resistance

Myotonic Dystrophy

Insulin resistance

Unusual diabetes
insulin resistance syndromes
Clinical features of insulin resistance
persistent hyperglycaemia
despite large doses of insulin

acanthosis nigricans
polycystic ovarian syndrome

Insulin resistance
genetic causes
Insulin receptor defects
loss of function mutations in the IR
range of resistance
Donahue syndrome
Rabsen-Mendenhall syndrome

Lipodystrophy syndromes

Unusual diabetes
lipodystrophy
Aetiology
genetic
acquired

Classification
anatomical distribution of lipodystrophy

Clinical features

partial or complete absence of adipose tissue

insulin resistance a feature of most
clinical expression more pronounced in women

Diagnosis clinically based

Unusual diabetes
lipodystrophy syndromes
Congenital generalised LD
autosomal recessive
generalised absence adipose
tissue
increased appetite
absence of leptin

DM develops in 10-20 yrs

Familial partial LD
FPLDI
loss limb fat
increased truncal fat
no identified gene to date

FPLD2
LOF mutations LMNA

FPLD3
paucity limb & gluteal fat
LOF mutation PPAR

Unusual diabetes
lipodystrophy

Unusual diabetes
diabetes & HIV
Epidemiology
incidence of DM in HIV positive men treated with HAART
four times greater than that of HIV negative men

Pathophysiology & mechanisms

high levels of insulin, proinsulin & glucagon

insulin resistance may have an HIV component

protease inhibitors

Protease inhibitors & NRTIs

associations following introduction
increased incidence insulin resistance & diabetes

effects on glucose metabolism varied

indanavir
blocks insulin mediated glucose uptake by blockade of GLUT-4
increases hepatic glucose production

Unusual diabetes
the big picture..
MODY is an important diagnosis
it can alter treatment & prognosis

Understanding unusual causes of DM is a catalyst

understanding pancreatic beta cell
pathophysiology of all types of DM

There are many secondary causes of diabetes

genetic
drug
endocrine causes

Clinical Science & Investigative Medicine 2015

Endocrine & Metabolic Disease

unusual diabetes

Dr Stuart Little
Newcastle upon Tyne Hospitals NHS Foundation Trust