Transcript A (Very) - Diabetes In Control

A (very) brief introduction
to monogenic diabetes
• Created by the University of Chicago
Kovler Diabetes Center
• See www.kovlerdiabetescenter.org
for more information and how to
contact us
www.monogenicdiabetes.org
www.kovlerdiabetescenter.org
Spectrum of neonatal diabetes
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HLA studies show that patients diagnosed with diabetes in the first 6
months of life are very likely to have monogenic neonatal diabetes rather
than type 1 diabetes (Except IPEX-related).
Neonatal diabetes is a rare disorder
– incidence of between 1 in 215,000-500,000 live births
– Several genes are also implicated in T2DM in GWAS
Approximately 40% have permanent neonatal diabetes (PNDM).
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20% have some aspect of developmental delay
Over 30% have an unknown cause
Heterozygous activating mutations in the KCNJ11 and ABCC8 genes which
encode the Kir6.2 and SUR1 subunits of the ATP-sensitive potassium (KATP)
channel and INS gene mutations are the commonest causes of PNDM.
A number of other rare genetic etiologies have been identified
(GCK, IPF1, PTF1A, GLIS3, FOXP3, EIF2AK3, GLUT2, HNF1B, RFX6).
Most rare causes show autosomal recessive inheritance; FOXP3 – IPEX
–
(immune dysregulation, polyendocrinopathy, enteropathy, X-linked
Summary: mutations in
ABCC8 and KCNJ11
can cause all of these syndromes:
HI, T2D, MODY, TNDM, PNDM, iDEND, DEND
iDEND:
learning disorders,
speech delay,
Seizures- absence,
hypotonia with delayed walking,
possible association, or confusion, with ADD.
Flanagan, S. E., Clauin, S., Bellanne-Chantelot, C., de Lonlay, P., Harries, L. W.,
Gloyn, A. L. & Ellard, S. (2008). Update of mutations in the genes encoding
the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and
sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism.
Hum Mutat.
INS Mutations and
PNDM, MODY, Type 1b
• Frequency - INS
– permanent neonatal diabetes series,
12%. (KCNJ11 mutations are the most
common cause, 30%). (<1/200,000 live
births)
– Rare cause of MODY
– Rare cause (1%) of Type 1b diabetes
(antibody negative Type 1 diabetes)
• Familial hyperinsulinemia
• Familial hyperproinsulinemia
Insulin and the Pancreatic Beta Cell
• Insulin is the major biosynthetic and secretory product
• Insulin mRNA - 20% of total mRNA (100-200,000 insulin
mRNA molecules/cell.
• Insulin - 10% of the total protein.
• Insulin - 50% or more of the total protein synthesis when
maximally stimulated - 1.3 x 106 molecules of insulin/min (and
3.9 million molecules of reactive oxygen species/H2O2
generated in the formation of the three disulfide bonds in
proinsulin).
• Insulin biosynthesis by it’s very nature induces ER stress
which is aggravated by increasing demand.
Neonatal Diabetes Registry
at the University of Chicago
http://kovlerdiabetescenter.org/registry
MODY genes are
transcription factors
Mody genes
Sensor of functional
beta cell mass
But also have other tissue
Expression:
Liver, brain, kidney
Uterus….
and GCK
Type 1
Affected gene - HNF4alpha
Prevalence - Uncommon
Type 2
Affected gene - GCK
Prevalence - Common
Type 3
Affected gene - TCF1 / HNF1alpha
Prevalence - Most common
Type 4
Affected gene - IPF1 / Pdx1
Prevalence - Uncommon
Type 5
Affected gene - TCF2 / Hnf1beta
Prevalence - Uncommon
Type 6
Affected gene - Neuro D1
Prevalence - Very rare
MODY types 1, 3, 4,
5, and 6 are
transcription
factors involved in
controlling the way
insulin is
adequately
produced and
released from the
beta cells.
RFX6 (2010)
Diabetes Mellitus: A Model for Genetics
and Personalized Medicine
Diabetes Mellitus
Neonatal Diabetes (diabetes diagnosed
before 6 months of age; both sporadic (usual)
and familial)
Transient
Test for
chromosome
6q24
abnormalities,
and, if negative,
ABCC8 and
KCNJ11
Transient
insulin
Observe for
relapse
Permanent
Familial, mild fasting
hyperglycemia
Onset at birth;
nonprogressive;
complications rare;
stable HbA1c, 6.1-7.0
Test KCNJ11, INS and
ABCC8
KCNJ11 and
ABCC8
INS
High dose
oral
sulfonylurea
Insulin
If parents have impaired
fasting glucose,
consider GCK
Familial (autosomal
dominant), onset
before 25 years of age
Onset in adolescence
or young adulthood;
progressive
hyperglycemia with
typical diabetic
complications
Diabetes diagnosed
after 6 months of age;
no family history;
presence of
antibodies to insulin
and other beta-cell
proteins; specific HLA
haplotypes
Diabetes associated
with obesity; onset in
middle age; familial
aggregation; insulin
independent
Type 1 diabetes
Type 2 diabetes
Test GCK
Test HNF1A, then
HNF4A, and if renal
features, HNF1B
No productive genetic
tests
No productive genetic
tests
No treatment in most
cases; may need
insulin in pregnancy
Low dose oral
sulfonylurea
Insulin
Diet and exercise;
oral hypoglycemic
agents; Metformin;
GLP1R agonists;
DPPIV inhibitors
When to Suspect a Diagnosis of Type 1 or
Type 2 Diabetes May Not be Correct
• Type 1 Diabetes
• Type 2 Diabetes
– Diagnosis before 6
– Nl BMI, Not markedly
months of age
obese or diabetic family
– [in T1DM: <1%].
members of normal
– Family history of
weight.
diabetes with an
– No acanthosis nigricans
affected parent [in
[in T2DM: 10%].
T1DM: 2-4%].
– Ethnic background with
– Evidence of endogenous
a low prevalence of
insulin/C-peptide
T2DM.
production outside the
honeymoon period (after
– No evidence of insulin
3 yrs of diabetes).
resistance with C– Pancreatic islet
peptide low or within
autoantibodies are
normal range.
absent (in T1DM: 3-30%).
Maturity-onset Diabetes of the Young (MODY) - 1989
• Rare monogenic form of diabetes mellitus with only a
handful of families described
• Characterized by autosomal dominant inheritance and
onset before 25 years of age although diagnosis may be
missed until later in life (younger at-risk subjects are
often asymptomatic)
• Not associated with obesity
• Unknown pathophysiology: defect in insulin action, insulin
secretion or both?
MODY - 2010
• Common disorder – 1-3% of all patients with
diabetes may have MODY
• Occurs in all racial and ethnic groups
• Can masquerade as type 1 diabetes or more
commonly type 2 diabetes
• Undiscovered MODY genes especially in
understudied populations may reveal links to
T2DM
Inclusion criteria for U of C MODY registry: Diagnosis of diabetes
after 12 months and before 50 years of age AND at least one of the
following:
-- Stable, non-progressive elevated fasting blood glucose
-- Diagnosis of type 1 diabetes with atypical features
-- Diagnosis of type 2 diabetes with atypical features
-- Family history of ≥3 consecutive generations of diabetes in a
dominantly inherited pattern
-- A personal or familial genetic diagnosis of MODY
•Subjects without a genetic diagnosis of MODY have DNA sequencing
performed
-- Saliva samples are obtained using Oragene™ DNA Self-Collection Kits
-- PCR amplification and sequencing of subject DNA is done to
identify mutations in the known MODY genes: HNF4A, GCK, HNF1A,
IPF1, HNF1B, NEUROD1
- whole exome sequencing on unknowns
•CLIA-certified laboratory confirmation is obtained