A (very) brief introduction to monogenic diabetes Created by the University of Chicago Kovler...
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Transcript of A (very) brief introduction to monogenic diabetes Created by the University of Chicago Kovler...
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
Spectrum of neonatal diabetes• 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).– 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 KCNJ11can cause all of these syndromes:
HI, T2D, MODY, TNDM, PNDM, iDEND, DEND
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.
iDEND: learning disorders, speech delay, Seizures- absence,hypotonia with delayed walking, possible association, or confusion, with ADD.
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 CellInsulin 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.
Sensor of functional beta cell mass
But also have other tissueExpression:
Liver, brain, kidneyUterus….
Mody genes
MODY genes are
transcription factors and GCK
Type 1Affected gene - HNF4alphaPrevalence - UncommonType 2Affected gene - GCKPrevalence - CommonType 3Affected gene - TCF1 / HNF1alphaPrevalence - Most commonType 4Affected gene - IPF1 / Pdx1Prevalence - UncommonType 5Affected gene - TCF2 / Hnf1betaPrevalence - UncommonType 6Affected gene - Neuro D1Prevalence - 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: A Model for Genetics and Personalized Medicine
Diabetes Mellitus
Neonatal Diabetes (diabetes diagnosed before 6 months of age; both sporadic
(usual) and familial)
Transient Permanent
Familial, mild fasting hyperglycemia
Familial (autosomal dominant), onset
before 25 years of age
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
Test KCNJ11, INS and ABCC8
Test for chromosome
6q24 abnormalities,
and, if negative, ABCC8 and KCNJ11
Onset at birth; nonprogressive;
complications rare; stable HbA1c, 6.1-7.0
Test GCK
Onset in adolescence or young adulthood;
progressive hyperglycemia with
typical diabetic complications
Test HNF1A, then HNF4A, and if renal
features, HNF1B
Type 1 diabetes
Insulin
No productive genetic tests
Type 2 diabetes
Diet and exercise; oral hypoglycemic agents; Metformin; GLP1R agonists; DPPIV inhibitors
No productive genetic tests
KCNJ11 and ABCC8
High dose oral
sulfonylurea
INS
InsulinTransient insulin
Observe for relapse
No treatment in most cases; may need
insulin in pregnancy
Low dose oral sulfonylurea
If parents have impaired fasting glucose, consider GCK
When to Suspect a Diagnosis of Type 1 or Type 2 Diabetes May Not be Correct
When to Suspect a Diagnosis of Type 1 or Type 2 Diabetes May Not be Correct
• Type 1 Diabetes– Diagnosis before 6
months of age – [in T1DM: <1%].– Family history of
diabetes with an affected parent [in T1DM: 2-4%].
– Evidence of endogenous insulin/C-peptide production outside the honeymoon period (after 3 yrs of diabetes).
– Pancreatic islet autoantibodies are absent (in T1DM: 3-30%).
• Type 2 Diabetes– Nl BMI, Not markedly
obese or diabetic family members of normal weight.
– No acanthosis nigricans [in T2DM: 10%].
– Ethnic background with a low prevalence of T2DM.
– No evidence of insulin resistance with C-peptide low or within normal range.
Maturity-onset Diabetes of the Young (MODY) - 1989
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 - 2010MODY - 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