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• 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.

Neonatal Diabetes Registryat the University of Chicago

http://kovlerdiabetescenter.org/registry

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