www.monogenicdiabetes.org
www.kovlerdiabetescenter.org

• 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

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 10 6 molecules of insulin/min (and
3.9 million molecules of reactive oxygen species/H
2
O
2 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.

http://kovlerdiabetescenter.org/registry

Mody genes
Sensor of functional beta cell mass
But also have other tissue
Expression:
Liver, brain, kidney
Uterus….
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 Permanent
Familial, mild fasting hyperglycemia
Onset at birth; nonprogressive; complications rare; stable HbA
1c
, 6.1-7.0
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 for chromosome
6q24 abnormalities, and, if negative,
ABCC8 and
KCNJ11
Test KCNJ11
ABCC8
KCNJ11 and
ABCC8
, INS and
INS
Test GCK Test HNF1A
HNF4A , and if renal features,
, then
HNF1B
No productive genetic tests
No productive genetic tests
Transient insulin
Observe for relapse
High dose oral sulfonylurea
Insulin No treatment in most cases; may need insulin in pregnancy
If parents have impaired fasting glucose, consider GCK
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
– 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 Cpeptide low or within normal range.

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