1. 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 uswww.kovlerdiabetescenter.org

2. www.monogenicdiabetes.orgwww.monogenicdiabetes.org www.kovlerdiabetescenter.org

3. 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

4. Summary: mutations in ABCC8 and KCNJ11 can 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.

5. 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

6. 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.

7. Neonatal Diabetes Registry at the University of Chicago http://kovlerdiabetescenter.org/registry

8. Sensor of functional beta cell mass But also have other tissue Expression: Liver, brain, kidney Uterus…. Mody genes MODY genes are transcription factors 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)

9. 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) TransientPermanent 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 HbA 1c, 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

10. 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.

11. 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?

12. 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

14. 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