Maturity Onset Diabetes of the Young

Aka: Maturity Onset Diabetes of the Young, Maturity Onset Diabetes of Youth (MODY), MODY, Mason-Type Diabetes

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II. Epidemiology

  1. MODY accounts for 1 to 5% of Diabetes Mellitus cases
  2. MODY is typically misdiagnosed as Type I Diabetes or Type II Diabetes

III. Pathophysiology

  1. MODY is typically Autosomal Dominant (50% inheritance if a parent has MODY)
  2. MODY results from non-autoimmune deficient Insulin secretion
    1. Contrast with Type I Diabetes which results from autoimmune beta-cell destruction
    2. Contrast with Type II Diabetes, due to Insulin Resistance, followed by progressive beta cell function loss

IV. Types: Gene Mutations

  1. MODY is caused by as many as 14 different gene defects
    1. However HNF4A, GCK and HNF1A represent 95% of cases
    2. Other mutations include IPF (MODY 4), HNF1B (MODY 5), NDF1 (MODY 6)
    3. Overall gene mutations affect beta cell development or function
  2. MODY 1: Gene Mutation HNF4A
    1. HNF4A Defect (like HNF1A) affects transcription factors that result in impaired Insulin secretion
      1. Defect in beta-cell signal in response to Glucose
      2. HNF = Hepatocyte Nuclear Factor
    2. Progressive symptomatic Diabetes Mellitus
      1. May start with normal Fasting Serum Glucose, but postprandial Hyperglycemia
      2. Significant Glucose Intolerance develops
    3. Risk of Diabetes Mellitus related cardiovascular complications (related to poor Glucose control)
    4. Associated with Fetal Macrosomia
    5. Similar treatment to MODY 3 (Sulfonylureas, Meglitinide, GLP-1 Agonist)
  3. MODY 2: Gene Mutation GCK (Glucokinase)
    1. GCK Defect results in a higher Glucose set-point for Insulin secretion
      1. Higher Glucose levels are required to stimulate Insulin secretion
    2. Stable, mild Fasting Hyperglycemia (e.g. 100 to 145 mg/dl, 5.55 to 8.05 mmol/L)
      1. Hemoglobin A1C typically 5.7 to 7.5%
      2. Postprandial Hyperglycemia is typically absent
      3. May develop Type II Diabetes at later age
    3. Lower risk of Diabetes Mellitus related cardiovascular complications
    4. May require Insulin in Pregnancy
    5. No treatment typically needed outside of pregnancy
  4. MODY 3: Gene Mutation HNF1A (30 to 50% of cases, most common)
    1. HNF1A Defect (like HNF4A) affects transcription factors that result in impaired Insulin secretion
      1. Defect in beta-cell signal in response to Glucose
    2. By age 25, MODY develops in >95% of patients with HNF1A mutation
    3. Progressive symptomatic Diabetes Mellitus
      1. May start with normal Fasting Serum Glucose, but postprandial Hyperglycemia
      2. Significant Glucose Intolerance develops
    4. Risk of Diabetes Mellitus related cardiovascular complications (related to poor Glucose control)
    5. Not associated with Fetal Macrosomia
    6. Similar treatment to MODY 1 (Sulfonylureas, Meglitinide, GLP-1 Agonist)

V. Findings

  1. Age <30 years old at diagnosis
  2. Not obese
  3. Family History of Type 2 Diabetes in non-obese, young family members
  4. Fasting only Hyperglycemia
    1. Beta cells respond at a higher set-point (e.g. 150 mg/dl)
  5. No signs of Insulin Resistance or Metabolic Syndrome (e.g. Acanthosis Nigricans, Androgenic Alopecia)
  6. Failed response to Metformin
  7. Highly sensitive to Sulfonylureas and Insulin

VI. Labs: Diagnosis

  1. Fasting Serum Glucose
  2. Hemoglobin A1C
  3. No findings suggestive of Type I Diabetes
    1. Pancreatic beta-cell autoantibodies negative
      1. Anti-Glutamic Acid Decarboxylase Antibody (Anti-GAD65 Antibody)
      2. Anti-islet cell surface Antibody (ICA)
      3. Anti-insulin Antibody (IA-2a and IA-2b)
    2. C-Peptide > 0.60 ng/ml

VII. Management: General

  1. Guidelines are for MODY 1 and MODY 3
    1. MODY 2 does not typically require management outside of pregnancy
  2. Goal Hemoglobin A1C in MODY
    1. Similar to Type I Diabetes and Type II Diabetes goals (Hemoglobin A1C<7-8%)
    2. Modify target based on Hypoglycemia risks, comorbidities
  3. Low Carbohydrate Diet
  4. Sulfonylureas
    1. Start at one fourth the typical starting dose (Hypoglycemia risk in MODY)
    2. MODY is highly sensitive to Sulfonylureas (4x non-MODY)
    3. Sulfonylureas often maintain their efficacy for decades
    4. Glimepiride (Amaryl) may be preferred for lower Hypoglycemia risk
  5. Meglitinides
    1. Consider instead of Sulfonylureas, if Hypoglycemia occurs frequently with Sulfonylureas
  6. Other medications
    1. MODY is typically poorly sensitive to Metformin
    2. GLP1-Agonist
      1. Liraglutide (Victoza) may be effective

VIII. Management: Gestational Diabetes

  1. MODY accounts for up to 6% of Gestational Diabetes
  2. Findings of MODY in pregnancy (if not already diagnosed)
    1. Age <25 years
    2. Normal prepregnant BMI
    3. Prior Gestational Diabetes
    4. Family History of diabetes, Gestational Diabetes or Fasting Hyperglycemia
  3. Medications
    1. Glyburide
      1. Only Sulfonylurea approved for use in pregnancy
      2. Glyburide has the highest risk of Hypoglycemia of the Sulfonylureas
      3. Glyburide has a 2 fold higher risk of Fetal Macrosomia and Neonatal Hypoglycemia than Insulin
    2. Insulin
      1. Preferred over Glyburide in MODY 1 and MODY 3 (especially in third trimester)
      2. Switch from Sulfonylurea preconception (or in second trimester if Glucose well controlled)
      3. MODY 2 requires Insulin only if mother is MODY 2 and fetus is not MODY 2
        1. Otherwise fetus and mother have same Glucose set point, and no macrosomia risk
  4. Precautions
    1. Neonatal Hypoglycemia
      1. Monitor and treat Neonatal Hypoglycemia as in all newborns of gestational diabetic mothers
      2. Monitor for 48 hours infants of MODY 1 Mothers (higher risk of severe Hypoglycemia)

IX. References

  1. Delvecchio (2020) Diabetes Ther 11(8): 1667-85 [PubMed]
  2. Dickens (2018) Curr Diab Rep 18(3): 12 +PMID:29450745 [PubMed]
  3. Kant (2022) Am Fam Physician 105(2): 162-7 [PubMed]
  4. Nkonge (2020) Clin Diabetes Endocrinol 6(1): 20 +PMID: 33292863 [PubMed]

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Related Studies

Ontology: Maturity onset diabetes mellitus in young (C0342276)

Concepts Disease or Syndrome (T047)
MSH C562772
SnomedCT 28453007, 609561005, 400971001, 390715006
English Maturity onset diabetes mellitus in young, Diab mell aut dom, Diabetes mellitus autosomal dominant, Mason-type diabetes, MODY, MATURITY-ONSET DIABETES OF THE YOUNG, MASON-TYPE DIABETES, MODY-Mat onset diab in youth 1, MODY - Maturity onset diabetes in youth type 1, MODY-Mat onset diab in youth I, Matur ons diab in youth, MODY - Maturity onset diabetes in youth type I, Maturity onset diabetes in youth, maturity onset diabetes in youth, mody, modi, diabetes maturity onset young, diabetes maturity onset youth, Mason-Type Diabetes, Maturity-Onset Diabetes of the Young, Maturity onset diabetes in youth type 1, Maturity-onset diabetes of the young (disorder), Maturity onset diabetes mellitus in young (disorder), Diabetes mellitus autosomal dominant (disorder), Autosomal dominant diabetes mellitus, NIDDY, Maturity-onset diabetes of the young, diabetes mellitus maturity onset in young (diagnosis), diabetes mellitus maturity onset in young, maturity-onset diabetes of the young (diagnosis)
Spanish Diabetes juvenil de aparición en la madurez, diabetes mellitus de inicio tardío en la juventud, diabetes mellitus de comienzo en la madurez en personas jóvenes, diabetes mellitus de comienzo en la madurez en personas jóvenes (trastorno), diabetes mellitus tipo 2 en el joven, diabetes mellitus autosómica dominante, diabetes mellitus de tipo adulto en el joven (trastorno), diabetes mellitus tipo MODY, diabetes mellitus de tipo adulto en el joven, diabetes mellitus de inicio tardío en la juventud (trastorno)
French Diabète de la maturité chez un sujet jeune
Dutch ouderdomsdiabetes bij een jongere
Portuguese Diabetes do adulto no jovem
German Maturity-onset diabetes of the young (juveniler Typ II)
Italian Diabete giovanile ad insorgenza in età adulta
Japanese 若年成人発症型糖尿病, ｼﾞｬｸﾈﾝｾｲｼﾞﾝﾊｯｼｮｳｶﾞﾀﾄｳﾆｮｳﾋﾞｮｳ
Czech Juvenilní diabetes s manifestací v dospělosti
Hungarian Időskori diabetes fiatalkorban
Derived from the NIH UMLS (Unified Medical Language System)

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