Maturity Onset Diabetes of the Young

See Also

Epidemiology

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

Pathophysiology

MODY is typically Autosomal Dominant (50% inheritance if a parent has MODY)
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

Types
Gene Mutations

MODY is caused by as many as 14 different gene defects
1. However HNF4A, GCK and HNF1A represent 95% of cases
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. 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)
MODY 2: Gene Mutation GCK
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
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)

Findings

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

Labs
Diagnosis

Fasting Serum Glucose
Hemoglobin A1C
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

Management
General

Guidelines are for MODY 1 and MODY 3
1. MODY 2 does not typically require management outside of pregnancy
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
Low Carbohydrate Diet
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
Meglitinides
1. Consider instead of Sulfonylureas, if Hypoglycemia occurs frequently with Sulfonylureas
Other medications
1. MODY is typically poorly sensitive to Metformin
2. GLP1-Agonist
  1. Liraglutide (Victoza) may be effective

Management
Gestational Diabetes

MODY accounts for up to 6% of Gestational Diabetes
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
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
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)

References