II. Epidemiology
- MODY accounts for 1 to 5% of Diabetes Mellitus cases
- MODY is typically misdiagnosed as Type I Diabetes or Type II Diabetes
III. Pathophysiology
- MODY is typically Autosomal Dominant (50% inheritance if a parent has MODY)
- MODY results from non-autoimmune deficient Insulin secretion
- Contrast with Type I Diabetes which results from autoimmune beta-cell destruction
- Contrast with Type II Diabetes, due to Insulin Resistance, followed by progressive beta cell function loss
IV. Types: Gene Mutations
- MODY is caused by as many as 14 different gene defects
- However HNF4A, GCK and HNF1A represent 95% of cases
- Other mutations include IPF (MODY 4), HNF1B (MODY 5), NDF1 (MODY 6)
- Overall gene mutations affect beta cell development or function
- MODY 1: Gene Mutation HNF4A
- HNF4A Defect (like HNF1A) affects transcription factors that result in impaired Insulin secretion
- Defect in beta-cell signal in response to Glucose
- HNF = Hepatocyte Nuclear Factor
- Progressive symptomatic Diabetes Mellitus
- May start with normal Fasting Serum Glucose, but postprandial Hyperglycemia
- Significant Glucose Intolerance develops
- Risk of Diabetes Mellitus related cardiovascular complications (related to poor Glucose control)
- Associated with Fetal Macrosomia
- Similar treatment to MODY 3 (Sulfonylureas, Meglitinide, GLP-1 Agonist)
- HNF4A Defect (like HNF1A) affects transcription factors that result in impaired Insulin secretion
- MODY 2: Gene Mutation GCK (Glucokinase)
- GCK Defect results in a higher Glucose set-point for Insulin secretion
- Stable, mild Fasting Hyperglycemia (e.g. 100 to 145 mg/dl, 5.55 to 8.05 mmol/L)
- Hemoglobin A1C typically 5.7 to 7.5%
- Postprandial Hyperglycemia is typically absent
- May develop Type II Diabetes at later age
- Lower risk of Diabetes Mellitus related cardiovascular complications
- May require Insulin in Pregnancy
- No treatment typically needed outside of pregnancy
- MODY 3: Gene Mutation HNF1A (30 to 50% of cases, most common)
- HNF1A Defect (like HNF4A) affects transcription factors that result in impaired Insulin secretion
- Defect in beta-cell signal in response to Glucose
- By age 25, MODY develops in >95% of patients with HNF1A mutation
- Progressive symptomatic Diabetes Mellitus
- May start with normal Fasting Serum Glucose, but postprandial Hyperglycemia
- Significant Glucose Intolerance develops
- Risk of Diabetes Mellitus related cardiovascular complications (related to poor Glucose control)
- Not associated with Fetal Macrosomia
- Similar treatment to MODY 1 (Sulfonylureas, Meglitinide, GLP-1 Agonist)
- HNF1A Defect (like HNF4A) affects transcription factors that result in impaired Insulin secretion
V. Findings
- Age <30 years old at diagnosis
- Not obese
- Family History of Type 2 Diabetes in non-obese, young family members
-
Fasting only Hyperglycemia
- 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
VI. Labs: Diagnosis
- Fasting Serum Glucose
- Hemoglobin A1C
- No findings suggestive of Type I Diabetes
- Pancreatic beta-cell autoantibodies negative
- Anti-Glutamic Acid Decarboxylase Antibody (Anti-GAD65 Antibody)
- Anti-islet cell surface Antibody (ICA)
- Anti-insulin Antibody (IA-2a and IA-2b)
- C-Peptide > 0.60 ng/ml
- Pancreatic beta-cell autoantibodies negative
VII. Management: General
- Guidelines are for MODY 1 and MODY 3
- MODY 2 does not typically require management outside of pregnancy
- Goal Hemoglobin A1C in MODY
- Similar to Type I Diabetes and Type II Diabetes goals (Hemoglobin A1C<7-8%)
- Modify target based on Hypoglycemia risks, comorbidities
- Low Carbohydrate Diet
-
Sulfonylureas
- Start at one fourth the typical starting dose (Hypoglycemia risk in MODY)
- MODY is highly sensitive to Sulfonylureas (4x non-MODY)
- Sulfonylureas often maintain their efficacy for decades
- Glimepiride (Amaryl) may be preferred for lower Hypoglycemia risk
-
Meglitinides
- Consider instead of Sulfonylureas, if Hypoglycemia occurs frequently with Sulfonylureas
- Other medications
- MODY is typically poorly sensitive to Metformin
- GLP1-Agonist
- Liraglutide (Victoza) may be effective
VIII. Management: Gestational Diabetes
- MODY accounts for up to 6% of Gestational Diabetes
- Findings of MODY in pregnancy (if not already diagnosed)
- Age <25 years
- Normal prepregnant BMI
- Prior Gestational Diabetes
- Family History of diabetes, Gestational Diabetes or Fasting Hyperglycemia
- Medications
- Glyburide
- Only Sulfonylurea approved for use in pregnancy
- Glyburide has the highest risk of Hypoglycemia of the Sulfonylureas
- Glyburide has a 2 fold higher risk of Fetal Macrosomia and Neonatal Hypoglycemia than Insulin
- Insulin
- Preferred over Glyburide in MODY 1 and MODY 3 (especially in third trimester)
- Switch from Sulfonylurea preconception (or in second trimester if Glucose well controlled)
- MODY 2 requires Insulin only if mother is MODY 2 and fetus is not MODY 2
- Otherwise fetus and mother have same Glucose set point, and no macrosomia risk
- Glyburide
- Precautions
- Neonatal Hypoglycemia
- Monitor and treat Neonatal Hypoglycemia as in all newborns of gestational diabetic mothers
- Monitor for 48 hours infants of MODY 1 Mothers (higher risk of severe Hypoglycemia)
- Neonatal Hypoglycemia