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Am Fam Physician. 2022;105(2):162-167

Patient information: See related handout on this maturity-onset diabetes of the young, written by the authors of this article.

This clinical content conforms to AAFP criteria for CME.

Author disclosure: Dr. Kant does not have a formal relationship with any commercial company to disclose, but a public database revealed food and beverage listings for several drugs related to the topic of this manuscript. None of these involved cash payments and are not considered a violation of AFP's conflict-of-interest policy. Drs. Davis and Verma have no relevant financial relationships.

Maturity-onset diabetes of the young (MODY) is a non–insulin-dependent form of diabetes mellitus that is usually diagnosed in young adulthood. MODY is most often an autosomal dominant disease and is divided into subtypes (MODY1 to MODY14) based on the causative genetic mutation. Subtypes 1 to 3 account for 95% of cases. MODY is often misdiagnosed as type 1 or 2 diabetes and should be suspected in nonobese patients who have diabetes that was diagnosed at a young age (younger than 30 years) and a strong family history of diabetes. Unlike those with type 1 diabetes, patients with MODY have preserved pancreatic beta-cell function three to five years after diagnosis, as evidenced by detectable serum C-peptide levels with a serum glucose level greater than 144 mg per dL and no laboratory evidence of pancreatic beta-cell autoimmunity. Patients with MODY1 and MODY3 have progressive hyperglycemia and vascular complication rates similar to patients with types 1 and 2 diabetes. Lifestyle modification including a low-carbohydrate diet should be the first-line treatment for MODY1 and MODY3. Sulfonylureas are the preferred pharmacologic therapy based on pathophysiologic reasoning, although clinical trials are lacking. Patients with MODY2 have mild stable fasting hyperglycemia with low risk of diabetes-related complications and generally do not require treatment, except in pregnancy. Pregnant patients with MODY may require insulin therapy and additional fetal monitoring for macrosomia.

Maturity-onset diabetes of the young (MODY) is an underrecognized type of diabetes mellitus that is usually diagnosed in young adulthood. Advances in genetic testing have led to the discovery of more subtypes of the disease. This article provides a summary of the most common subtypes of MODY to help primary care clinicians distinguish the condition from types 1 and 2 diabetes.

Epidemiology and Genetics

 

  • MODY accounts for approximately 1% to 5% of diabetes cases.1

  • It is most often an autosomal dominant disease, with 50% of offspring affected. In the most common subtype (MODY3), more than 95% of people with the mutation will develop diabetes, most by 25 years of age.2

  • At least 14 genes have been found to cause MODY. The glucokinase (GCK), hepatocyte nuclear factor 1 alpha (HNF1A), and HNF4A genes are implicated in approximately 95% of cases.3 This article focuses on subtypes 1 to 3, which are caused by these mutations (Table 138).

 

SubtypeGene mutationProminent features
1HNF4AProgressive symptomatic diabetes mellitus with significant glucose intolerance
Prone to diabetes-related vascular complications
Associated with fetal macrosomia and neonatal hypoglycemia
Treatment: sensitive to sulfonylureas; meglitinide and glucagon-like peptide 1 agonist may be considered
2GCKAsymptomatic with stable mild fasting hyperglycemia and A1C levels ranging from 5.7% to 7.5%
Low risk of diabetes-related vascular complications
Pregnancy: use of insulin determined by mutation status of mother and fetus and/or evidence of accelerated fetal growth on ultrasonography
Treatment: not required except in pregnancy
3HNF1AMost common subtype (30% to 50%)
Progressive symptomatic diabetes with significant glucose intolerance
Prone to diabetes-related vascular complications
Postprandial glycosuria develops before the onset of diabetes
HNF1A mutation in the fetus does not affect birth weight
Treatment: sensitive to sulfonylureas; meglitinide and glucagon-like peptide 1 agonist may be considered

Diagnosis

  • Up to 80% of MODY cases are misdiagnosed as type 1 or 2 diabetes.9

  • MODY should be considered in nonobese patients who have diabetes that was diagnosed at a young age (younger than 30 years), preserved pancreatic beta-cell function, lack of pancreatic beta-cell autoimmunity, and a strong family history of diabetes.1

  • Accurate diagnosis of MODY guides treatment. Based on the pathophysiology of the disease, sulfonylureas are thought to be the most effective pharmacologic therapy for the most common subtypes.3,4,10 However, there is no evidence from randomized trials showing that early diagnosis and appropriate therapy improve patient-oriented outcomes.

  • Commercially available genetic testing can confirm the diagnosis of MODY. Targeted genetic testing is appropriate because of high cost (Figure 1). Referral to an endocrinologist and/or a clinical genetics consultant should be considered when clinical suspicion for MODY is high.

TYPE 1 DIABETES VS. MODY

  • The pathogenesis of MODY does not involve pancreatic beta-cell autoimmunity.

  • Type 1 diabetes is caused by autoimmune beta-cell destruction, usually leading to absolute insulin deficiency. A laboratory test confirming autoantibodies to islet cells, glutamic acid decarboxylase 65, insulin, tyrosine phosphatase IA-2 and IA-2beta, or zinc transporter 8 is diagnostic for type 1 diabetes.11

  • Adding the zinc transporter 8 autoantibody to commercially available beta-cell autoantibody test combinations has increased autoimmunity detection rates for new-onset type 1 diabetes to 96% to 98%.12,13

  • Clinicians may consider the cost-saving approach of checking glutamic acid decarboxylase 65 and tyrosine phosphatase IA-2 at the initial assessment and testing for other autoantibodies only if both are negative.14

  • Repeat autoantibody testing after a few years in patients with autoantibody-negative type 1 diabetes has been shown to improve detection of beta-cell autoimmunity.15

  • Patients with autoantibody-negative type 1 diabetes are more likely to have clinical characteristics associated with other diabetes subtypes (e.g., older age, higher body mass index, family history of diabetes). A subset of these patients may have monogenic or type 2 diabetes.16

  • Levels of C-peptide, a product of the insulin prohormone, is used to assess pancreatic beta-cell function and insulin secretion. In healthy people, fasting C-peptide levels range from 0.9 to 1.8 ng per mL (0.3 to 0.6 nmol per L) and increase to 3 to 9 ng per mL (1 to 3 nmol per L) after meals.17 A fasting C-peptide level of less than 0.60 ng per mL (0.20 nmol per L) represents insulin deficiency and is associated with type 1 diabetes.17

  • A detectable serum C-peptide level with a serum glucose level greater than 144 mg per dL (8 mmol per L) three to five years after diagnosis is unusual in a patient with type 1 diabetes and favors the diagnosis of MODY.4

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