What is the most likely monogenic cause of diabetes that is often mild and common, usually not requiring any treatment, in young adults?

GCK-MODY (MODY2) is the Monogenic Diabetes That is Mild, Common, and Usually Requires No Treatment

GCK-MODY (MODY2) is the answer to this question—it presents with stable, nonprogressive mild fasting hyperglycemia (typically 100-150 mg/dL), rarely causes microvascular complications, and typically requires no pharmacological treatment except during pregnancy. 1, 2, 3

Why GCK-MODY Stands Out

GCK-MODY results from mutations in the glucokinase gene, which acts as the pancreatic "glucose sensor." 1 This mutation causes a higher glucose threshold (set-point) for glucose-stimulated insulin secretion, leading to stable elevated fasting blood glucose from birth. 1 The key distinguishing features include:

• Stable, nonprogressive hyperglycemia that remains mild throughout life 1
• Small rise in 2-hour plasma glucose on OGTT (less than 54 mg/dL or 3 mmol/L), which helps differentiate it from other MODY subtypes 1
• Rare microvascular complications, making it fundamentally different from other forms of diabetes 1
• Asymptomatic presentation with fasting glucose typically between 100-150 mg/dL and HbA1c between 5.6% and 7.6% 3, 4

Treatment Approach for GCK-MODY

No pharmacological treatment is required for GCK-MODY in most circumstances. 1, 2, 3 The management strategy is:

• Lifestyle modifications only for non-pregnant individuals 2, 5
• Treatment during pregnancy is the main exception, as pregnant patients may require insulin therapy and additional fetal monitoring for macrosomia 1, 5
• No sulfonylureas or insulin needed outside of pregnancy, unlike HNF1A-MODY or HNF4A-MODY 1, 2

Contrast with Other Common MODY Subtypes

Understanding why GCK-MODY doesn't require treatment becomes clearer when contrasted with other common MODY forms:

• HNF1A-MODY (MODY3) causes progressive insulin secretory defects requiring low-dose sulfonylureas as first-line therapy, with eventual need for insulin in many patients 1, 2, 6
• HNF4A-MODY (MODY1) similarly requires sulfonylureas and has progressive beta-cell dysfunction 1, 2, 6
• Both HNF1A and HNF4A subtypes carry similar vascular complication risks to type 1 and type 2 diabetes if inadequately controlled 2, 5

Clinical Recognition

Suspect GCK-MODY in patients with:

• Mild fasting hyperglycemia discovered incidentally (often during routine screening or pregnancy) 3, 4
• Strong multigenerational family history of mild diabetes 2, 6
• Diagnosis at young age (classically before 25 years, though can be older) 1
• Absence of obesity and metabolic syndrome features 3, 6
• Negative diabetes autoantibodies 6
• Small increment on OGTT (2-hour glucose rise less than 54 mg/dL) 1

Importance of Genetic Diagnosis

Genetic testing is essential because it prevents decades of unnecessary treatment. 2, 3 Many patients with GCK-MODY are misdiagnosed as type 1 or type 2 diabetes and inappropriately treated with insulin or oral medications. 7, 4, 8

The American Diabetes Association recommends genetic testing for children and young adults with diabetes not characteristic of type 1 or type 2 diabetes that occurs in successive generations. 1, 6 Consultation with a center specializing in diabetes genetics is recommended to interpret mutations and guide management. 1, 6

Common Pitfalls to Avoid

• Do not assume autoantibody positivity rules out MODY—autoantibodies have been reported in patients with monogenic diabetes 1, 6
• Do not overtreating GCK-MODY—aggressive glucose lowering provides no benefit and may cause hypoglycemia 2, 3
• Do not delay genetic testing in patients with atypical diabetes presentations, as this leads to years of inappropriate treatment 6