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Hepatocyte nuclear factor-1-alpha maturity-onset diabetes of the young (HNF1A-MODY) is a monogenic form of diabetes that is frequently misinterpreted as type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM), resulting in inappropriate long-term insulin therapy. A 20-year-old woman on long-term insulin experienced frequent hypoglycemia despite good adherence. The Exeter MODY calculator suggested >10% MODY probability. A gliclazide challenge test (GCT) revealed a >50% early-phase increase in connecting peptide (C-peptide), demonstrating sulfonylurea sensitivity. Genetic testing later confirmed HNF1A MODY.
Insulin was discontinued, and low-dose gliclazide achieved excellent glycemic control with minimal hypoglycemia. The case highlights GCT as a practical functional tool to identify MODY when genetic testing is delayed or unavailable. Prompt identification facilitates safe transition from insulin to sulfonylureas, reduces hypoglycemic episodes, and improves long-term life quality. Clinicians must consider MODY in young patients having atypical diabetes profiles.
Introduction
MODY is a rare, monogenic diabetes form, accounting for <2% of all diabetes cases. It is characterized by mild, non-progressive fasting high blood glucose. MODY is often misdiagnosed as T1DM or T2DM, leading to prolonged and unnecessary insulin therapy or inappropriate management strategies.
In those with mild, stable fasting hyperglycemia that does not show progression, early genetic evaluation for glucokinase mutations is recommended. Among MODY subtypes, HNF1A mutations are the most common, notably in Western populations. HNF1A-MODY usually manifests during early adulthood or adolescence. Unlike autoimmune T1DM, insulin therapy is often unnecessary, as these patients respond remarkably well to low-dose sulfonylureas such as gliclazide.
For the diagnosis of MODY, genetic testing remains the gold standard. However, in many regions—especially low- and middle-income countries—testing is limited by availability, cost, and delays. In this context, functional tests such as the GCT, which involves oral gliclazide administration with serial C-peptide measurements, can assess endogenous insulin secretion and sulfonylurea sensitivity. The GCT provides a practical, interim diagnostic tool for suspected MODY cases when genetic testing is unavailable or delayed.
This case study presents a young adult initially detected with T1DM who, eight years later, was found to have HNF1A-MODY following a positive GCT and subsequent genetic validation
Medical History
Eight years prior, the patient had presented to a secondary healthcare facility with symptoms suggestive of a UTI and was incidentally noted to have significant hyperglycemia. Based on her young age and biochemical findings, she was diagnosed with T1DM and initiated on a basal-bolus insulin regimen.
Over the subsequent eight years, she received more than 2,600 insulin injections with regular dose titration and reported good adherence. Despite this, she experienced frequent hypoglycemic episodes. Family history was notable for a father with prediabetes and a maternal great-grandmother with T2DM.
Given the clinical suspicion of HNF1A-MODY and limited immediate access to genetic testing, a structured GCT was performed to assess sulfonylurea responsiveness and dynamic beta-cell function. Insulin therapy was discontinued under careful medical supervision. The patient underwent two standardized oral glucose tolerance tests using 75 grams of anhydrous glucose. One test was conducted without gliclazide, and the other was performed after administration of 80 mg oral gliclazide. The tests were separated by 1 week.
The patient fasted for 10 hours prior to each procedure. Capillary glucose, venous glucose, and C-peptide levels were estimated at baseline and at 30-minute intervals over three hours. Dietary intake and physical activity were standardized for three days prior to each test to minimize confounding variables. Following functional testing and subsequent genetic confirmation, insulin therapy was permanently discontinued and low-dose gliclazide (20–40 mg daily) was initiated.
Discussion
The GCT demonstrated a marked early insulin secretory response to sulfonylurea therapy. At 30 minutes following glucose ingestion, C-peptide rose from 450 pmol/l without gliclazide to 708 pmol/l with gliclazide, representing a 57.3% rise. Venous and capillary glucose levels were consistently lower during the gliclazide test, indicating superior glycemic control despite lower late-phase C-peptide concentrations.
This pattern suggests enhanced first-phase insulin secretion, which is characteristically impaired in HNF1A–related diabetes due to defective glucose sensing and transcriptional regulation in pancreatic beta cells. Sulfonylureas such as gliclazide stimulate insulin secretion by directly closing adenosine triphosphate-sensitive potassium (K-ATP) channels, thereby bypassing the defective ATP-dependent signalling pathway.
Several months later, genetic testing performed at the Exeter MODY centre confirmed an HNF1A mutation, establishing the diagnosis of HNF1A-MODY. Over two years of follow-up, the patient’s HbA1c improved from 66 mmol/mol to 36 mmol/mol, with a marked reduction in hypoglycemic episodes. She continues on low-dose gliclazide with regular diabetes monitoring.
Learning
European Journal of Case Reports in Internal Medicine
Gliclazide Challenge Testing as an Alternative Diagnostic Tool for Hepatocyte Nuclear Factor-1-Alpha Maturity Onset Diabetes of the Young
Sunjay Pandya et al.
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