Hyperinsulinemic hypoglycemia in renal glucosuria in the presence of a novel sodium–glucose cotransporter 2 variant

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Renal glucosuria (OMIM #233100) is a rare inherited condition caused by pathogenic variants in SLC5A2, which encodes sodium–glucose cotransporter 2. Although typically considered asymptomatic, renal glucosuria has recently been associated with hypoglycemia, with only 4 cases reported to date. We describe an 18-year-old woman with persistent glucosuria and recurrent postprandial hypoglycemia, presenting with lightheadedness, fatigue, and hunger. A 24-hour urine collection showed elevated glucose excretion of 4 g/1.73 m2/day (22.2 mmol/1.73 m2/day; reference range: 0-0.32 g/1.73 m2/day [0-1.8 mmol/1.73 m2/day]). A 5-hour oral glucose tolerance test confirmed symptomatic hypoglycemia with an exaggerated insulin and C-peptide response, consistent with reactive hyperinsulinemia. Genetic testing identified a novel heterozygous potentially significant SLC5A2 variant which may affect a functionally important amino acid. The patient’s symptoms improved substantially following dietary counseling and adherence to a low-glycemic index diet. This case suggests that hypoglycemia in SLC5A2-related renal glucosuria may result from a hyperinsulinemic response rather than urinary glucose loss alone, a mechanism that has received limited attention in the literature. It supports considering renal glucosuria in patients with unexplained hypoglycemia and highlights the value of prolonged glucose tolerance testing and potentially genetic analysis.