Neonatal Diabetes Mellitus in a Resource-Limited Setting: Clinical Spectrum, Genetic Heterogeneity, Impact of Malnutrition, and Outcomes with Simplified Basal Insulin Therapy.

Abstract

Introduction: The aim of the study was to characterize genetic heterogeneity, clinical spectrum, and management outcomes of neonatal diabetes mellitus (NDM) in a tertiary care center in a resource-limited region, with emphasis on emerging genetic etiologies and simplified insulin regimens.

Methods: Observational case series with systematic prospective data collection at defined intervals. Seven consecutive infants with insulin-dependent hyperglycemia diagnosed within 6 months of life were enrolled and followed from presentation through periodic follow-up. Clinical features, biochemical parameters, genetic testing results, and treatment responses were documented daily during hospitalization and at scheduled follow-up visits. Time to glycemic control (defined as blood glucose 100-180 mg/dL for ≥24 h on stable therapy) and prognostic factors were analyzed.

Results: Three of 7 cases (42.9%) had identified genetic mutations: two GCK mutations and one homozygous NARS2 variant (c.583T>C; p.Phe195Leu; variant of uncertain significance). Four cases (57.1%) remained genetically unsolved; three of these initially received glibenclamide following a provisional ARMS PCR report suggestive of ABCC8 variant, which was subsequently reclassified as benign on whole exome sequencing, prompting discontinuation of sulfonylurea therapy. GCK and NARS2-mutated cases required insulin-only therapy. A novel NARS2 case with severe intrauterine growth restriction (IUGR; birth weight 1.5 kg) and marked hyperglycemia (640 mg/dL) achieved glycemic control in 7 days using simplified Neutral Protamine Hagedorn (NPH) insulin monotherapy without mealtime boluses, enabling exclusive breastfeeding. Severe malnutrition combined with metabolic acidosis was the strongest independent predictor of delayed control (40 days vs. 5-7 days). All cases achieved glycemic control within the follow up period.

Conclusions: Genetic testing provides essential precision-medicine guidance for NDM management despite a 42.9% diagnostic yield limited by current gene panels. This series expands the NARS2-associated NDM phenotypic spectrum and demonstrates that simplified basal-only NPH insulin regimens achieve excellent outcomes in IUGR neonates while enabling exclusive breastfeeding. Pragmatic strategies optimized for resource-limited settings enable equitable, high-quality NDM care.