JCEM Case Rep. 2026 Apr 6;4(4):luag049. doi: 10.1210/jcemcr/luag049. eCollection 2026 Apr.
ABSTRACT
Insulin resistance due to lipodystrophy syndromes is an uncommon but important cause of diabetes. It is often overlooked due to limited awareness. Standard glucose-lowering therapies often fail to achieve durable metabolic control in patients with lipodystrophy. Long-term complications include cardiovascular events, pancreatitis, kidney failure, metabolic dysfunction associated steatotic liver disease, and sepsis. We report a case of a 15-year-old boy presenting with darkening of skin and inability to gain weight. There was no family history of diabetes or similar disorders. Laboratory evaluation showed high insulin levels, glycosylated hemoglobin (HbA1c) 6.6% (SI: 49 mmol/mol) (reference range, < 5.7% [SI: < 39 mmol/mol]), normal lipid levels, and grade 1 fatty liver on ultrasound. He was advised on a diabetic diet and prescribed metformin; subsequently, pioglitazone was also added. Follow-up evaluations showed persistently high insulin levels, leading us to recommend genetic analysis. Whole exome sequencing revealed a heterozygous pathogenic variant in exon 15 of the regulatory subunit of phosphoinositide 3-kinase 1 (PIK3R1) gene, leading to a genetic diagnosis of SHORT syndrome (short stature, joint hyperextensibility, ocular depression, rieger anomaly, and teething delay). This case underscores the importance of considering lipodystrophy syndromes in lean individuals with diabetes, insulin resistance, and dysmorphic features.
PMID:41948357 | PMC:PMC13050754 | DOI:10.1210/jcemcr/luag049