Monogenic diabetes accounts for 1-5% of diabetes mellitus. Recognition helps to improve precision in treatment and allows for familial risk management. Adipose tissue is a dynamic endocrine organ, not only serving as a caloric reservoir for storing essential surplus nutrients but also playing a role in influencing metabolic health. Dysregulation of adipose tissue differentiation and deposition in peripheral tissues results in significant metabolic consequences. This can stem from dysfunction of the peroxisome proliferator-activated receptor (PPAR). In this case report, we describe a patient with hereditary pancreatitis who displayed emerging metabolic dysregulation, subsequently found to have a novel PPARγ mutation.
A 34-year-old Chinese woman with a background of recurrent pancreatitis thought to be secondary to a pancreatic divisum anomaly and hereditary pancreatitis (PRSS1 mutation carrier) was admitted to hospital for pancreatitis. On this occasion, she was identified to have new diabetes, with admission BGL 14.7mmol/L and HBA1C 9%, as well as severe hypertriglyceridaemia of 43.2mmol/L (<2mmol/L). Further assessment demonstrated features of partial lipodystrophy and she was confirmed to have a novel heterogenous p.Arg395His mutation affecting the ligand binding domain (LBD) of PPARγ. She was also identified to have hypertension and hepatic steatosis. She is awaiting further cardiovascular risk stratification. Cascade testing of her siblings is underway.
PPARγ mutations result in a wide spectrum of phenotypes including familial partial lipodystrophy, diabetes, hyperlipidaemia, hepatic steatosis, obesity and polycystic ovarian syndrome. Management hinges on identifying and ameliorating cardiometabolic complications. Synthetic PPARγ agonists such as thiazolidinediones may be useful adjuncts as it binds in proximity to the LBD, leading to restoration of the molecule’s transcriptional function. Thus, variants with mutations within the LBD such as our patient may gain the most therapeutic benefit. Further understanding of the genotype-phenotype correlation is required, as it may be used to guide therapeutic decisions for these patients.