(CSEMP045) AN INTERESTING CASE OF INSULIN RESISTANCE

Abstract: A 5 month old was evaluated for small head circumference in the context of being below the 3rd percentile for weight and having triangular facies. At 5 years, he was evaluated for short stature. At his initial visit, he had a growth velocity of 5.8 cm/year, which dropped to 4.1 cm/year 6 months later. He was otherwise well, with no concerns for glucose regulation. On exam, he was 98 cm (0.15th percentile) with deep set eyes, and hyperextensible joints. Investigations demonstrated a normal thyroid screen, normal IGF-1 level, an A1c of 5.3% with an appropriate bone age. He had a mid-parental height of 177.3 cm, but a predicted adult height of 150 cm.

Whole exome sequencing demonstrated that he has SHORT syndrome (short stature, hyperextensibility, ocular depression, Rieger anomaly, and teething delay). It is an autosomal dominant disorder caused by mutations in the PI3KR1 gene. This gene encodes the regulation of the p85α subunit. It binds to p110 α activating PI3K which converts PIP-2 to PIP-3, thus activating the membrane bound PDK1. The PDK1 molecule acts on AKT activating it by phosphorylation which inhibits the AS160 protein, allowing GLUT4 transporters to come up to the cell membrane. AKT inhibits GSK-3beta allowing for increased glycogen synthesis. AKT activates the mTOR pathway involved in beta cell insulin production. Downregulation of both mechanisms is why we see both insulin resistance as well as decreased insulin secretion in SHORT syndrome. IGF-1 acts similarly to insulin and requires AKT action, in this case to inhibit TSC2, and thus activate mTOR, allowing for increased protein synthesis and growth. The defects in PI3K are thought to induce lipodystrophy as well because the insulin signaling through AKT to inhibit lipolysis is not functional causing both an inability to maintain adipocytes as well as an increased release of free fatty acids into the serum, worsening insulin resistance.

Insulin resistance develops in adolescence, with risk for diabetes in early adulthood. There have been cases of diabetic ketoacidosis reported. Management remains largely empirical including diet, exercise, and insulin. Metformin has sometimes been effective but occasionally paradoxically worsens the insulin resistance. For short stature management, growth hormone is avoided due to adverse impacts on glucose homeostasis. IGF-1 therapy is not well studied but there is known IGF-1 resistance in this population. Metreleptin use has been evaluated in other lipodystrophies, but not in SHORT syndrome. Further research for optimal patient management is needed.