Background: Metabolic stresses, including hyperinsulinemia, promote insulin resistance. Results: Monoclonal antibodies raised against Ser(P)/Thr(P) residues in IRS1 were used to quantify phosphorylation in response to insulin or agents that model metabolic stress. Conclusion: Similar IRS1 Ser(P)/Thr(P) residues are increased by insulin or metabolic stress, and some correlate significantly with reduced IRS1 tyrosine phosphorylation. Significance: Metabolic stress co-opts insulin-dependent IRS1 phosphorylation to aggravate insulin resistance.

Congenital hypothyroidism occurs in approximately 1 in 2000 newborns and can have devastating neurodevelopmental consequences if not detected and treated promptly. While newborn screening has virtually eradicated intellectual disability due to severe congenital hypothyroidism in the developed world, more stringent screening strategies have resulted in increased detection of mild congenital hypothyroidism. Recent studies provide conflicting evidence about the potential neurodevelopmental risks posed by mild congenital hypothyroidism, highlighting the need for additional research to further define what risks these patients face and whether they are likely to benefit from treatment. Moreover, while the apparent incidence of congenital hypothyroidism has increased in recent decades, the underlying cause remains obscure in most cases. However, ongoing research into genetic causes of congenital hypothyroidism continues to shed new light on the development and physiology of the hypothalamic-pituitary-thyroid axis. The identification of IGSF1 as a cause of central congenital hypothyroidism has uncovered potential new regulatory pathways in both pituitary thyrotropes and gonadotropes, while mounting evidence suggests that a significant proportion of primary congenital hypothyroidism may be caused by combinations of rare genetic variants in multiple genes involved in thyroid development and function. Much remains to be learned about the origins of this common disorder and about the optimal management of less severely-affected infants.

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