Syndromes associated with mutations in the insulin signalling pathway

Insulin resistance is a common feature of type 2 diabetes mellitus and the metabolic syndrome, in which it is believed to be a key pathogenic factor. In such common diseases, insulin resistance is likely to have an oligogenic or polygenic aetiology. It may also more rarely be caused by monogenic defects affecting components of the insulin signalling pathway. The most commonly identified mutations, first described in 1988, lie in the INSR gene, encoding the insulin receptor. These may lead to either extreme infantile insulin resistance with autosomal recessive inheritance, or to autosomal dominant insulin resistance presenting peripubertally. Insulin receptor defects may present with hyperinsulinaemic hypoglycaemia and concomitant postprandial hyperglycaemia, but by the time of diagnosis insulin-resistant diabetes is more common. Frequently, however, the syndromes are recognised first by severe clinical hyperandrogenism in peripubertal girls, or by growth disorders including impaired linear growth, acanthosis nigricans, and pseudoacromegaly. Since 2004, several other genetic defects in the canonical insulin signalling pathway have been identified, affecting PIK3R1, AKT2, or TBC1D4. An overview of the genetic, metabolic, and syndromic features of the resulting forms of severe insulin resistance is given.