GH-Induced Insulin Resistance

Growth hormone opposes insulin without competing at the insulin receptor. The dominant route is lipid-mediated: growth hormone drives adipocyte lipolysis, the resulting rise in circulating free fatty acids suppresses glucose uptake and oxidation in skeletal muscle, and the increased substrate flux to the liver supports gluconeogenesis. Growth hormone also interferes with hepatic and muscle insulin signalling, partly through induction of SOCS proteins. The effect appears within hours of a pulse and is dose-related.

Acromegaly supplies the chronic case, where impaired glucose tolerance affects a large minority and frank diabetes a substantial fraction, both improving when growth hormone is normalised by surgery or by blockade at the receptor with pegvisomant. The relationship appears in reverse with pasireotide, a somatostatin analogue that lowers growth hormone effectively but worsens hyperglycaemia through somatostatin receptor 5 on beta cells. In adult replacement, insulin sensitivity typically worsens in the early weeks before body composition changes partially offset it.

This is the tradeoff any growth hormone raising intervention carries, and it sits directly against the effect people usually want. It also means the relevant baseline is metabolic rather than hormonal: the same rise in IGF-1 has different consequences for someone with normal glucose tolerance than for someone already insulin resistant.

The specific misreading is treating the lipolysis and the insulin resistance as separable, as though the fat mobilisation could be kept and the glucose effect avoided. They are one mechanism read at two points in the same pathway. A second error is relying on a fasting index such as HOMA-IR to exclude the problem, since the impairment shows itself in post-load glucose disposal and can be missed by a fasting measurement that still looks normal.