Context: Since growth hormone (GH) stimulates lipolysis, an increase in circulating free fatty acid (FFA) levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and FFAs to the development of insulin resistance in patients with T1D.

Patients: 7 (4/3) non-obese patients with T1D aged 21–30 years were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by Octreotide. Three 1-hour pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an anti-lipolytic drug, or a placebo were ingested every four hours on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a 2-step hyperinsulinaemic euglycaemic clamp on each visit.

Main Outcome: rhGH administration led to increases in the insulin infusion rate required to maintain euglycaemia overnight (p=0.008), elevated basal endogenous glucose production (p=0.007), decreased basal peripheral glucose uptake (p=0.03) and reduced glucose uptake during step 1 of the clamp (p<0.0001). Co-administration of rhGH and Acipimox reversed these effects, and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity.

Results: GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by Acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis.