Patients with active acromegaly are insulin resistant and glucose intolerant, whereas children with GH deficiency are insulin sensitive and may develop fasting hypoglycemia. Surprisingly, however, hypopituitary adults with unsubstituted GH deficiency tend to be insulin resistant which may worsen during GH substitution. A unifying mechanism explaining insulin resistance in both conditions could be increased flux of free fatty acids (FFA) caused by visceral obesity (untrated GHDA) and enhanced lipid oxidation (GH substitution), respectively. During fasting, which may be considered the natural domain for the metabolic effects of GH, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation. In this particular context, insulin resistance appears to constitute a favorable metabolic adaptation. The problem is that GH substitution results in elevated circadian GH levels in non-fasting patients. The best way to address this challenge is to employ evening administration of GH and to tailor the dose. Insulin therapy may cause hypoglycemia, and GH substitution may cause hyperglycemia. Such untoward effects should be minimised by carefully monitoring the individual patient. It is also plausible that the long-term beneficial effects of GH on body composition will balance the insulin antagonistic effects on glucose metabolism.