More than 60 years ago it was shown, in dogs, that anterior pituitary extracts may cause glucose intolerance and that hypophysectomy was associated with increased insulin sensitivity. Accordingly, active acromegaly is characterized by insulin resistance at the hepatic and muscular level, whereas children with growth hormone (GH) deficiency are insulin hypersensitive and prone to developing fasting hypoglycemia. Somewhat unexpectedly, hypopituitary adults with untreated GH deficiency tend to be insulin resistant, which may be aggravated by somatropin (GH) therapy. The explanation for this apparent paradox has not been fully established. It is, however, likely that high circulating levels of free fatty acids (FFA) are responsible for insulin resistance, both before and after somatropin therapy. In the untreated state, patients have abdominal obesity, which increases circulating FFA levels. Since GH has potent lipolytic effects, somatropin therapy will further increase FFA levels. Theoretically, this GH replacement effect will eventually be compensated for by favorable alterations in body composition, including a reduction of fat mass. Subcutaneous somatropin therapy, however, will cause some degree of hypersomatropinemia in the prandial phase, which will inevitably antagonize the physiologic effects of insulin. At present, the best way to circumvent this inherent problem is to employ evening injections of somatropin and to ensure that the dosage is not too high. In the latter regard, it is important to realize that dosage requirements are lower in adults compared with children, and that the dosage will probably need to be reduced with age in the individual patient.