Growth Hormone Feedback to Insulin-like Growth Factor-I (IGF-1) and Oral Glucose Tolerance Test (OGTT)

Acromegaly is characterized by unrestrained growth hormone (GH) secretion and subsequent elevated insulin-like growth factor (IGF)-1 resulting from a benign somatotroph GH-secreting adenoma in the pituitary. In healthy individuals, the negative feedback loop regulating GH secretion is modulated in part by IGF-1, which inhibits basal GH secretion as well as GH secretion mediated by hypothalamic growth hormone releasing hormone (GHRH). IGF-1 also suppresses basal and GHRH-induced gene transcription and downregulates GH receptors in the periphery to limit local GH action. In acromegaly, somatotroph proliferation and transformation may lead to disrupted GH feedback regulation, leading to tonically elevated GH and IGF-1 levels that remain unrestrained.

Elevated serum IGF-1 levels in patients with acral or soft tissue overgrowth and/or disease-associated comorbidities is suggestive of the disorder, and demonstrated evidence of GH excess is required to confirm the diagnosis. The standard confirmatory diagnostic test for acromegaly is the oral glucose tolerance test (OGTT). In healthy adults, acute oral glucose administration suppresses GH secretion for 1-3 hours before rebounding; failure to suppress GH in response to a 75 g glucose load on OGTT indicates abnormal GH hypersecretion and thus confirms the acromegaly diagnosis.

This diagnostic approach, however, assumes that GH suppression after a glucose load is unaffected by factors other than acromegaly. Low GH levels have been reported in younger women after OGTT, and high GH levels are observed in those with anorexia nervosa, bulimia, and nutritional deficiencies. Whether and how these factors might affect OGTT interpretation in the diagnosis of acromegaly is unknown.

Importantly, poorly controlled diabetes mellitus also results in GH hypersecretion that may not suppress on OGTT. As an estimated one-quarter of patients with newly diagnosed acromegaly have impaired fasting glycemia or glucose intolerance, and one-quarter have frank diabetes, disruptions in the glucose/GH axis could undermine use of OGTT as a diagnostic tool. Earlier consensus recommendations cautioned against the use of OGTT in patients with impaired glucose metabolism; current recommendations do not advise this, although the risk of inducing hyperglycemia in these patients remains a concern.

Following on the investigators' earlier work describing the molecular basis for IGF-1 regulation of GH synthesis and its role in the negative feedback loop regulating GH secretion and action, the investigators considered whether recombinant human (rh) IGF-1 could reproducibly discriminate between normal and excessive GH secretion, and whether administering this peptide could be useful as an alternative to OGTT as a confirmatory diagnostic test for acromegaly.

In healthy subjects with an intact GH/IGF-1 feedback loop, rhIGF-1 administration markedly increases levels of circulating IGF-1 and suppresses GH, primarily by inhibiting hypothalamic-mediated GH secretion and blunting GH pulse amplitude, although effects on GH may be dose-dependent. rhIGF-1 administration in patients with obesity and diabetes has also been shown to suppress GH. By contrast, in patients with acromegaly, where the GH/IGF-1 feedback loop is usually not intact, rhIGF-1 administration fails to suppress, or attenuates, GH secretion and reduces exogenous GHRH responses while only minimally affecting GH pulsatility patterns .

Building on these observations, the investigators propose to analyze GH responses to rhIGF-1 administration and OGTT in non-acromegaly patients with type 2 diabetes mellitus (T2DM), nondiabetic patients with acromegaly, and healthy controls. The aims are to determine whether rhIGF-1 administration could be used to elicit a sufficiently distinct GH response in acromegaly versus those without acromegaly, without conferring adverse glycemic effects.