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 nonacromegaly, without conferring adverse glycemic effects.

Inclusion Criteria:

- Active acromegaly due to excess GH produced by a pituitary adenoma.

- Patients must have an elevated IGF-I compared to age and gender matched controls (as
supplied by the laboratory) and fail to suppress GH to below 1 ng/ml after a standard
75g oral glucose tolerance test.

- Type 2 diabetes mellitus, defined by elevated fasting glucose ≥ 126 mg/dl (verified by
two historical measurements), or plasma glucose ≥ 200 mg/dl two hours after a 75 g
oral glucose load, or a random glucose ≥ 200 mg/dl.

Exclusion Criteria:

1. Acromegaly Group

- Current medical therapy for acromegaly including dopamine agonists, somatostatin
analogues, or growth hormone antagonists.

- For subjects on current therapy the following washout periods may be used:

- Cabergoline: 4 weeks

- Bromocriptine: 1 week

- Sandostatin LAR: 3 months

- Short-acting octreotide: 1 week

- Lanreotide: 3 months

- Pegvisomant: 4 weeks

- Subjects with a history of surgical therapy for treatment of acromegaly must have
verification of active disease with verified elevated IGF-I for the subjects' age
and gender compared to healthy controls (as supplied by the laboratory) (two
measures) as well as a failure to suppress GH to below 1 ng/ml after OGTT.

- Current treatment for insulin resistance or type 2 DM including oral or injection
medications.

- Fasting glucose ≥ 126 mg/dl at screening evaluation.

- Evidence of hepatic or renal disease defined as elevated transaminases, elevated
serum creatinine.

- Pregnancy or breast feeding.

2. Type 2 diabetes mellitus group

- Patients taking non-insulin medications for diabetes treatment will be excluded.

- Diagnosis of acromegaly.

- Evidence of hepatic or renal disease defined as elevated transaminases, elevated
serum creatinine.

- Pregnancy or breast feeding.

3. Healthy Control Group

- History of diabetes mellitus or impaired glucose tolerance, history of
acromegaly.

- Fasting glucose ≥ 126 mg/dl at screening evaluation.

- Evidence of hepatic or renal disease defined as elevated transaminases, elevated
serum creatinine.

- Pregnancy or breast feeding.