Growth Hormone Feedback to Insulin-like Growth Factor-I (IGF-1) and Oral Glucose Tolerance Test (OGTT)
Growth Hormone Feedback to Insulin-like Growth Factor-I (IGF-1) and Oral Glucose Tolerance Test (OGTT)
Growth hormone (GH) and Insulin-like growth factor-I (IGF-I) secretion are altered in
 acromegaly and type 2 Diabetes Mellitis (DM). The secretion of GH is mediated by central
 hypothalamic hormones (GH Releasing Hormone and somatostatin) as well as peripheral factors
 providing feedback inhibition (IGF-I and glucose, among others). The purpose of this study is
 to compare growth hormone suppression after an oral glucose tolerance test (OGTT) to growth
 hormone suppression after recombinant human IGF-I (rhIGF-I) administration. This study will
 recruit participants with active acromegaly, type 2 diabetes mellitus, and healthy control
 subjects. Each participant will undergo a screening evaluation, and three subsequent visits.
 Each participant will receive a placebo subcutaneous injection, OGTT, and administration of
 rhIGF-I, on separate visit days. Glucose, insulin, GH, bioactive IGF-I and IGF-I binding
 proteins will be measured after each intervention. Results will be compared between the three
 groups. It is predicted that the administration of rhIGF-I will demonstrate GH suppression in
 all healthy subjects and subjects with type 2DM. Some acromegaly subjects may demonstrate GH
 suppression in response to IGF-I administration, but not to the degree seen in healthy
 subjects or type 2 DM. OGTT will demonstrate suppression of GH in normal subjects, and will
 show attenuated suppression in type 2 DM and a failure of suppression in acromegaly.
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.
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.