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

Growth Hormone Feedback In Patients With Acromegaly, Type 2 Diabetes Mellitus, And Healthy Adults

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.