Type 2 Diabetes Mellitus Clinical Trial
Official title:
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.
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