Ignite Creation Date:
2024-05-05 @ 9:33 PM
Last Modification Date:
2024-10-26 @ 10:06 AM
Study NCT ID:
NCT00915954
Status:
COMPLETED
Last Update Posted:
2019-07-09
First Post:
2009-06-05
Brief Title:
Growth Hormone Feedback to Insulin-like Growth Factor-I IGF-1 and Oral Glucose Tolerance Test OGTT
Sponsor:
Cedars-Sinai Medical Center
Organization:
Cedars-Sinai Medical Center
Study Overview
Official Title:
Growth Hormone Feedback In Patients With Acromegaly Type 2 Diabetes Mellitus And Healthy Adults
Status:
COMPLETED
Status Verified Date:
2019-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
Detailed Description:
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 andor 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 glucoseGH 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 GHIGF-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 GHIGF-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
Elevated serum IGF-1 levels in patients with acral or soft tissue overgrowth andor 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 glucoseGH 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 GHIGF-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 GHIGF-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None