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

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Brief Title

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

Official Title

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

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 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.
    


Study Type

Interventional


Primary Outcome

Percentage With Growth Hormone (GH) Suppression to < 0.4 ng/ml

Secondary Outcome

 Median Insulin Like Growth Factor Binding Protein 1 (IGFBP-1) Area Under the Curve in Response to Placebo, Oral Glucose Tolerance Test (OGTT), and rhIGF1 Suppression Testing

Condition

Acromegaly

Intervention

Oral Glucose Tolerance Test

Study Arms / Comparison Groups

 Active Acromegaly
Description:  Placebo, oral glucose tolerance test, and subcutaneous administration of recombinant human IGF-1 will be given at visits 2, 3, and 4 respectively. All visits will be performed within a 4 week period.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

28

Start Date

December 2008

Completion Date

June 2014

Primary Completion Date

August 2013

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Odelia Cooper, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00915954

Organization ID

17015


Responsible Party

Principal Investigator

Study Sponsor

Cedars-Sinai Medical Center


Study Sponsor

Odelia Cooper, MD, Principal Investigator, Cedars-Sinai Medical Center


Verification Date

July 2019