An interventional study of Oral Glucose Tolerance Test and Subcutaneous administration of recombinant human IGF-1 in Acromegaly and Type 2 Diabetes Mellitus, sponsored by Cedars-Sinai Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-07-09.
Sponsored by Cedars-Sinai Medical Center · Not applicable, Interventional, and Other
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.
196 studies on the registry are indexed under Acromegaly; 18 are open to participants now.
This study's enrollment of 28 is below the median of 43 across 115 interventional studies indexed under Acromegaly.
Browse Acromegaly studies →Cedars-Sinai Medical Center is the lead sponsor of 441 studies on the registry; 108 are open to participants now.
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Exclusion Criteria:
Acromegaly Group
For subjects on current therapy the following washout periods may be used:
Type 2 diabetes mellitus group
Healthy Control Group
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.
Diagnostic Test: Oral Glucose Tolerance Test · Diagnostic Test: Subcutaneous administration of recombinant human IGF-1 · Diagnostic Test: Placebo
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.
Diagnostic Test: Oral Glucose Tolerance Test · Diagnostic Test: Subcutaneous administration of recombinant human IGF-1 · Diagnostic Test: Placebo
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.
Diagnostic Test: Oral Glucose Tolerance Test · Diagnostic Test: Subcutaneous administration of recombinant human IGF-1 · Diagnostic Test: Placebo
Participants will have their blood drawn for a baseline value and then will be asked to drink a beverage with 75 grams of sugar. Blood will then be drawn every 30 minutes for 2 hours.
Participants will receive a subcutaneous injection of recombinant human IGF-1 followed by a series of blood draws.
Participants will receive a subcutaneous injection of saline followed by a series of blood draws.
Percentage With Growth Hormone (GH) Suppression to < 0.4 ng/ml
Subjects underwent recombinant insulin like growth factor 1 (rhIGF1) suppression testing and growth hormone levels were measured at time 0, 15, 30, 60, 90, 120, and 180 minutes after injection of rhIGF-1. A response \</= 0.4 ng/ml is considered a normal response in the healthy control and diabetic control subjects. The percentage of subjects with a normal GH suppression to \</= 0.4 ng/ml was calculated.
Time frame: Before injection and at time 15, 30, 60, 90, 120 and 180 minutes after rhIGF-1 injection on week 4
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
IGFBP1 levels were measured at time 0 prior to the injection and measured at 15, 30, 60, 90, 120, and 180 minutes after injection. The area under the curve of IGFBP1 was calculated for each subject and the medians calculated for each cohort during the placebo, OGTT, and rhIGF1 tests.
Time frame: Before injection at time 0 and then at 15, 30, 60, 90, 120, and 180 minutes after injection for week 2, 3, and 4 for each cohort for placebo, OGTT, and rhIGF1, respectively.
Median Insulin Level in Response to Placebo, OGTT, and rhIGF1 Testing
Insulin levels were measured at time 120 minutes after injection. Median insulin was calculated for each cohort during the placebo, OGTT, and rhIGF1 tests.
Time frame: Measured at 120 minutes after injection for week 2, 3, and 4 for each cohort for placebo, OGTT, and rhIGF1, respectively.
Median Bioactive IGF-1 Area Under the Curve in Response to Placebo, OGTT, and rhIGF1 Testing
Bioactive IGF-1 levels were measured at time 0 prior to the injection and measured at 15, 30, 60, 90, 120, and 180 minutes after injection. The area under the curve of bioactive IGF-1 was calculated for each subject and the medians calculated for each cohort during the placebo, OGTT, and rhIGF1 tests.
Time frame: Before injection at time 0 and then at 15, 30, 60, 90, 120, and 180 minutes after injection for week 2, 3, and 4 for each cohort for placebo, OGTT, and rhIGF1, respectively.
| Milestone | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls |
|---|---|---|---|
| Started | 10 | 8 | 10 |
| Completed | 10 | 8 | 10 |
| Not completed | 0 | 0 | 0 |
Subjects underwent recombinant insulin like growth factor 1 (rhIGF1) suppression testing and growth hormone levels were measured at time 0, 15, 30, 60, 90, 120, and 180 minutes after injection of rhIGF-1. A response \</= 0.4 ng/ml is considered a normal response in the healthy control and diabetic control subjects. The percentage of subjects with a normal GH suppression to \</= 0.4 ng/ml was calculated.
| Participants | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls |
|---|---|---|---|
| Percentage With Growth Hormone (GH) Suppression to < 0.4 ng/ml | 0 | 7 | 8 |
IGFBP1 levels were measured at time 0 prior to the injection and measured at 15, 30, 60, 90, 120, and 180 minutes after injection. The area under the curve of IGFBP1 was calculated for each subject and the medians calculated for each cohort during the placebo, OGTT, and rhIGF1 tests.
| ng*min/mL | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls |
|---|---|---|---|
| Placebo | 10927 (2963 to 85103) | 5079 (2317 to 12915) | 9105 (2645 to 16808) |
| OGTT | 5603 (3758 to 63248) | 2538 (2207 to 28208) | 4266 (637 to 27870) |
| IGF-1 suppression test | 10901 (3098 to 62873) | 7347 (1578 to 10911) | 7681 (3318 to 16256) |
Insulin levels were measured at time 120 minutes after injection. Median insulin was calculated for each cohort during the placebo, OGTT, and rhIGF1 tests.
| mU/L | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls |
|---|---|---|---|
| Placebo | 7 (3 to 16) | 9 (4 to 91) | 4 (0.5 to 6) |
| OGTT | 55 (6 to 395) | 39.5 (22 to 217) | 41.5 (11 to 124) |
| IGF-1 suppression test | 4 (0.5 to 13) | 4.5 (2 to 108) | 2.5 (0.5 to 9) |
Bioactive IGF-1 levels were measured at time 0 prior to the injection and measured at 15, 30, 60, 90, 120, and 180 minutes after injection. The area under the curve of bioactive IGF-1 was calculated for each subject and the medians calculated for each cohort during the placebo, OGTT, and rhIGF1 tests.
| ng*min/mL | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls |
|---|---|---|---|
| Placebo | 716 (353 to 1154) | 291 (127 to 842) | 302 (138 to 902) |
| OGTT | 699 (379 to 1038) | 270 (219 to 422) | 339 (89 to 874) |
| IGF-1 suppression test | 1004 (853 to 1464) | 659 (108 to 876) | 642 (338 to 970) |
Collected over Adverse events were collected over the 4 weeks of the study period.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Active Acromegaly | — | 0/10 (0%) | 2/10 (20%) |
| Type 2 Diabetes Mellitus(DM) | — | 0/8 (0%) | 0/8 (0%) |
| Heathly Controls | — | 0/10 (0%) | 0/10 (0%) |
| Event | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls |
|---|---|---|---|
| Low blood pressureCardiac disorders | 1/10 | 0/8 | 0/10 |
| RashSkin and subcutaneous tissue disorders | 1/10 | 0/8 | 0/10 |
| Age, Categorical(Participants) | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls | Total |
|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 8 | 6 | 8 | 22 |
| >=65 years | 2 | 2 | 2 | 6 |
| Age, Continuous(years) | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls | Total |
|---|---|---|---|---|
| Mean | 47 ± 18 | 54 ± 9 | 38 ± 17 | 46 ± 17 |
| Sex: Female, Male(Participants) | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls | Total |
|---|---|---|---|---|
| Female | 4 | 3 | 5 | 12 |
| Male | 6 | 5 | 5 | 16 |
| Region of Enrollment(participants) | Active Acromegaly | Type 2 Diabetes Mellitus(DM) | Heathly Controls | Total |
|---|---|---|---|---|
| United States | 10 | 8 | 10 | 28 |
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Cedars-Sinai Medical Center