Human Models of Selective Insulin Resistance: Graded Insulin Suppression Test (GIST) Pilot & Feasibility Study
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Columbia University
- Enrollment
- 15
- Locations
- 1
- Primary Endpoint
- Steady-state plasma glucose at euinsulinemia (E-SSG)
Overview
Brief Summary
The goal of this study is to learn about how the hormone insulin controls blood sugar in a variety of people. The main question it aims to answer is about how much insulin the body actually needs to maintain a normal blood sugar level. Participants will be asked to come in for a one-day study visit in which they will undergo a "graded insulin suppression test" ("GIST"). The GIST involves intravenous (into the vein) infusions of octreotide, a medication that turns off the body's own production of insulin, as well as replacement of insulin at two different levels (low and high), with or without replacement of glucagon, and glucose (sugar). The study investigators will check blood sugar levels every few minutes during the procedure to determine the effect of the two different insulin levels. This study will evaluate the GIST in both healthy volunteers and those at higher risk for type 2 diabetes.
Detailed Description
This study aims to determine to what extent the hyperinsulinemia commonly associated with insulin resistance (IR) in those at risk for type 2 diabetes (T2D) is a primary phenomenon, rather than merely a secondary, compensatory response to IR. The hypothesis is that some people with obesity and hyperinsulinemia exhibit a primary, non-compensatory hyperinsulinemia that may foment IR and its dysmetabolic sequelae. If this were the case, lowering insulin levels should not result in a proportional rise in blood glucose as might be expected if the hyperinsulinemia truly were purely compensatory. This hypothesis has been difficult to prove, however, because of the tight feedback mechanism between blood glucose and insulin secretion; under normal circumstances insulin secretion declines only alongside blood glucose. As such, an attempt to lower insulin levels independently of blood glucose will raise blood glucose and trigger further insulin secretion, negating the purpose of the experiment. In order to circumvent this feedback regulation of glucose-stimulated insulin secretion, this study will adapt the existing insulin suppression test (IST) technique, which employs the somatostatin receptor ligand octreotide to suppress endogenous insulin secretion and then replaces insulin and dextrose exogenously as a measure of insulin action. In addition to employing the current standard hyperinsulinemic IST protocol to assess insulin sensitivity, this study will introduce a preceding, euinsulinemic step, in which insulin is lowered toward a healthy fasting serum insulin while assessing the resultant steady-state glucose, potentially with replacement of basal glucagon. The primary endpoints in this study are the steady-state plasma glucose and serum insulin levels during low- and high-dose insulin infusions meant to induce euinsulinemia and hyperinsulinemia, respectively. The study investigators will carefully monitor plasma glucose levels every 5-15 min, drawing from an indwelling peripheral IV catheter and performing the analysis using a dedicated bedside glucose analyzer. These glucose values will be used to detect and arrest any trends toward hypo or hyperglycemia and will also serve as the readout of the primary outcome - the euinsulinemic steady-state glucose (E-SSG) and hyperinsulinemic steady-state glucose (H-SSG). Serum insulin, C-peptide, growth hormone, and glucagon levels will be measured periodically during the procedure, but these results will not be available until several days later.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Body mass index of 18-25 and 30-45 kg/m2
- •Able to understand written and spoken English and/or Spanish
- •Fasting euinsulinemia (fasting serum insulin of 4-10 μU/mL) for reference group or hyperinsulinemia (fasting serum insulin ≥ 13 μU/mL) for hyperinsulinemic group on screening labs
- •Written informed consent (in English or Spanish) and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) obtained from the participant prior to performing any protocol-related procedures, including screening evaluations.
Exclusion Criteria
- •Unable to provide informed consent in English or Spanish
- •Unwillingness to use only bedpan or urinal to void or to refrain from non-emergent mobile device use during the GIST
- •Documented weight loss of ≥ 5% of baseline within the previous 6 months
- •Systolic blood pressure \< 90 mm Hg or \> 160 mm Hg, and/or
- •Diastolic blood pressure \< 60 mm Hg or \> 100 mm Hg
- •Abnormal resting heart rate: \< 60 or ≥ 110 bpm
- •Sinus brady or tachycardia that has been worked up and considered benign by the recruit's personal physician may be permitted at the PI's discretion
- •Abnormal screening electrocardiogram (or if on file, performed within previous 90 d):
- •Non-sinus rhythm
- •Heart conduction blocks
Arms & Interventions
Reference (healthy control) group
Healthy volunteers with body mass index of 18-25 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Insulin regular, 2.0-3.2 mU/m2/min (euinsulinemia) (Drug)
Reference (healthy control) group
Healthy volunteers with body mass index of 18-25 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Insulin regular, 32 mU/m2/min (hyperinsulinemia) (Drug)
Reference (healthy control) group
Healthy volunteers with body mass index of 18-25 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Octreotide Acetate, 6-45 ng/kg/min (Drug)
Reference (healthy control) group
Healthy volunteers with body mass index of 18-25 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Dextrose 20 % in Water (Drug)
Reference (healthy control) group
Healthy volunteers with body mass index of 18-25 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Glucagon, 0-0.5 ng/kg/min (Drug)
Euinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Insulin regular, 2.0-3.2 mU/m2/min (euinsulinemia) (Drug)
Euinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Insulin regular, 32 mU/m2/min (hyperinsulinemia) (Drug)
Euinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Octreotide Acetate, 6-45 ng/kg/min (Drug)
Euinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Dextrose 20 % in Water (Drug)
Euinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin < 10 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Glucagon, 0-0.5 ng/kg/min (Drug)
Hyperinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin >= 13 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Insulin regular, 2.0-3.2 mU/m2/min (euinsulinemia) (Drug)
Hyperinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin >= 13 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Insulin regular, 32 mU/m2/min (hyperinsulinemia) (Drug)
Hyperinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin >= 13 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Octreotide Acetate, 6-45 ng/kg/min (Drug)
Hyperinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin >= 13 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Dextrose 20 % in Water (Drug)
Hyperinsulinemic group
Volunteers with body mass index of 30-45 kg/m2, fasting serum insulin >= 13 mU/L, hemoglobin A1c < 5.7%, and fasting plasma glucose < 100 mg/dL
Intervention: Glucagon, 0-0.5 ng/kg/min (Drug)
Outcomes
Primary Outcomes
Steady-state plasma glucose at euinsulinemia (E-SSG)
Time Frame: 150-180 minutes during GIST protocol
Plasma glucose level at steady state while insulin infusion rate is 4 mU/m2/min (units: mg/dL)
Steady-state plasma glucose at hyperinsulinemia (H-SSG)
Time Frame: 270-300 minutes during GIST protocol
Plasma glucose level at steady state while insulin infusion rate is 32 mU/m2/min and glucose infusion rate is 267 mg/m2/min, reflective of insulin sensitivity (units: mg/dL)
Secondary Outcomes
- Steady-state plasma free fatty acids (FFA) at euinsulinemia(150-180 minutes during GIST protocol)
- Steady-state plasma free fatty acids (FFA) at hyperinsulinemia(270-300 minutes during GIST protocol)
Investigators
Joshua Cook
Assistant Professor of Medicine
Columbia University