Insulin Regulation for Insulin Resistance

(GIST Trial)

Overseen By Joshua R Cook, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Columbia University

Must not be taking: Antidiabetics, Antipsychotics, Antidepressants, others

Disqualifiers: Diabetes, Cardiovascular diseases, Liver disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that participants stop taking most antidiabetic medications, except for metformin, at least 30 days before screening. If you are on other medications, it's best to discuss with the study team to see if they are allowed.

What data supports the effectiveness of the treatment Graded Insulin Suppression Test for insulin resistance?

The research indicates that using octreotide acetate, a somatostatin analogue, in a modified insulin suppression test can effectively measure insulin sensitivity by suppressing certain hormones and maintaining steady insulin levels, which is crucial for assessing insulin resistance. ^{1 2 3 4 5}

How does the drug used in the Insulin Regulation for Insulin Resistance trial differ from other treatments for insulin resistance?

The drug used in the trial, octreotide acetate (Sandostatin), is unique because it is a somatostatin analogue that can suppress certain hormones like C-peptide, glucagon, and growth hormone, which are involved in insulin regulation. This approach is different from other treatments that typically focus on enhancing insulin action or increasing insulin sensitivity directly. ^{1 6 7 8 9}

Research Team

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for people with insulin resistance, hyperinsulinemia, obesity, and also healthy individuals. Participants should be interested in a one-day study visit to understand how their body handles blood sugar. Specific eligibility details are not provided but typically include health status and willingness to undergo the test.

Inclusion Criteria

Body mass index of 18-25 and 30-45 kg/m2

I can understand English or Spanish, both written and spoken.

Fasting euinsulinemia (fasting serum insulin of 5-10 μU/mL) for reference group or hyperinsulinemia (fasting serum insulin ≥ 13 μU mL-1) for hyperinsulinemic group on screening labs

Exclusion Criteria

Abnormal sodium, potassium, chloride, or bicarbonate levels that are considered potentially significant according to the clinical judgment of the PI

Hemoglobin < 10 g/dL or hematocrit < 30%

History of gestational diabetes mellitus within the previous 5 years

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

GIST Procedure

Participants undergo a one-day study visit for the Graded Insulin Suppression Test, involving intravenous infusions of octreotide, insulin, and glucose, with blood sugar levels monitored every few minutes.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the GIST procedure

1-2 weeks

Treatment Details

Interventions

• Graded Insulin Suppression Test (Hormone Therapy)

Trial Overview The study tests how different levels of insulin affect blood sugar control during a graded insulin suppression test (GIST). It involves giving participants octreotide to stop natural insulin production and then providing two levels of replacement insulin along with glucose while monitoring blood sugar.

Participant Groups

Group I: Reference (healthy control) group Experimental Treatment 5 Interventions

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

Group II: Hyperinsulinemic group Experimental Treatment 5 Interventions

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

Group III: Euinsulinemic group Experimental Treatment 5 Interventions

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

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

University of Pisa

Collaborator

Trials

153

Recruited

84,700+

Findings from Research

In a study involving 52 tests on 45 hypertensive and 7 healthy subjects, octreotide acetate effectively suppressed C-peptide, glucagon, and growth hormone levels, similar to somatostatin, indicating its potential as a reliable alternative for insulin sensitivity testing.

The modified steady state plasma glucose (SSPG) method using a continuous intravenous infusion of octreotide at 150 micrograms over 2 hours was found to be adequate for measuring insulin sensitivity, demonstrating its efficacy in both hypertensive and healthy individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified method using a somatostatin analogue, octreotide acetate (Sandostatin) to assess in vivo insulin sensitivity. Ikebuchi, M., Suzuki, M., Kageyama, A., et al.[2019]

The study developed modified models for estimating insulin resistance (IR) using data from 327 participants, showing that the full model (model 5) had the highest accuracy in predicting IR, with r² values of 0.505 for normal glucose tolerance (NGT) and 0.556 for abnormal glucose tolerance (AGT).

These modified models, particularly the full model that incorporates multiple time points from the oral glucose tolerance test (OGTT) and metabolic syndrome components, provide a more accurate and convenient method for measuring IR compared to traditional surrogates, making them suitable for both clinical practice and research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accurate method to estimate insulin resistance from multiple regression models using data of metabolic syndrome and oral glucose tolerance test. Wu, CZ., Lin, JD., Hsia, TL., et al.[2021]

In a study involving 27 normoglycaemic subjects, the glucose effectiveness (SG) measured by the dynamic non-insulin-assisted intravenous glucose tolerance test (IVGTT) showed significant concordance with the glucose effectiveness measured during prolonged euglycaemic hyperinsulinaemic clamps, indicating that both methods can reliably assess glucose disposal.

The study found that insulin sensitivity (SI) derived from the IVGTT was comparable to that obtained from the clamp method, suggesting that both approaches are effective for evaluating insulin sensitivity in a clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glucose effectiveness and insulin sensitivity measurements derived from the non-insulin-assisted minimal model and the clamp techniques are concordant. Henriksen, JE., Alford, F., Ward, G., et al.[2013]

The combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT) effectively measures both insulin secretion and sensitivity in a single session, demonstrating strong reproducibility and correlation with established methods like the Botnia clamp.

In a study involving 10 subjects with normal glucose tolerance and 9 patients with type 2 diabetes, the GITT showed good discrimination of beta-cell function across different glucose tolerance levels, making it a valuable tool for metabolic studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Independent measures of insulin secretion and insulin sensitivity during the same test: the glucagon-insulin tolerance test. Dorkhan, M., Tripathy, D., Malm, G., et al.[2019]

The hyperinsulinemic-euglycemic clamp is the gold standard method for measuring insulin resistance, allowing researchers to differentiate between decreased insulin sensitivity and the maximum capacity for glucose uptake.

Insulin resistance is linked to various conditions, including genetic syndromes and diabetes, highlighting its importance in understanding metabolic health and the need for specialized testing to investigate its underlying mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hyperinsulinism syndromes caused by insulin resistance]. Robert, JJ.[2013]

Insulin resistance is linked to various physiological states and medical conditions, such as puberty, pregnancy, obesity, and type 2 diabetes, highlighting its importance in understanding metabolic health.

The abstract reviews both indirect and direct tests for measuring insulin sensitivity, discussing their respective advantages and disadvantages, which is crucial for selecting appropriate methods in clinical and research settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tests for evaluating insulin sensitivity in vivo]. Majkowska, L.[2006]

The study established insulin dose-response curves for glucose metabolism in conscious mice, showing that half-maximal suppression of endogenous glucose output and stimulation of glucose disposal occurs at insulin infusion rates of 4 to 5 mU/kg/min.

Maximal effects on glucose metabolism were observed at an insulin infusion rate of 10 mU/kg/min, providing a valuable reference for evaluating insulin resistance in various mouse models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse. Shen, HQ., Zhu, JS., Baron, AD.[2019]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Modified method using a somatostatin analogue, octreotide acetate (Sandostatin) to assess in vivo insulin sensitivity. [2019]

2. China (Republic : 1949- ) pubmed.ncbi.nlm.nih.gov

Comparison of insulin secretion and insulin sensitivity between normal and impaired glucose tolerance subjects with normal fasting plasma glucose. [2018]

3. Japan pubmed.ncbi.nlm.nih.gov

Accurate method to estimate insulin resistance from multiple regression models using data of metabolic syndrome and oral glucose tolerance test. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Glucose effectiveness and insulin sensitivity measurements derived from the non-insulin-assisted minimal model and the clamp techniques are concordant. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Independent measures of insulin secretion and insulin sensitivity during the same test: the glucagon-insulin tolerance test. [2019]

6. France pubmed.ncbi.nlm.nih.gov

[Hyperinsulinism syndromes caused by insulin resistance]. [2013]

7. Poland pubmed.ncbi.nlm.nih.gov

[Tests for evaluating insulin sensitivity in vivo]. [2006]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Measurement of insulin resistance in vivo. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse. [2019]