Insulin Regulation for Insulin Resistance

(GIST Trial)

Overseen By Joshua R Cook, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

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

Disqualifiers: Diabetes, Cardiovascular diseases, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how insulin, a hormone that controls blood sugar, functions in different individuals. It aims to determine the amount of insulin needed to maintain normal blood sugar levels. The study involves the Graded Insulin Suppression Test, where participants receive varying levels of insulin and other substances to observe their blood sugar response. Individuals who are healthy or at risk for type 2 diabetes, and who have issues with insulin levels, might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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 prior data suggests that the Graded Insulin Suppression Test is safe?

Research shows that the Graded Insulin Suppression Test (GIST) helps researchers understand how insulin affects blood sugar. This test uses a medication called octreotide to temporarily stop the body's insulin, and then insulin is reintroduced at different levels. Studies have found that octreotide and insulin are usually well-tolerated. Common side effects of octreotide include mild and temporary nausea and stomach cramps.

Since this trial is in its early phase, the main focus is on safety. Early-phase trials often have fewer participants, so there is limited data on the treatment's safety for everyone. However, because insulin and octreotide are used in other treatments, some safety information is available. Insulin is commonly used to manage diabetes, and octreotide is approved for other conditions, suggesting they are relatively safe when used correctly.

Participants will be closely monitored during the test, with blood sugar levels checked every few minutes. This careful observation ensures that any side effects are quickly managed. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the Graded Insulin Suppression Test because it offers a novel approach to understanding and managing insulin resistance. Unlike current treatments that primarily focus on managing symptoms with medications like metformin or lifestyle changes, this test aims to directly measure and regulate insulin activity. By assessing how different levels of insulin affect the body, this method could lead to more personalized and effective treatment strategies. The potential to tailor interventions based on individual insulin responses could revolutionize how insulin resistance is managed, providing insights that standard treatments cannot offer.

What evidence suggests that the Graded Insulin Suppression Test is effective for insulin resistance?

Research has shown that the Graded Insulin Suppression Test (GIST) effectively assesses how the body manages insulin, often linked to type 2 diabetes. In past studies, GIST results closely matched those from other well-known methods, demonstrating a strong correlation (r = 0.93). This indicates that GIST reliably measures the body's response to insulin. In this trial, participants will be divided into different groups: a reference (healthy control) group, a euinsulinemic group, and a hyperinsulinemic group, to assess insulin regulation. The test adjusts insulin levels to evaluate blood sugar control, helping to determine the necessary insulin amount. This is valuable for understanding insulin control in individuals at risk for diabetes. Overall, GIST provides crucial information on insulin function, aiding in the development of treatment and prevention strategies. ^{2 6 7 8 9}

Who Is on the Research Team?

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Graded Insulin Suppression Test

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

In a study of 34 non-obese subjects, those with impaired glucose tolerance (IGT) showed significantly higher plasma glucose levels during an oral glucose tolerance test (OGTT) compared to those with normal glucose tolerance, indicating a clear difference in glucose metabolism.

IGT patients also had higher insulin concentrations at later time points during the OGTT and higher steady-state plasma glucose levels during a modified insulin suppression test, suggesting that they have both impaired insulin sensitivity and increased insulin secretion in response to glucose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of insulin secretion and insulin sensitivity between normal and impaired glucose tolerance subjects with normal fasting plasma glucose. Tang, KT., Ho, LT., Jap, TS., et al.[2018]

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 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]

Insulin sensitivity is an important marker for predicting the risk of developing diabetes and cardiovascular issues, and it can be impaired in both glucose-intolerant and non-glucose-intolerant individuals.

Various methods exist to measure insulin sensitivity, ranging from complex techniques like the glucose clamp to simpler model assessments, and the choice of method depends on the specific information needed for patient evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measurement of insulin resistance in vivo. Del Prato, S.[2018]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06592261?term=peptide

Graded Insulin Suppression Test P&F (GIST) 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 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/7014307/

Assessment of insulin resistance with the ... - PubMed - NIH The results indicated that estimates of insulin resistance generated by the two methods were highly correlated (r = 0.93). Furthermore, both methods of ...

3. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/534896

Graded Insulin Suppression Test P&F - Carebox Connect 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 ...

4. e-dmj.org e-dmj.org/journal/view.php?doi=10.4093/dmj.2021.0220

Assessment of Insulin Secretion and Insulin Resistance in ... The HEC test, developed by DeFronzo et al. [39], is widely accepted as the gold standard for the direct determination of insulin resistance/sensitivity in ...

5. journals.physiology.org journals.physiology.org/doi/full/10.1152/ajpendo.2000.278.3.E501?doi=10.1152/ajpendo.2000.278.3.E501

Roles of insulin resistance and obesity in regulation ... Plasma glucose, insulin, and C-peptide concentrations were significantly (P < 0.01) higher in obese women in response to the graded intravenous glucose infusion ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06592261

Graded Insulin Suppression Test P&F (GIST) 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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8497920/

Assessment of Insulin Secretion and Insulin Resistance in ... This review summarized a variety of traditional methods and indices to evaluate pancreatic β-cell function and insulin resistance/sensitivity and introduced ...

8. clin.larvol.com clin.larvol.com/trial-detail/NCT06592261

Graded Insulin Suppression Test P&F Outcome Measure, Measure Description, Time Frame ; Steady-state plasma glucose at euinsulinemia (E-SSG), Plasma glucose level at steady state while insulin ...

9. ahajournals.org ahajournals.org/doi/10.1161/ATVBAHA.121.316159

Statins Are Associated With Increased Insulin Resistance ... The 4-quadrant scatterplot shows data on 63 individuals who underwent both the insulin suppression test and the graded-glucose infusion test.