Insulin Aspart for Gestational Diabetes

Overseen By Anna Reid-Stanhewicz, PHD

Age: 18 - 65

Sex: Female

Trial Phase: Phase < 1

Sponsor: Anna Stanhewicz, PhD

Must not be taking: Statins, Antihypertensives

Disqualifiers: Tobacco use, Diabetes, Hypertension, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how endothelin-1 affects blood flow in women with a history of gestational diabetes (a type of diabetes during pregnancy). Researchers aim to determine whether physical activity or prolonged sitting alters endothelin-1's function. Participants will receive various treatments affecting blood vessels to identify what improves blood flow. Women who experienced a healthy pregnancy or gestational diabetes within the last five years and do not use tobacco or certain medications may qualify for this trial. As an Early Phase 1 trial, this research seeks to understand the treatment's effects in people, providing participants an opportunity to contribute to groundbreaking medical knowledge.

Will I have to stop taking my current medications?

The trial requires that you do not take statins, other cholesterol-lowering medications, or antihypertensive medications. If you are on these medications, you would need to stop taking them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the treatments in this trial are still being developed, so limited safety information exists for humans. However, some information is available about the individual components of these treatments.

BQ-788 and BQ-123 are drugs that help prevent blood vessels from tightening. Studies have found that they can reduce the effects of endothelin-1, a substance that narrows blood vessels. In lab tests, these drugs effectively stop blood vessels from tightening, but detailed safety information for humans is lacking.

L-NAME is another drug in this trial. It inhibits the production of nitric oxide, a chemical that helps blood vessels relax. Detailed safety information for L-NAME in humans is also unavailable, so caution is necessary.

Since this study is in the early stages, safety information remains limited. Prospective participants should discuss any potential risks and benefits with the study team or their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for gestational diabetes because they take a unique approach by targeting the endothelin-1 (ET-1) pathway, which is not a focus of current standard treatments like insulin therapy. ET-1 modulation, through the use of inhibitors like BQ-788, BQ-123, and L-NAME, offers a novel way of potentially improving blood sugar control by influencing blood vessel function and nitric oxide synthase activity. This innovative mechanism provides a fresh angle for managing gestational diabetes, which could lead to more effective and tailored treatments for patients.

What evidence suggests that this trial's treatments could be effective for gestational diabetes?

This trial will compare treatments involving endothelin-1 modulation to improve blood flow in participants with a history of gestational diabetes. Research has shown that certain medications, BQ-123 and BQ-788, can reduce blood vessel tightening caused by endothelin-1 (ET-1). BQ-123 blocks one part of the blood vessel system, while BQ-788 targets another, both crucial for proper blood vessel function. Studies indicate that these medications, used alone or together, can lessen blood vessel narrowing in various situations. Additionally, L-NAME blocks a process that helps blood vessels widen. Participants in this trial may receive local perfusion of BQ-123 and BQ-788, either alone or with L-NAME, to evaluate their effectiveness in addressing blood vessel issues related to gestational diabetes history. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for women who had a baby within the last 5 years and either had a healthy pregnancy or were diagnosed with gestational diabetes. They should meet the American College of Obstetricians and Gynecologists criteria for gestational diabetes.

Inclusion Criteria

I have not been pregnant in the last 5 years.

I had a healthy pregnancy or was diagnosed with gestational diabetes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive local perfusion of ET-1 inhibitors and L-NAME through microdialysis fibers to study microvascular function

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Endothelin-1 Modulation

Trial Overview The study investigates how endothelin-1, which narrows blood vessels, affects small vessel function in women with past gestational diabetes. It also looks at whether physical activity or sitting too much can change this effect.

How Is the Trial Designed?

Group I: local L-NAME perfusion Experimental Treatment 1 Intervention

local L-NAME is perfused through the microdialysis fiber to inhibit nitric oxide synthase

Group II: local BQ-788 and BQ-123 perfusion Experimental Treatment 1 Intervention

local ET-1 inhibitors perfused through the microdialysis fiber to serve as the experimental treatment

Group III: local BQ-788 + BQ-123 + L-NAME perfusion Experimental Treatment 1 Intervention

local ET-1 inhibitors and L-NAME are perfused through the microdialysis fiber to inhibit nitric oxide synthase during the experimental treatment

Group IV: local lactated Ringer's perfusion Placebo Group 1 Intervention

lactated Ringer's is perfused through the microdialysis fiber to serve as the vehicle control

Endothelin-1 Modulation is already approved in European Union, United States for the following indications:

Approved in European Union as Bosentan for:

• Pulmonary arterial hypertension

Approved in United States as Bosentan for:

• Pulmonary arterial hypertension

Approved in European Union as Macitentan for:

• Pulmonary arterial hypertension

Approved in United States as Macitentan for:

• Pulmonary arterial hypertension

Approved in European Union as Ambrisentan for:

• Pulmonary arterial hypertension

Approved in United States as Ambrisentan for:

• Pulmonary arterial hypertension

Approved in United States as Sparsentan for:

• Primary immunoglobulin A nephropathy

Who Is Running the Clinical Trial?

Anna Stanhewicz, PhD

Lead Sponsor

Trials

12

Recruited

460+

Published Research Related to This Trial

In a study of 15 women with gestational diabetes mellitus (GDM), insulin aspart was found to provide better post-meal blood sugar control compared to regular human insulin, as indicated by significantly lower glucose levels after meals.

Insulin aspart resulted in higher peak insulin concentrations and reduced the need for the body to produce its own insulin, suggesting it may be a more effective option for managing GDM in women who require insulin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Pettitt, DJ., Ospina, P., Kolaczynski, JW., et al.[2019]

In a study of 361 pregnant women with gestational diabetes, over 40% achieved target glucose levels using a simple insulin injection regimen (SII) without increasing adverse perinatal outcomes.

The SII regimen was as effective as a more complex multiple daily injection (MDI) regimen in controlling blood glucose levels, indicating that a simpler treatment approach can be safe and effective for managing gestational diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Achievement of Target Glycemic Goal with Simple Basal Insulin Regimen in Women with Gestational Diabetes: A Prospective Cohort Study. Fukuoka, M., Yasuhi, I., Yamashita, H., et al.[2023]

Gestational diabetes (GD) significantly increases the risk of adverse outcomes for both mothers and their babies, including higher chances of type 2 diabetes later in life and complications like macrosomia and neonatal hypoglycemia.

While insulin has traditionally been used to manage GD, recent studies indicate that glyburide may be an effective alternative, and metformin shows promise in potentially preventing the development of GD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The contentious nature of gestational diabetes: diet, insulin, glyburide and metformin. Glueck, CJ., Goldenberg, N., Streicher, P., et al.[2019]

In a study of 102 patients with spleen deficiency type gestational diabetes mellitus, combining insulin aspart with exercise therapy significantly lowered blood glucose levels and improved overall treatment efficacy (96.08% vs. 74.51% for insulin alone).

The combination therapy also resulted in fewer adverse pregnancy outcomes (3.92% vs. 37.25%) and complications (5.88% vs. 41.17%), suggesting it is a safer and more effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin Aspart Combined with Exercise Therapy in Spleen Deficiency Type Gestational Diabetes Mellitus: The Effect on Disease Control and Pregnancy Outcomes. Shi, Y., Meng, X.[2023]

Chronic activation of the endothelin-1 (ET-1) system can lead to insulin resistance and cardiovascular issues by disrupting insulin signaling pathways and reducing insulin delivery to tissues, which may result in glucose intolerance and hyperinsulinemia.

ET-1 antagonists show promise in improving heart function and glucose tolerance in obese individuals and those with early insulin sensitivity, suggesting they could be a beneficial treatment option, especially when combined with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin resistance, obesity and the metabolic syndrome. Is there a therapeutic role for endothelin-1 antagonists? Shaw, SG., Boden, PJ.[2019]

Endothelin-1 (ET-1) reduces insulin-stimulated glucose uptake in skeletal muscle by suppressing the phosphorylation of Akt, a key protein in insulin signaling, indicating a mechanism for insulin resistance.

The negative effects of ET-1 on insulin signaling can be countered by blocking ETA receptors or inhibiting GRK2, suggesting that targeting these pathways may help improve insulin sensitivity in muscle cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells. Horinouchi, T., Hoshi, A., Harada, T., et al.[2021]

In a study involving 80 women with gestational diabetes, both human aspart and regular human insulin showed comparable efficacy and safety in managing glucose levels during pregnancy.

No significant differences were found in insulin dosage, glucose control, or delivery outcomes between the two insulin types, indicating that either can be effectively used for treating gestational diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of insulin aspart versus regular human insulin for women with gestational diabetes mellitus]. Zhou, L., Fan, L.[2013]

Insulin aspart (IAsp) is at least as safe and effective as regular human insulin (HI) for managing type 1 diabetes in pregnant women, with a lower risk of major hypoglycemia (1.4 vs. 2.1 episodes/year) and a 52% reduction in major nocturnal hypoglycemia risk.

IAsp showed better postprandial glucose control compared to HI, with significantly lower plasma glucose levels after meals, while maintaining comparable A1C levels, indicating it may be a preferable option for meal-time insulin in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Mathiesen, ER., Kinsley, B., Amiel, SA., et al.[2022]

Endothelin peptides, discovered in the 1980s, are linked to insulin resistance, suggesting they play a role beyond just causing blood vessels to constrict.

The review highlights how endothelin interacts with insulin signaling at various physiological levels, potentially contributing to vascular and metabolic issues associated with insulin resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactions of endothelin and insulin: expanding parameters of insulin resistance. Strawbridge, AB., Elmendorf, JS., Mather, KJ.[2019]

The study found that using an endothelin-B (ET(B)) receptor antagonist in pregnant rats led to significantly lower fetal and placental weights at higher doses (10 and 15 mg/kg per day), indicating a negative impact on fetal growth.

While the antagonist increased maternal blood pressure initially, this effect was not sustained throughout the pregnancy, suggesting that ET(B) receptor antagonism is harmful to pregnancy outcomes in rats.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of ET(B) receptor antagonism on pregnancy outcome in rats. Madsen, KM., Neerhof, MG., Wessale, JL., et al.[2019]

Insulin aspart, a fast-acting insulin analogue, has been shown to improve postprandial blood sugar control in pregnant women with Type 1 diabetes, potentially leading to fewer severe hypoglycemia episodes compared to traditional human insulin.

The use of insulin aspart during pregnancy is considered safe, as it does not appear in fetal circulation and does not increase insulin antibodies, while also being associated with lower rates of fetal losses and preterm deliveries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin aspart in diabetic pregnancy: state of the art. Mathiesen, ER.[2022]

Long-term treatment with the endothelin antagonist atrasentan significantly improved whole body glucose metabolism in insulin-resistant Zucker fatty rats compared to control, indicating its potential efficacy in managing insulin resistance.

Atrasentan treatment enhanced insulin signaling in the liver by normalizing the expression of the regulatory subunit of PI-3 kinase, suggesting a mechanism through which it may help correct insulin resistance, although it did not have the same effect in muscle tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endothelin antagonism improves hepatic insulin sensitivity associated with insulin signaling in Zucker fatty rats. Berthiaume, N., Carlson, CJ., Rondinone, CM., et al.[2018]

Insulin aspart was found to be safe for use in pregnant women with gestational and pregestational diabetes, with no significant difference in the incidence of macrosomia (large babies) between the two groups studied (5.1% in gestational diabetes and 8.9% in pregestational diabetes).

The study involved 355 patients and monitored their blood glucose levels and insulin dosages over several weeks, indicating that insulin therapy was effective in managing blood glucose levels after medical nutrition therapy failed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin aspart in patients with gestational diabetes mellitus and pregestational diabetes mellitus. Deepaklal, MC., Joseph, K., Rekha, K., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10603897/

Uncovering the Vascular Effects of Insulin - PMC We observed that both antagonists, BQ123 and BQ788, singularly and in combination, were successful in dampening constriction induced by ET-1 in ...

2. withpower.com withpower.com/trial/early-phase-1-gestational-diabetes-mellitus-gdm-8-2024-af4e8

Insulin Aspart for Gestational Diabetes Research shows that insulin aspart is effective in managing blood sugar levels in women with gestational diabetes, achieving target glucose levels similar to ...

3. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.117.10849

Causative Effects of Genetically Determined High Maternal/ ... After incubation, medium and cells were collected at 4, 8, 12, and 18 hours for analysis. ET-1, BQ123, and BQ788 were purchased from Sigma- ...

4. researchgate.net researchgate.net/publication/374283983_The_Regulation_of_Endothelin-1_in_Pregnancies_Complicated_by_Gestational_Diabetes_Uncovering_the_Vascular_Effects_of_Insulin

(PDF) The Regulation of Endothelin-1 in Pregnancies ... This figure highlights the antagonism of the endothelin-1 receptors, ETA and ETB, using BQ123 and BQ788 antagonists, respectively (indicated by ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5922254/

Alterations in Endothelin Type B Receptor Contribute to ... Mean ± SEM vasoconstriction (cutaneous conductance, %base) responses to endothelin-1 (ET-1) in control, ETAR-inhibited (+ BQ-123), and ETBR-inhibited (+ BQ-788) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8334338/

Endothelin-1 axes in the framework of predictive, preventive ... In fact, a study in which an ETB receptor antagonist (BQ-788) was administered to healthy subjects revealed ETB receptor-mediated vasoconstriction in men and ...

7. link.springer.com link.springer.com/article/10.1007/s13167-021-00248-z

Endothelin-1 axes in the framework of predictive ... In fact, a study in which an ETB receptor antagonist (BQ-788) was administered to healthy subjects revealed ETB receptor-mediated ...