Pulsatile vs Continuous Insulin for Insulin Sensitivity

Overseen By Frank L Greenway, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Pennington Biomedical Research Center

Disqualifiers: Non-completion of Motivate study

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

Compensation: Varies

Number of Visits: 3

Duration: 1 week

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to compare two methods of insulin delivery to determine which better manages blood sugar levels. One group will receive a constant insulin infusion, while the other will receive insulin in pulses every five minutes (pulsatile hormone administration). The goal is to determine if pulsing insulin improves insulin sensitivity, which can help maintain steady blood sugar levels. The trial seeks participants who have completed the Motivate Study and its final insulin sensitivity test. As an unphased trial, this study offers a unique opportunity to contribute to innovative research that could enhance diabetes management strategies.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications.

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

Research has shown that the insulin used in the hyperinsulinemic euglycemic clamp test is generally well-tolerated. This test is the best method for measuring the body's insulin sensitivity. Past studies have safely used both continuous and on-and-off (every few minutes) insulin infusions.

The clamp test, whether using continuous or on-and-off insulin, allows researchers to assess the body's response to insulin by maintaining steady blood sugar levels. Although specific side effects are not detailed, the frequent use of this method in research suggests it is generally safe for participants.

For those considering joining a trial with on-and-off insulin, it is reassuring that this method has been used in many studies and is a standard way to measure insulin sensitivity. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a new approach to insulin delivery that could improve insulin sensitivity. Unlike the standard continuous insulin infusion, which delivers insulin at a steady rate, the pulsatile approach administers insulin in bursts every five minutes. This mimics the natural release patterns of insulin in the body more closely, potentially enhancing the body's ability to respond to insulin and improve glucose control. By comparing these two methods, researchers hope to uncover whether pulsatile administration offers a significant advantage in managing insulin sensitivity.

What evidence suggests that this trial's treatments could be effective for insulin sensitivity?

This trial will compare pulsatile insulin delivery with continuous insulin delivery. Research has shown that delivering insulin in bursts, rather than continuously, may help the body use insulin more effectively and control blood sugar better. In one study, this method helped the liver respond more efficiently to insulin, leading to improved blood sugar regulation. Another study found that this burst method significantly enhanced insulin's effectiveness. These findings suggest that using insulin in bursts might better imitate the body's natural insulin release, potentially offering more precise control of blood sugar levels. ^{6 7 8 9 10}

Who Is on the Research Team?

Candida Rebello, PhD

Principal Investigator

Pennington Biomedical Research Center

Are You a Good Fit for This Trial?

This trial is for individuals who have completed the Motivate Study (NCT05649176) and are interested in further examining insulin resistance and sensitivity. Participants must have finished the end-of-study hyperinsulinemic euglycemic clamp test from the Motivate study to be eligible.

Inclusion Criteria

Completion of the Motivate Study (NCT05649176)

Exclusion Criteria

Non-completion of the end-of-study hyperinsulinemic euglycemic clamp test of the Motivate study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo two hyperinsulinemic euglycemic clamp tests with different insulin infusion methods

1 week

2 visits (in-person)

Follow-up

Participants return to the clinic in a fasted state for blood tests to measure glucose and insulin

1 day

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Pulsatile Hormone Administration

Trial Overview The study investigates how different methods of insulin administration affect insulin action. It compares continuous infusion with pulsatile infusion, where insulin is given every five minutes, during a hyperinsulinemic euglycemic clamp test—a procedure that measures how sensitive the body is to insulin.

How Is the Trial Designed?

Group I: Pulsatile insulin at 40mU/m2/min Experimental Treatment 1 Intervention

Participants will receive insulin infused every five minutes during the hyperinsulinemic euglycemic clamp test of insulin sensitivity

Group II: Continuous insulin at 40mU/m2/min Active Control 1 Intervention

Paricipants will receive insulin infused continuously during the hyperinsulinemic euglycemic clamp test of insulin sensitivity.

Who Is Running the Clinical Trial?

Pennington Biomedical Research Center

Lead Sponsor

Trials

314

Recruited

183,000+

Published Research Related to This Trial

In a study involving five diabetic baboons, pulsatile intravenous insulin delivery did not show significant differences in glucose control compared to continuous insulin infusion, indicating similar efficacy in managing blood sugar levels.

Both pulsatile and continuous insulin methods effectively suppressed hepatic glucose production and maintained stable glucagon levels, suggesting that pulsatile insulin delivery may not provide additional metabolic benefits over continuous delivery in this model of diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of evidence for improvement in long-term glycemic control by pulsatile insulin infusion in streptozocin-induced diabetic baboon. Weigle, DS., Rumbaoa, AV., Goodner, CJ.[2022]

In a study involving seven normal volunteers, both pulsatile and continuous insulin infusions produced similar metabolic effects, including glucose metabolism and suppression of endogenous glucose production, indicating that the method of insulin delivery may not significantly impact its effectiveness under certain conditions.

Despite previous findings suggesting that pulsatile insulin could have a greater hypoglycemic effect at lower concentrations, this study concluded that under normoglycemic and moderately hyperinsulinemic conditions, pulsatile insulin does not demonstrate superior activity compared to continuous insulin delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar metabolic effects of pulsatile versus continuous human insulin delivery during euglycemic, hyperinsulinemic glucose clamp in normal man. Verdin, E., Castillo, M., Luyckx, AS., et al.[2019]

Prolonged pulsatile insulin infusion (0.5 mU.kg-1.min-1 for 20 hours) resulted in a 55% greater hypoglycemic effect compared to continuous insulin infusion, indicating its superior efficacy in managing blood sugar levels.

Unlike continuous hyperinsulinemia, pulsatile insulin administration did not induce insulin insensitivity; in fact, insulin sensitivity improved post-infusion, suggesting that pulsatile delivery may be a safer and more effective method for insulin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of prolonged pulsatile hyperinsulinemia in humans. Enhancement of insulin sensitivity. Ward, GM., Walters, JM., Aitken, PM., et al.[2019]

Pulsatile insulin administration can effectively suppress hepatic glucose production (HGP) in type I diabetic patients, achieving similar results to continuous insulin infusion while reducing total insulin delivery by 40%.

Both pulsatile and continuous insulin methods showed no significant difference in insulin-stimulated glucose utilization, indicating that pulsatile insulin is equally effective in managing glucose levels without increasing the total amount of insulin needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of pulsatile versus continuous insulin administration on hepatic glucose production and glucose utilization in type I diabetic humans. Bratusch-Marrain, PR., Komjati, M., Waldhäusl, WK.[2022]

In a study involving 17 Type 2 diabetic patients, overnight pulsatile insulin infusion did not improve insulin sensitivity compared to constant insulin infusion, indicating that abnormal insulin pulsatility may not play a direct role in insulin resistance.

The research found that while 7-minute insulin pulses required lower glucose infusion rates to maintain euglycaemia than 13-minute pulses, there was no overall benefit to pulsatile insulin over constant infusion, suggesting that the frequency of insulin pulses may not significantly impact metabolic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of manipulation of basal pulsatile insulin on insulin action in Type 2 diabetes. Au, S., Courtney, CH., Ennis, CN., et al.[2018]

In a study involving nine well-controlled Type 1 diabetic patients, pulsatile intravenous insulin infusion did not improve glucose tolerance, as indicated by a significant increase in maximal glucose concentration after glucose load following the treatment.

Despite the insulin pulsing, key metabolic parameters such as plasma free insulin and glucagon levels remained unchanged, suggesting that this method of insulin delivery may not enhance oral glucose homeostasis in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulsatile insulin infusion and glucose-homeostasis in well-controlled type 1 (insulin-dependent) diabetic patients. Heinemann, L., Sonnenberg, GE., Hohmann, A., et al.[2019]

In a study involving 19 normal volunteers, overnight pulsatile insulin administration did not significantly improve subsequent insulin sensitivity compared to continuous insulin infusion during a hyperinsulinemic euglycemic clamp.

The results suggest that the normal pulsatile secretion of insulin is not necessary for maintaining insulin sensitivity, indicating that the relationship between insulin pulsatility and peripheral insulin action may not be causal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the priming effects of pulsatile and continuous insulin delivery on insulin action in man. Courtney, CH., Atkinson, AB., Ennis, CN., et al.[2019]

In a study involving six normal subjects, pulsed insulin administration resulted in significantly lower plasma glucose levels compared to steady insulin infusion, particularly noticeable 7 hours after treatment began.

The increased hypoglycemic effect of pulsed insulin may be due to enhanced binding of insulin to its receptors on monocytes, suggesting a more effective mechanism of action for this delivery method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Matthews, DR., Naylor, BA., Jones, RG., et al.[2019]

Citations

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Insulin Pulse Characteristics and Insulin Action in Non- ... On a separate study day, insulin action was measured using a hyperinsulinemic, euglycemic clamp designed to produce ~50% suppression of EGP to measure the ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0026049503001562#!

Comparison of the priming effects of pulsatile and ... The power of the study, calculated from previous clamp data, gave a 90% chance of detecting a 10% change in insulin action at the 5% level of significance.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3425431/

Pulsatile Portal Vein Insulin Delivery Enhances Hepatic ... We conclude that the physiological pulsatile pattern of insulin delivery is important in hepatic insulin signaling and glycemic control.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1056872716307310

Assessment of insulin sensitivity by the hyperinsulinemic ... We compare spectral analysis of photoplethysmography (PTG) with insulin resistance measured by the hyperinsulinemic euglycemic clamp (HEC) technique.

5. academic.oup.com academic.oup.com/jcem/article/103/11/4155/5096792

Physiology of Glycemic Recovery and Stabilization After ... After hyperinsulinemic euglycemic clamp, ∼50% of subjects achieve glycemic stability within 1 hour; glucose tolerance, insulin sensitivity, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6194810/

Physiology of Glycemic Recovery and Stabilization After ... After hyperinsulinemic euglycemic clamp, ∼50% of subjects achieve glycemic stability within 1 hour; glucose tolerance, insulin sensitivity, and secretion are ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S1646343913000734

Assessment of methods and indexes of insulin sensitivity The validity of glucose clamp measurements of insulin sensitivity depends on achieving steady-state conditions. “Steady-state” is often defined as a period ...

8. journals.physiology.org journals.physiology.org/doi/abs/10.1152/ajpendo.1979.237.3.E214

Glucose clamp technique: a method for quantifying insulin ... Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion ...

9. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06216665/effect-of-pulsatile-hormone-administration-on-insulin-action

Effect of Pulsatile Hormone Administration on Insulin Action In this study, insulin sensitivity measured using the standard clamp will be compared with a clamp in which the same total amount of insulin as ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3379600/

Defining Insulin Resistance From Hyperinsulinemic- ... The hyperinsulinemic-euglycemic clamp technique is the gold standard for assessing insulin sensitivity in humans. This method is widely used in research studies ...