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

Trial Summary

What is the purpose of this trial?

In humans, insulin is secreted in pulses from the pancreatic beta-cells, and these oscillations help to maintain fasting plasma glucose levels within a narrow normal range. Given the fluctuations in insulin concentrations, oscillations enhance precision of control. The hyperinsulinemic euglycemic clamp test (clamp) involves a continuous infusion of insulin and is the gold standard for measuring insulin sensitivity. 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 the standard clamp is infused every five minutes instead of continuously.

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.

What data supports the effectiveness of the treatment Pulsatile Hormone Administration for improving insulin sensitivity?

Research shows that pulsatile insulin administration can be as effective as continuous insulin in controlling liver glucose production, even with a reduced total insulin dose, suggesting potential benefits in insulin sensitivity. ^{1 2 3 4 5}

Is pulsatile insulin administration safe for humans?

Research indicates that pulsatile insulin administration is generally safe in humans, as studies have shown similar metabolic effects and safety profiles compared to continuous insulin delivery. No significant adverse effects were reported in the studies involving both diabetic and non-diabetic participants. ^{1 2 6 7 8}

How does pulsatile insulin treatment differ from continuous insulin treatment for diabetes?

Pulsatile insulin treatment involves delivering insulin in bursts, mimicking the body's natural insulin release, whereas continuous insulin treatment provides a steady flow of insulin. Research suggests that pulsatile insulin can be as effective as continuous insulin in controlling glucose production in the liver, but it may reduce the total amount of insulin needed by up to 40%. ^{1 2 3 4 6}

Research Team

Candida Rebello, PhD

Principal Investigator

Pennington Biomedical Research Center

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

References

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

Lack of evidence for improvement in long-term glycemic control by pulsatile insulin infusion in streptozocin-induced diabetic baboon. [2022]

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

Efficacy of pulsatile versus continuous insulin administration on hepatic glucose production and glucose utilization in type I diabetic humans. [2022]

3. England pubmed.ncbi.nlm.nih.gov

The effect of manipulation of basal pulsatile insulin on insulin action in Type 2 diabetes. [2018]

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

Pulsatile insulin infusion and glucose-homeostasis in well-controlled type 1 (insulin-dependent) diabetic patients. [2019]

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

Comparison of the priming effects of pulsatile and continuous insulin delivery on insulin action in man. [2019]

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

Similar metabolic effects of pulsatile versus continuous human insulin delivery during euglycemic, hyperinsulinemic glucose clamp in normal man. [2019]

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

Pulsatile insulin has greater hypoglycemic effect than continuous delivery. [2019]

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

Effects of prolonged pulsatile hyperinsulinemia in humans. Enhancement of insulin sensitivity. [2019]