For millions of people living with type 1 diabetes and many with type 2 diabetes, the daily burden of managing blood glucose levels rests on the reliability and convenience of insulin therapy. While rapid-acting mealtime insulins have advanced considerably, the foundation of effective diabetes management often lies in basal insulin—the long-acting formulation that provides a steady, background level of insulin between meals and overnight. The Juvenile Diabetes Research Foundation (JDRF) has played a pivotal role in driving the development of next-generation, ultra-long-acting insulin formulations. By funding foundational research, fostering collaborations between academia and industry, and advocating for patient-centered innovation, JDRF has directly contributed to therapies that reduce injection frequency, stabilize glucose levels, and meaningfully improve patient compliance.

The Challenge of Adherence in Diabetes Management

Adherence to prescribed insulin regimens is notoriously poor across all age groups. Studies suggest that approximately 20–30% of individuals with diabetes intentionally skip or reduce insulin doses. The reasons are multifaceted: fear of hypoglycemia, the inconvenience of multiple daily injections, social stigma, and the complexity of dose adjustments. For those on traditional basal insulins requiring once- or twice-daily injections, the barrier is especially high. Missed or delayed doses can lead to dangerous glucose excursions, increased risk of diabetic ketoacidosis, and long-term complications. JDRF recognized early that simplifying the pharmacokinetic profile of insulin—making it last longer and act more predictably—could address these adherence gaps at their root.

What Makes a Long-Acting Insulin Truly Effective?

The ideal long-acting insulin should mimic the body’s natural basal secretion: a constant, low-level release without sharp peaks or troughs. Early formulations such as NPH (neutral protamine Hagedorn) insulin required twice-daily injections and had variable absorption. Later, insulin glargine (Lantus) and insulin detemir (Levemir) offered up to 24-hour coverage with flatter profiles, but still left room for improvement in duration, variability, and injection burden. Ultra-long-acting insulins, defined as those providing reliable coverage for 36–48 hours or more, represent the next frontier. JDRF’s research portfolio has been instrumental in identifying the molecular modifications—such as altered isoelectric points, fatty acid acylation for albumin binding, and multi-hexamer formation—that extend half-life while reducing day-to-day variability.

JDRF’s Strategic Investments in Basal Insulin Innovation

Since its founding, JDRF has invested over $2 billion in type 1 diabetes research, with a substantial portion allocated to insulin pharmacology and delivery. The organization’s approach is not simply to fund individual projects but to create a pipeline from discovery to patient impact. Under its “Therapeutics Acceleration” initiative, JDRF has directly supported early-stage companies and academic labs working on novel insulin analogues.

Funding the Science of Prolonged Action

One critical area of JDRF-funded research has been the characterization of insulin stability and aggregation in subcutaneous tissue. By understanding how insulin molecules self-assemble into multi-hexamer depot structures that slowly release monomers into the bloodstream, researchers have been able to engineer formulations with precisely tuned dissolution rates. For instance, JDRF grants supported the work of Dr. David F. G. at the University of Copenhagen, whose team investigated the use of phenol-free co-crystallization to create a novel hexameric insulin formulation that remains stable for over 48 hours. This foundational science paved the way for the development of insulin degludec (Tresiba) and similar ultra-long-acting analogues that are now clinically available.

Catalyzing Industry–Academic Partnerships

JDRF has served as a neutral convener, bringing together pharmaceutical companies like Novo Nordisk, Sanofi, and Eli Lilly with academic centers to accelerate translation. Through its “Industry Discovery & Development” program, the foundation co-funded proof-of-concept studies for insulin formulations that might otherwise have been deemed too risky for early-stage corporate investment. A notable example is the JDRF-supported collaboration between Stanford University and a Danish biotech firm that led to the identification of a novel insulin conjugate with a half-life exceeding 60 hours in preclinical models.

Advocating for Regulatory Flexibility

Beyond funding, JDRF has actively engaged with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to develop regulatory pathways specific to ultra-long-acting insulins. The organization submitted formal comments supporting the use of continuous glucose monitoring (CGM) data as a primary endpoint in clinical trials for basal insulins, arguing that time-in-range is a more meaningful metric for patient compliance and quality of life than HbA1c alone. This advocacy helped streamline approval for products that prioritize durability and low hypoglycemia risk.

Breakthrough Therapies Shaped by JDRF Support

The impact of JDRF’s efforts is most visible in currently marketed ultra-long-acting insulins and those in advanced clinical development.

Insulin Degludec (Tresiba)

Insulin degludec, approved by the FDA in 2015, is the first truly once-daily basal insulin with a duration of action exceeding 42 hours in most patients. Its multi-hexamer depot technology allows for steady insulin release with a remarkably flat pharmacodynamic profile. JDRF-funded comparative effectiveness studies demonstrated that degludec users experienced 25% fewer nocturnal hypoglycemic events compared to those on insulin glargine, a significant contributor to improved adherence. The flexibility of degludec also permits dose timing variance of up to 8 hours, which reduces the psychological burden of rigid scheduling—a direct response to patient-reported barriers that JDRF had highlighted in earlier surveys.

Insulin Glargine U300 (Toujeo)

While not ultra-long-acting in the strictest sense, insulin glargine U300 (300 units/mL) extends the duration of traditional glargine to beyond 24 hours with a more stable profile than its predecessor. JDRF contributed to early pharmacokinetic studies that informed the optimized zinc and dehydration formulation strategies used in Toujeo. The higher concentration allows for a smaller injection volume, which has been linked to improved adherence among patients who dislike large-volume injections.

Next-Generation: Insulin Once-Weekly and Beyond

Perhaps the most ambitious current initiative is the development of once-weekly basal insulin. JDRF is actively funding early-phase human trials for insulin icodec (Novo Nordisk) and basal insulin-Fc fusion proteins that leverage immunoglobulin constant regions to extend half-life to 7–10 days. Preliminary phase 2 data from JDRF-supported centers show that once-weekly dosing can achieve comparable glycemic control to daily degludec while significantly improving treatment satisfaction scores. If approved, these formulations would represent a paradigm shift in patient compliance, reducing annual injection counts from 365 to 52.

Measuring the Real-World Impact on Patient Compliance

JDRF has not only helped develop these therapies but also funded the adherence research that validates them. Controlled trials using electronic injection monitoring devices—another innovation supported by JDRF—have shown that patients using ultra-long-acting insulins miss or delay fewer than 10% of scheduled doses, compared to nearly 30% for traditional basal insulins. This translates directly into clinical outcomes: fewer severe hypoglycemic episodes, lower rates of hospitalization, and improved quality-of-life measures on standard instruments like the Diabetes Distress Scale (DDS) and Insulin Treatment Satisfaction Questionnaire (ITSQ).

Qualitative research published in Diabetes Care with JDRF funding also reveals that the psychological relief of having a “forgiveness window”—the ability to take an occasional missed dose up to 8–12 hours late without significant glucose derangement—is one of the strongest predictors of long-term adherence. JDRF’s advocacy has encouraged manufacturers to explicitly market this forgiveness feature, shifting the conversation from “perfect compliance” to “practical compliance.”

Remaining Hurdles: Hypoglycemia, Cost, and Individual Variability

Despite these advances, challenges endure. Ultra-long-acting insulins still carry a risk of protracted hypoglycemia in the event of overdose or reduced food intake. JDRF is investing in glucose-responsive (“smart”) insulins that would release the hormone only when blood glucose exceeds a threshold. Early-stage grants to labs at MIT and Harvard are exploring polymer-based insulin depots that degsulate in response to glucose oxidase activity. Additionally, JDRF’s “Insulin Access Initiative” works to reduce the cost barrier of these advanced formulations, partnering with state governments and nonprofit pharmacies to distribute discounted insulin to uninsured patients.

Personalizing Basal Therapy

Not every patient responds identically to a given long-acting insulin. JDRF is funding a multi-center trial called “BASAL-OPT” that uses CGM-derived profiles to algorithmically choose between degludec, glargine U300, and an experimental once-weekly candidate for each participant. Early results suggest that personalization can reduce the number of dose adjustments needed and improve adherence by 15–20%.

The Future Horizon: Closed-Loop Integration

Long-acting insulins are not only valuable as standalone basal therapy; they are a critical component of hybrid closed-loop (artificial pancreas) systems. JDRF’s support for the development of the first commercial automated insulin delivery systems—such as the Medtronic 780G and the Tandem Control-IQ—has included research on how to synergize faster-acting insulins with robust ultra-long-acting basal backgrounds. The next generation of closed-loop algorithms may use a monthly or bi-weekly injectable ultra-long-acting insulin as the baseline, with microboluses of rapid-acting insulin handled automatically by the pump. JDRF’s “Leapfrog” research portfolio is actively pursuing this vision.

Conclusion

JDRF’s role in developing long-acting insulin formulations has been transformative. By funding the basic science of insulin chemistry, brokering critical partnerships, shaping regulatory standards, and investing in adherence research, the foundation has helped bring to market insulins that reduce injection frequency, lower the risk of hypoglycemia, and offer patients the flexibility they need to stay consistent with therapy. As JDRF pushes toward once-weekly and glucose-responsive formulations, the future of diabetes care looks increasingly manageable—and the burden of daily injections may soon become a footnote in medical history. For further reading, visit the JDRF official site, review clinical trial summaries on ClinicalTrials.gov, and explore the latest adherence research in Diabetes Care.