Elucidating the heterogeneity of impaired awareness of hypoglycemia in Type 1 Diabetes (T1D) Clinical Centers (U01 Clinical Trial Required) | RFA DK 21 020

Opportunity Information: Apply for RFA DK 21 020

This funding opportunity (RFA DK 21 020) is an NIH cooperative agreement (U01) intended to build a coordinated set of clinical centers, organized as a consortium, focused on adults with Type 1 Diabetes (T1D) who have impaired awareness of hypoglycemia (IAH). The central problem the FOA targets is that IAH is common, clinically dangerous, and poorly understood in terms of why some people regain hypoglycemia awareness while others do not. A major reason for the knowledge gap is practical and historical: people with IAH are often excluded from clinical trials, which limits the field's ability to define the clinical and physiological characteristics that predict recovery of awareness and improvement in counter-regulatory defenses.

The scientific premise is that modern diabetes technologies, especially continuous glucose monitoring (CGM) and automated insulin delivery or closed-loop systems (often referred to as artificial pancreas systems), can reduce exposure to hypoglycemia. Reducing hypoglycemia is believed to be an important step toward restoring symptom awareness and hormonal counter-regulation, but the FOA emphasizes that awareness does not reliably return for everyone even when hypoglycemic events decline. In addition, the physiologic consequences of technology-driven hypoglycemia reduction, particularly whether counter-regulatory responses (such as glucagon and epinephrine responses and endogenous glucose production) improve, remain uncertain. The consortium is therefore meant to study this heterogeneity directly, rather than treating IAH as a uniform condition.

The FOA lays out three main goals for the consortium. First, it aims to determine whether state-of-the-art diabetes technology can optimize glycemic control (including HbA1c targets) while minimizing hypoglycemia in a way that actually restores hypoglycemia awareness and improves counter-regulatory responses in adults with T1D. This goes beyond showing fewer low-glucose events; it asks whether the brain-and-body warning systems that fail in IAH can be rehabilitated under real-world conditions supported by advanced devices. Second, it seeks to identify which CGM-derived exposure metrics are associated with recovery, including the magnitude and duration of time in range (TIR), time spent in hypoglycemia, and potentially other CGM measures (for example, frequency, depth, or duration of lows, or patterns that might matter more than averages). The intent is to define measurable CGM thresholds or profiles that correlate with restored awareness, which could become practical targets for clinical care and future trials. Third, the FOA prioritizes validating commonly used self-report questionnaires or assessments of IAH against objective physiological measurements, because self-reported awareness can be subjective and inconsistent, and the field needs stronger evidence about what these instruments truly capture.

Methodologically, the FOA expects participating centers to use rigorous, state-of-the-art physiological testing to quantify counter-regulatory responses and recovery. It specifically highlights hypoglycemic, hyperinsulinemic clamp techniques, with or without stable isotope tracers, to measure hormonal responses and endogenous glucose production during controlled hypoglycemia. These approaches allow investigators to standardize the hypoglycemic stimulus across participants and quantify how well key defenses respond, providing an objective basis for comparing individuals and for testing whether device-enabled hypoglycemia avoidance changes physiology over time. This emphasis signals that the consortium is intended to generate high-quality mechanistic and translational evidence, not only observational CGM summaries.

Structurally, this is a cooperative agreement, which typically means NIH expects substantial involvement in the program's coordination, milestones, and cross-site harmonization. The award instrument is explicitly "Clinical Trial Required," reflecting that the consortium work is expected to include interventional clinical research rather than purely observational studies. The overall activity area is health (CFDA 93.847), and the opportunity is categorized under discretionary funding.

Eligibility is broad and includes many types of domestic applicants such as state and local governments, public and private institutions of higher education, nonprofits with and without 501(c)(3) status, for-profit organizations (other than small businesses), and small businesses, along with tribal governments and tribal organizations. The FOA also explicitly mentions additional eligible applicant categories that NIH emphasizes for inclusivity and reach, including Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Hispanic-serving institutions, HBCUs, tribally controlled colleges and universities, faith-based or community-based organizations, U.S. territories or possessions, and even non-U.S. entities (foreign organizations) and regional organizations. Taken together, that eligibility language underscores an intent to build a consortium that can recruit and study diverse adult T1D populations affected by IAH and to support participation from a wide range of institutional settings.

Key administrative identifiers from the notice include the funding opportunity title "Elucidating the heterogeneity of impaired awareness of hypoglycemia in Type 1 Diabetes (T1D) Clinical Centers (U01 Clinical Trial Required)," the opportunity number RFA DK 21 020, and the original closing date of 2022-03-31. The FOA does not provide an award ceiling or expected number of awards in the text provided, but the overarching deliverable is clear: a multi-center, technology-enabled, physiologically grounded research consortium designed to explain why recovery from IAH varies so widely, to define CGM-based exposure targets linked to recovery, and to strengthen how IAH is assessed by anchoring self-report tools to objective counter-regulatory measurements.

• The National Institutes of Health in the food and nutrition, health sector is offering a public funding opportunity titled "Elucidating the heterogeneity of impaired awareness of hypoglycemia in Type 1 Diabetes (T1D) Clinical Centers (U01 Clinical Trial Required)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.847.
• This funding opportunity was created on 2022-01-04.
• Applicants must submit their applications by 2022-03-31. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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