Clinical Context
Hypoglycemia remains the major limiting factor in achieving tight glycemic control in type 1 diabetes. The normal counterregulatory response to falling glucose involves coordinated release of glucagon (from pancreatic alpha cells), epinephrine, cortisol, and growth hormone. In type 1 diabetes, this defense system is impaired: glucagon responses to hypoglycemia are lost within years of diagnosis (due to alpha-cell dysfunction in the diabetic islet), and with disease duration, epinephrine responses and hypoglycemia awareness often diminish as well.
This loss of counterregulation creates a dangerous situation: patients can develop severe hypoglycemia (requiring external assistance) without adequate warning or protective hormonal responses. Severe hypoglycemia causes seizures, accidents, cardiac arrhythmias, and even death. Fear of hypoglycemia is a major barrier to intensive insulin therapy and optimal glycemic control.
GPR119 is a G-protein coupled receptor expressed on pancreatic islet cells (both beta and alpha cells) and intestinal L-cells. Activation of GPR119 stimulates incretin secretion (GLP-1, GIP) and directly modulates islet hormone release. In this study, a GPR119 agonist (MBX-2982) was tested for its ability to augment glucagon release during experimentally induced hypoglycemia in type 1 diabetes—addressing a fundamental defect in T1D physiology.
Study Summary (PICO Framework)
Summary:
In adults with type 1 diabetes, MBX-2982 (GPR119 agonist) significantly augmented glucagon counterregulatory responses during experimental hypoglycemia compared to placebo, with nausea as the main side effect and no severe adverse events.
| PICO | Description |
|---|---|
| Population | Adults aged 20-60 years with type 1 diabetes. |
| Intervention | MBX-2982, a GPR119 agonist. |
| Comparison | Placebo (double-masked, crossover design). |
| Outcome | Significantly augmented glucagon counterregulatory response. Nausea in some participants; no severe adverse events. |
Clinical Pearls
1. Restoring glucagon counterregulation addresses a fundamental T1D defect. Unlike type 2 diabetes therapies that focus on improving insulin action or secretion, this approach targets the alpha cell—specifically its failure to respond appropriately to hypoglycemia. If glucagon counterregulation can be restored, patients might be protected from severe hypoglycemia while still achieving intensive glycemic control. This represents a fundamentally different therapeutic strategy.
2. Alpha cells in T1D are dysfunctional, not absent. Patients with type 1 diabetes still have alpha cells (often more than normal, as the islet architecture becomes alpha-cell predominant). However, these alpha cells fail to respond normally to hypoglycemia. The finding that GPR119 agonism can augment glucagon release suggests the machinery for glucagon secretion is present but requires appropriate stimulation—a targetable defect.
3. The crossover design is well-suited for this proof-of-concept study. Each participant served as their own control, receiving both MBX-2982 and placebo in random order. This design increases statistical power by controlling for inter-individual variability in counterregulatory responses, which can be substantial. The double-masked nature prevents bias in outcome assessment.
4. This is early-phase research, not a clinical therapy yet. MBX-2982 is an investigational compound, not an approved medication. This study establishes proof-of-concept that GPR119 agonism can modulate glucagon responses in T1D, but clinical utility would require demonstration that this translates to reduced severe hypoglycemia events in real-world use—requiring larger, longer trials with clinical endpoints.
Practical Application
This study informs future directions, not current practice: GPR119 agonists are not currently available for clinical use in T1D. However, this research advances understanding of potential therapeutic approaches. Clinicians should be aware of the evolving landscape of T1D adjunctive therapies targeting pathways beyond insulin replacement.
Current strategies for hypoglycemia protection remain standard of care: Until novel therapies reach clinical application, existing approaches remain essential: CGM with predictive low glucose alerts, automated insulin delivery (hybrid closed-loop) systems that suspend or reduce insulin before hypoglycemia, hypoglycemia awareness training programs, and appropriate glucose/glucagon access for treatment of low episodes.
Glucagon formulations are available for severe hypoglycemia treatment: Injectable glucagon (emergency kits) and nasal glucagon (Baqsimi) are FDA-approved for severe hypoglycemia treatment. The GPR119 approach differs—it attempts to augment endogenous glucagon release rather than administer exogenous glucagon, potentially providing a more physiological protective response.
Consider the broader context of T1D adjunctive therapies: Beyond GPR119 agonists, other approaches are being investigated: SGLT2 inhibitors (approved in some regions for T1D with caution), pramlintide (amylin analog), and various immunomodulatory approaches to preserve beta-cell function. The T1D therapeutic landscape is expanding beyond insulin alone.
How This Study Fits Into the Broader Evidence
GPR119 has been investigated primarily for type 2 diabetes, where its ability to stimulate GLP-1 secretion and potentiate glucose-stimulated insulin secretion made it an attractive target. Several pharmaceutical companies developed GPR119 agonists, though none have reached widespread clinical use in T2D due to modest efficacy in that population.
This study represents a pivot: examining GPR119 agonism for a different purpose (glucagon augmentation) in a different population (T1D). The finding that GPR119 activation can enhance glucagon responses during hypoglycemia opens a new potential application for this receptor target.
Other approaches to restoring counterregulation in T1D have been investigated: beta-2 adrenergic agonists, amino acid supplements (targeting alpha-cell stimulation), and islet transplantation (which can restore glucagon responses). The GPR119 approach adds to this portfolio of potential strategies.
Limitations to Consider
Sample size for this early-phase study is small. Hypoglycemia was induced experimentally in a controlled setting—real-world spontaneous hypoglycemia may differ. The glucagon response augmentation, while statistically significant, needs clinical validation (does it prevent severe hypoglycemia events?). Nausea as a side effect might limit tolerability at effective doses. Duration of effect and chronic dosing effects are unknown. MBX-2982’s development status and path to potential approval are uncertain.
Bottom Line
In this crossover RCT, the GPR119 agonist MBX-2982 significantly augmented glucagon counterregulatory responses during experimental hypoglycemia in adults with type 1 diabetes, with nausea as the main side effect. This proof-of-concept study demonstrates that pharmacological targeting of GPR119 can enhance glucagon release in T1D, potentially addressing the lost glucagon counterregulation that makes these patients vulnerable to severe hypoglycemia. While not yet a clinical therapy, this research advances understanding of therapeutic approaches beyond insulin in type 1 diabetes management.
Source: Anika Bilal, et al. “A Randomized Controlled, Double-Masked, Crossover Study of a GPR119 Agonist on Glucagon Counterregulation During Hypoglycemia in Type 1 Diabetes.” Diabetes Research and Clinical Practice. Read article here.
