Proposed section structure
This study is best interpreted through a clinically oriented structure that moves from unmet need to mechanism, trial design, efficacy signal, safety, and translational implications. The most suitable sections are: Highlights; Clinical background and unmet need; Biological rationale for SSTR2 antagonism; Study design and methods; Key results; Safety and tolerability; Expert commentary and limitations; Clinical implications and next steps; Funding, trial registration, and citation.
Highlights
ZT-01, a novel somatostatin receptor 2 antagonist, increased glucagon responses during both level 1 and level 2 insulin-induced hypoglycaemia in adults with long-standing type 1 diabetes.
The glucagon signal appeared despite the well-recognized defect in alpha-cell counterregulation that characterizes established type 1 diabetes, supporting the mechanistic role of somatostatin-SSTR2 signalling in impaired glucagon release.
Both 3 mg and 20 mg subcutaneous doses produced transient glucagon rises after dosing and enhanced the frequency and amplitude of glucagon responses during subsequent hypoglycaemia.
No drug treatment-related adverse events were reported in this phase 1b crossover study, but the findings remain proof-of-concept and do not yet establish reduction in real-world severe hypoglycaemia.
Clinical background and unmet need
Hypoglycaemia remains one of the central therapeutic barriers in type 1 diabetes. Even with advances in continuous glucose monitoring, automated insulin delivery, and insulin analogues, many adults with long-standing disease continue to experience biochemical hypoglycaemia, symptomatic episodes, and in some cases severe events requiring assistance. The problem is not simply excessive insulin exposure. Over time, many patients lose the normal glucagon counterregulatory response to falling plasma glucose, which markedly increases vulnerability when exogenous insulin drives glucose downward.
Under normal physiology, pancreatic alpha cells increase glucagon secretion when glucose falls. This glucagon response stimulates hepatic glucose production and represents a primary defense against insulin-induced hypoglycaemia. In type 1 diabetes, this defense is frequently blunted or absent, especially in long-standing disease. As a result, patients become dependent on behavioral detection of symptoms, adrenergic activation, carbohydrate rescue, and technology alarms. Restoring glucagon counterregulation has therefore been an important but elusive therapeutic goal.
Somatostatin, secreted by pancreatic delta cells, inhibits glucagon release through somatostatin receptor 2, or SSTR2, on alpha cells. Experimental work has suggested that inappropriate somatostatin signalling may contribute to impaired alpha-cell output during hypoglycaemia in diabetes. The present study tests a translationally appealing hypothesis: if SSTR2-mediated inhibition is blocked, glucagon secretion during falling glucose may be restored.
Biological rationale for SSTR2 antagonism
The concept behind ZT-01 is mechanistically straightforward. During hypoglycaemia, alpha cells should increase glucagon secretion, but that response is constrained by inhibitory paracrine signals, including somatostatin. Antagonizing SSTR2 could release this inhibitory brake and allow a more physiologic glucagon response. This approach differs from simply administering exogenous glucagon rescue. Instead, it attempts to re-enable endogenous counterregulation during hypoglycaemia itself.
That distinction matters clinically. A therapy that selectively improves endogenous glucagon responsiveness during hypoglycaemia could, in principle, reduce event severity without chronic hyperglycaemia. Whether that promise can be realized outside the clamp laboratory remains uncertain, but the mechanism is biologically plausible and directly targets a major defect in type 1 diabetes.
Study design and methods
Abitbol and colleagues conducted a randomized crossover phase 1b study at a single site, with blinding of both participants and researchers. Adults aged 18 to 65 years with long-standing type 1 diabetes were eligible if they had a BMI of 18.5 to 27 kg/m2, HbA1c 42.1 to 74.9 mmol/mol, and C-peptide below 200 pmol/l, consistent with limited endogenous insulin secretion.
Participants underwent three separate hyperinsulinaemic euglycaemic-hypoglycaemic clamp procedures. In equal randomized sequence, they received placebo, 3 mg ZT-01, or 20 mg ZT-01 administered subcutaneously during euglycaemia, with a plasma glucose target of 5.0 mmol/l. Hypoglycaemia was then induced using variable-rate insulin infusion, without dextrose supplementation, to reach level 1 hypoglycaemia at 3.5 mmol/l and level 2 hypoglycaemia at 2.6 mmol/l.
The primary endpoint was glucagon response. Secondary or supportive assessments included plasma glucose, other counterregulatory hormones, symptom scores, and safety. The crossover design is a strength for an early mechanistic study because each participant serves as his or her own control, reducing between-subject variability in counterregulatory physiology.
Twenty-four randomized participants, including 9 women and 15 men, received at least one dose of placebo or ZT-01 and were included in the safety analysis. Twenty-two participants completed at least one glucose clamp and contributed to the pharmacodynamic analysis.
Key results
Early pharmacodynamic effect before hypoglycaemia
ZT-01 caused a transient rise in plasma glucagon after dosing during euglycaemia. Mean glucagon increased by 25.7 ± 2.4 ng/l with 3 mg ZT-01 and by 28.4 ± 2.4 ng/l with 20 mg ZT-01. Importantly, glucagon levels then declined toward predose values before the onset of level 1 hypoglycaemia. This pattern suggests a clear on-target biological effect, but not a sustained uncontrolled hyperglucagonaemic state across the entire pre-hypoglycaemic period.
With placebo, glucagon levels remained unchanged after dosing, which strengthens the inference that the early glucagon rise was drug related rather than a clamp artifact.
Glucagon response during level 1 hypoglycaemia
The most clinically interesting finding was the behavior of glucagon during induced hypoglycaemia. During level 1 hypoglycaemia, mean glucagon rose above baseline by 15.6 ± 2.3 pg/l with 3 mg ZT-01 and by 14.9 ± 2.4 pg/l with 20 mg ZT-01. In contrast, glucagon was unchanged during level 1 hypoglycaemia with placebo.
This matters because early counterregulation at milder hypoglycaemic thresholds may help prevent progression to more dangerous levels. A treatment that restores glucagon responsiveness at 3.5 mmol/l could theoretically provide earlier physiologic defense than therapies that act only after more profound hypoglycaemia has developed.
Glucagon response during level 2 hypoglycaemia
During level 2 hypoglycaemia, the glucagon effect persisted and appeared larger. Mean glucagon rose above baseline by 22.8 ± 2.7 pg/l with 3 mg ZT-01 and by 29.6 ± 2.8 pg/l with 20 mg ZT-01. With placebo, glucagon rose only modestly during level 2 hypoglycaemia, by 8.9 ± 2.5 ng/l.
Although the abstract reports mixed units for some glucagon values, the directional signal is clear: both active doses produced greater glucagon responses than placebo during more severe insulin-induced hypoglycaemia. The report also notes that both the frequency and amplitude of glucagon increases were higher with ZT-01 than with placebo during both level 1 and level 2 hypoglycaemia. That suggests the effect was not limited to a small subgroup of responders.
Dose-response considerations
The two dose levels produced broadly similar effects at level 1 hypoglycaemia, while the 20 mg dose appeared numerically greater at level 2 hypoglycaemia. However, this early study was not designed or powered for definitive dose optimization. The data support biological activity at both doses rather than a conclusive statement that 20 mg is superior overall.
Other counterregulatory and symptomatic outcomes
The abstract indicates that other counterregulatory hormones and symptom scores were measured, but detailed numerical results are not presented there. Therefore, no strong conclusion can be drawn from the abstract alone about whether ZT-01 improved autonomic symptom awareness, neuroglycopenic symptoms, or broader hormonal counterregulation beyond glucagon. Those details will be important when the full study report is assessed in depth.
Safety and tolerability
No drug treatment-related adverse events were reported. For a first-in-human or early-phase mechanistic program focused on alpha-cell disinhibition, this is reassuring, although it should be interpreted cautiously. The sample size was small, exposure was brief, and the highly controlled clamp setting may not reveal adverse effects that could emerge with repeated outpatient dosing.
Potential safety questions for future studies include whether SSTR2 antagonism could increase fasting or postprandial glucose, alter glycaemic variability, provoke nausea or gastrointestinal effects through off-target or downstream pathways, or behave differently in broader populations with higher BMI, more comorbidity, or recurrent severe hypoglycaemia. None of those concerns were identified here, but neither were they fully tested.
Expert commentary and interpretation
This trial provides a persuasive proof-of-concept that impaired glucagon counterregulation in type 1 diabetes is not necessarily irreversible. Instead, at least part of the defect may be pharmacologically modifiable by interrupting inhibitory somatostatin signalling at SSTR2. That is a meaningful mechanistic advance.
From a translational standpoint, the study sits at the intersection of physiology and therapeutics. Current hypoglycaemia prevention strategies largely rely on better insulin delivery, improved sensing, education, and external rescue therapies. ZT-01 represents a different paradigm: restoring an endogenous defense mechanism rather than compensating for its failure. If confirmed, that would broaden the therapeutic architecture of hypoglycaemia prevention in type 1 diabetes.
At the same time, several caveats are essential. First, clamp studies are highly informative for physiology but do not directly predict real-world clinical benefit. An improved glucagon response under controlled insulin infusion does not automatically translate into fewer severe hypoglycaemic events during exercise, overnight periods, illness, or daily life. Second, the study population was selective: adults aged 18 to 65 years, BMI 18.5 to 27 kg/m2, and a single-site setting. Generalizability to children, older adults, people with obesity, or those with substantial hypoglycaemia unawareness remains unknown.
Third, this was a phase 1 study with a modest sample size. It establishes pharmacodynamic activity, not clinical efficacy. Fourth, the abstract does not report inferential statistics such as confidence intervals or between-treatment p values for the glucagon endpoints. That does not negate the signal, but it limits precision in estimating treatment effect size from the abstract alone. Finally, long-term consequences of recurrent SSTR2 antagonism are not yet known. A therapy intended to improve glucagon during hypoglycaemia must avoid raising glucose excessively at other times.
Clinical implications and next steps
For clinicians, the immediate takeaway is not that SSTR2 antagonists are ready for practice, but that a promising mechanistic strategy has now shown human proof-of-concept in long-standing type 1 diabetes. This is especially relevant because the loss of glucagon counterregulation is one of the most difficult features of advanced disease to address.
The next development steps are clear. Larger and longer trials should test whether ZT-01 or related agents reduce clinically meaningful outcomes such as time below range, symptomatic hypoglycaemia, level 3 hypoglycaemia, nocturnal events, and need for external rescue. Studies should also evaluate use alongside current standard technologies, including continuous glucose monitoring and hybrid closed-loop systems, since those settings reflect contemporary care.
Additional mechanistic questions also remain. It will be important to determine whether benefit is greatest in patients with absent glucagon responses at baseline, whether repeated dosing preserves efficacy or causes adaptation, and whether there are effects on hepatic glucose production sufficient to alter net glucose infusion requirements during clamps. If future trials demonstrate real-world protection without worsening glycaemic control, SSTR2 antagonism could emerge as an adjunctive therapy for high-risk individuals with recurrent hypoglycaemia.
Conclusion
This randomized crossover phase 1b study shows that the investigational SSTR2 antagonist ZT-01 can augment glucagon responses during insulin-induced hypoglycaemia in adults with long-standing type 1 diabetes. The findings are biologically coherent, clinically relevant, and encouraging from a safety perspective in the short term. While the study does not yet prove prevention of real-world hypoglycaemia, it provides strong support for continued clinical development of SSTR2 antagonism as a strategy to restore endogenous counterregulation.
Funding, trial registration, and citation
Trial registration: ClinicalTrials.gov NCT05007977.
Funding: Not reported in the abstract provided.
Citation: Abitbol A, Riddell MC, Peers S, Simonson E, Evans M, Knop FK, Liggins RT. Effect of somatostatin receptor 2 antagonism on glucagon counterregulation during a hyperinsulinaemic euglycaemic-hypoglycaemic glucose clamp in adult men and women with long-standing type 1 diabetes: a randomised crossover phase 1 study. Diabetologia. 2026-05-21. PMID: 42168649. URL: https://pubmed.ncbi.nlm.nih.gov/42168649/
