Zucara Therapeutics’ ZT-01 shows promise in phase 1 trials by enhancing glucagon response during hypoglycaemia, potentially offering a new approach to managing low blood sugar episodes in type 1 diabetics without increasing overall glucose levels.
Type 1 diabetes carries a built-in glucagon problem: the hormone that should help defend against falling glucose often fails when it is needed most, yet may stay too active when it is not. That imbalance is why Zucara Therapeutics’ ZT-01 has attracted attention. In a recent Diabettech analysis of the company’s phase 1 work, the drug was presented as a selective somatostatin receptor 2 antagonist designed to lift the normal brake on pancreatic alpha cells so they can release more glucagon as glucose falls.
The idea rests on a simple but important biological point. In healthy islets, insulin, somatostatin and other local signals help suppress glucagon when glucose is rising, particularly after a meal. In type 1 diabetes, the loss of beta cells disrupts that local control system, and alpha cells can become poorly matched to the surrounding metabolic state. A 2026 tracer study cited by Diabettech found that people with type 1 diabetes had higher early post-meal glucagon appearance than those without diabetes, suggesting that excessive glucagon after food may contribute to post-meal glucose excursions as well as low-glucose vulnerability.
Zucara’s phase 1 clamp study suggests ZT-01 can restore part of the lost low-glucose response. According to the published trial, glucagon responsiveness improved during experimentally induced hypoglycaemia, and counterregulatory events became more frequent with the active drug than with placebo. But the same experiment also showed a transient glucagon rise during euglycaemia, along with a modest increase in glucose and a higher intravenous insulin infusion rate needed to keep the clamp on target. That does not prove a problem in everyday use, but it does underline the central question: can the drug improve protection against lows without creating a new glucose burden when levels are already normal?
The broader history of glucagon research supports that concern. Earlier human studies with somatostatin showed that suppressing glucagon could reduce glucose production and even blunt diabetic ketoacidosis in tightly controlled experimental settings, although those studies were small, short and used systemic somatostatin rather than a selective receptor blocker. More recent work has taken the opposite approach: a phase 2 trial of the glucagon-receptor antibody volagidemab in adults with type 1 diabetes missed its main endpoint for insulin reduction, although it did lower HbA1c modestly and raised safety questions including changes in liver enzymes, LDL cholesterol and blood pressure. Taken together, those findings suggest glucagon signalling matters, but they do not yet settle how best to manipulate it in routine care.
That is where ZT-01’s next clinical test becomes important. Zucara’s ongoing phase 2 ZONE study is designed to see whether the drug can reduce nocturnal hypoglycaemia in adults with type 1 diabetes. The most relevant read-outs will not be limited to time spent below range; they will also need to show what happens to mean glucose, variability, insulin use and rescue carbohydrate. If the treatment lowers overnight lows without pushing glucose up at other times, it could offer a useful new way to strengthen counterregulation. If not, the glucagon timing problem in type 1 diabetes may remain unresolved, merely shifted from one metabolic context to another.
Disclaimer: This content is for informational purposes only and is not intended to be a substitute for professional medical judgment, advice, diagnosis, or treatment.
