110: Rethinking Type 1 & Type 2 Diabetes: Glucagon’s Hidden Role, a Bi-Hormonal Theory w/ Dr. Bikman

Bikman describes that multiple glucagon receptor antagonist drugs have been developed and tested in human trials with promising results. Studies in type 1 diabetics demonstrate reductions in both fasting and postprandial glucose, decreased glucose variability, and lower ketone levels—all without changes in the insulin regimen. This directly supports Unger’s thesis that if you remove the glucagon signal, the diabetic phenotype resolves. Because the liver no longer receives the ‘make glucose’ command, the entire metabolic cascade—gluconeogenesis, glycogenolysis, ketone production—is dampened. Bikman predicts these agents could become first‑line add‑on therapies once approved, finally attacking the glucagon limb of the bi‑hormonal defect.

Bikman explains that somatostatin analogues are another avenue being explored. Although systemically suppressing both insulin and glucagon sounds counterproductive, the unique physiology of type 1 diabetes—where there is no endogenous insulin left to suppress—makes it a cleverly selective intervention. By dampening the alpha cells, these drugs could cut off the inappropriate glucagon signal that perpetuates hepatic glucose and ketone production, potentially smoothing glucose excursions and reducing ketoacidosis risk. He frames it as part of a multi‑target future where insulin replacement is partnered with one or more glucagon‑modulating agents.

Bikman notes growing interest in such systems and suggests they could be particularly valuable even in the context of islet or whole‑pancreas transplants, where native paracrine signaling may still be disrupted. By delivering glucagon on demand, the pump directly addresses one core problem: the absence of the alpha‑cell braking signal. While still an experimental technology, it embodies the bi‑hormonal principle that diabetes is a disorder of glucagon as much as insulin.

Bikman highlights that the original anti‑diabetic indication of GLP‑1 drugs was precisely due to this glucagon‑lowering effect. In type 1 diabetes, where the beta cells are absent, the insulin‑secreting effect is moot, leaving a clean, on‑target suppression of glucagon. He personally finds this avenue promising and is watching for clinical data. The approach aligns with Unger’s principle that if you take away glucagon action, you ameliorate diabetes—even if insulin is still missing.

Bikman explains the therapeutic paradox: people with type 1 diabetes typically need larger doses of insulin than would be expected from their size and carbohydrate intake. This is because they are not just replacing the insulin needed for glucose uptake by muscle and fat; they must also fight the glucose being poured out by the liver under glucagon’s command. The constant tug‑of‑war between injected insulin and un–checked glucagon creates the glucose variability that patients experience. Recognizing this mechanism allows clinicians and patients to understand why higher insulin doses are necessary and why perfect control remains elusive, reinforcing the need for glucagon‑targeting therapies.

Bikman builds on Roger Unger’s six-decade career, starting with the 1959 demonstration that glucagon is a major glucose-regulating hormone opposing insulin. Unger proposed that diabetes is a ‘bi-hormonal’ disease: too little insulin and, critically, too much glucagon. He showed that hyperglucagonemia is present in every form of diabetes and is responsible for hepatic glucose overproduction, ketogenesis, and some degree of protein wasting. In animal models, when glucagon action is blocked—by receptor antagonists or genetic knockout—all the metabolic derangements of diabetes resolve, even though insulin is still absent. This shifts the therapeutic target from insulin replacement alone to glucagon suppression. Clinical trials of glucagon receptor antagonists in type 1 patients have already shown reductions in fasting and postprandial glucose, less glucose variability, and lower ketone production without changing insulin regimens.

Bikman highlights Unger’s paper from about 10 years ago that demonstrated that alpha cells themselves can become resistant to insulin’s suppressive effect. In type 2 diabetes, the islets contain abundant beta cells pouring out insulin, yet the neighboring alpha cells do not ‘hear’ it and continue to secrete glucagon. This explains why many type 2 diabetics have inappropriately elevated glucagon despite high insulin and glucose levels—a state that further drives hepatic glucose output and worsens hyperglycemia. It reframes type 2 diabetes as a bi‑hormonal disorder as well and opens the door to glucagon‑lowering therapies (GLP‑1 agonists, glucagon receptor antagonists) in type 2 care.

Bikman expresses personal curiosity about emerging evidence for GLP‑1 agonists in type 1 diabetes. He points out that one of the original anti‑diabetic mechanisms of these drugs—before they were repurposed for weight loss—is suppression of glucagon. Because type 1 diabetics have no endogenous insulin, the insulinotropic effect of GLP‑1 is irrelevant, but glucagon suppression could be highly relevant. This could directly address the uncontrolled alpha cell activity that drives glucose variability and ketogenesis. He sees it as a ‘more on‑target’ use of the drug class than the popular obesity indication, and he anticipates clinical data in type 1 patients.