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From the triumvirate to the ominous octet and beyond, the pathophysiology of type 2 diabetes (T2D) has been progressively expanded to integrate an increasingly complex network of metabolic abnormalities.1 Nevertheless, despite these advances and the recognition of numerous additional contributors to dysglycemia, our conceptual framework for T2D in 2026 still rests on two fundamental defects: insulin resistance and progressive β-cell dysfunction. These abnormalities have shaped both our understanding of disease progression and the development of modern glucose-lowering therapies. Yet despite major advances in diabetes care, an important physiological question remains unresolved: why does glucagon secretion remain inappropriately elevated even in the presence of hyperglycemia and hyperinsulinemia?1The study by Chang and colleagues offers an important clue. In a cohort of 247 individuals with T2D undergoing oral glucose tolerance testing (OGTT), the authors demonstrated that hyperglucagonemia and impaired glucagon suppression were consistently associated with markers of insulin resistance, whereas indices of β-cell secretory capacity showed no comparable relationship. Most notably, mediation analyses suggested that impaired insulin secretion did not explain the association between insulin resistance and glucagon dysregulation. While these findings do not negate the contribution of β-cell dysfunction, they invite us to reconsider whether insulin resistance itself may be a major determinant of abnormal glucagon secretion in T2D (figure 1).Figure 1Is hyperglucagonemia a consequence of β-cell failure or a manifestation of α-cell insulin resistance? Conceptual comparison between the traditional β-cell-centric model of diabetic hyperglucagonemia and an emerging model in which impaired insulin signaling within the α-cell contributes directly to abnormal glucagon secretion. While reduced insulin secretion remains an important determinant of glucagon regulation, accumulating experimental and clinical evidence suggests that α-cell insulin resistance may represent an additional mechanism linking systemic insulin resistance to hyperglycemia.The notion that glucagon contributes to diabetic hyperglycemia is not new. For more than four decades, Unger proposed the bihormonal hypothesis, challenging the insulin-centric view of diabetes by proposing that excess glucagon action plays an equally important role in the development of hyperglycemia. However, subsequent research largely focused on β-cell biology, while the α-cell was pushed to the sidelines. Recent advances in islet physiology have renewed interest in glucagon and suggest that the α-cell may be more than a passive responder to β-cell dysfunction.1 2In fact, Kawamori and colleagues provided an elegant proof of principle. Using a conditional knockout of the insulin receptor in the pancreatic α-cells, they produced animals that developed hyperglucagonemia, impaired glucose tolerance, and exaggerated glucagon responses to physiologic stimuli. Perhaps most importantly, these abnormalities developed without major defects in peripheral insulin sensitivity, suggesting that impaired insulin signaling within the α-cell alone can significantly alter glucagon secretion. In many ways, this study laid the experimental foundation for the concept that the α-cell may itself be an insulin-resistant tissue.2These findings introduced a concept that remains underappreciated in clinical diabetology: insulin resistance may not be restricted to classical target tissues such as liver, skeletal muscle, and adipose tissue. The endocrine pancreas itself may also become insulin-resistant. In this context, α-cell dysfunction is another result of systemic insulin resistance, rather than a mere consequence of insufficient insulin secretion. The biology of the α-cell is considerably more complex than simply responding to glucose concentrations. Under basal conditions, glucagon secretion is continuously modulated by signals from neighboring β- and δ-cells. Insulin and somatostatin have local effects to prevent glucagon secretion from rising as glucose concentrations rise. But this intra-islet communication seems to be broken down in T2D. Omar-Hmeadi et al showed that paracrine regulation of glucagon exocytosis is impaired in human diabetic islets, highlighting the fact that α-cell dysfunction is more than an isolated secretory deficiency.3 This concept is also biologically plausible. Elliott and colleagues showed that insulin and somatostatin act together within the α-cell to suppress cyclic AMP signaling, an important mechanism limiting glucagon secretion. When responsiveness to either signal is impaired, glucagon release may persist under conditions in which it would normally be restrained.4Observations in humans point in the same direction. A recent systematic review and meta-analysis found that individuals with pre-diabetes exhibit impaired glucagon suppression during an OGTT despite rising glucose and insulin concentrations.5 This finding suggests that abnormalities in α-cell regulation may emerge well before the clinical diagnosis of T2D. In addition, Wagner et al demonstrated that abnormal glucagon responses during glucose challenges were associated with different metabolic phenotypes and may provide insight into future trajectories of glucose tolerance.6 More recently, Mohan et al showed that abnormal glucagon secretion is independently associated with progressive deterioration in glucose tolerance and contributes to worsening glycemic control over time.7Taken together, these observations suggest that glucagon dysregulation may not simply reflect advanced β-cell failure. Instead, α-cell dysfunction appears to evolve in parallel with insulin resistance throughout the natural history of dysglycemia.8 Importantly, the relationship between glucagon and insulin resistance may extend beyond the pancreatic islet. The emerging concept of the liver–α-cell axis proposes a bidirectional communication network linking hepatic amino acid metabolism with glucagon secretion. In this model, liver steatosis impairs glucagon-mediated amino acid turnover, resulting in hyperaminoacidemia and compensatory hyperglucagonemia.8In light of these experimental and clinical observations, the findings reported by Chang et al take on a broader significance. Rather than simply viewing hyperglucagonemia as a consequence of inadequate insulin secretion, their results suggest the possibility that it may represent another manifestation of insulin resistance itself. This view may help explain a long-standing paradox in T2D. Glucagon concentrations are often elevated despite substantial endogenous insulin secretion and, in some individuals, overt hyperinsulinemia. If the α-cell gradually loses its ability to respond to insulin, circulating insulin levels may no longer reflect the efficacy of intraislet insulin signaling. Under these circumstances, glucagon secretion may persist even when physiological conditions would be expected to suppress it.The therapeutic implications are difficult to ignore. For years, glucagon was viewed largely as a counterregulatory hormone, important during hypoglycemia but of limited relevance to everyday diabetes management. That perception has changed. Many of the most effective therapies currently available exert at least part of their benefit through pathways that influence glucagon secretion and α-cell function.1 9This raises an interesting possibility. Perhaps some of the success of modern incretin-based therapies reflects effects on the α-cell that we have not fully appreciated. Tirzepatide lowers fasting glucagon concentrations, and similar observations have been reported with retatrutide despite its glucagon receptor agonist activity.9 Whether these findings represent improved α-cell responsiveness, restoration of intraislet signaling, or simply a consequence of improved metabolic health remains uncertain. What seems increasingly clear, however, is that the α-cell is no longer merely a bystander in contemporary diabetes therapeutics.As expected, the study has some limitations. The cross-sectional design does not permit causality to be established, and OGTT-derived surrogate indices cannot directly quantify α-cell insulin sensitivity. Moreover, glucagon secretion is influenced by many factors other than insulin, including incretins, amino acids, autonomic inputs, and somatostatin signaling. Therefore, the precise mechanisms linking systemic insulin resistance to α-cell dysfunction require further investigation. Nevertheless, the study contributes to an important conceptual shift. For many years, diabetic hyperglucagonemia has been interpreted primarily as a consequence of inadequate β-cell-derived insulin signaling. The accumulating evidence now supports a broader model in which α-cell dysfunction develops as a parallel pathological process closely linked to insulin resistance and may precede advanced β-cell failure. The key question in T2D is no longer just how much insulin β-cells can produce. Equally important is whether α-cells can respond properly to insulin after production. Chang and colleagues suggest this deserves renewed focus. Understanding α-cell insulin resistance may be as crucial as understanding β-cell failure.