Revisiting the β-Cell: The Key to the Type 2 Diabetes Puzzle: The 2025 Banting Medal for Scientific Achievement Award Lecture

Major discoveries in the past have laid the foundation on which modern diabetes research has been built, and future findings can be anticipated. From this groundwork, we have pursued studies evaluating the role of β-cell function and β-cell mass in the pathogenesis of type 2 diabetes. In considering β-cell function, studies of β-cell responses to intravenous and oral glucose have highlighted the critical nature of interpreting these responses in the face of the prevailing insulin sensitivity, and not as isolated responses. The critical role of β-cell dysfunction in the pathogenesis of prediabetes and diabetes has become apparent. When prediabetes is present, β-cell function is reduced by 40%, while in recent-onset type 2 diabetes it is reduced by >80%. In youth with prediabetes and type 2 diabetes, β-cell function deteriorates at a faster rate than in adults, compatible with their disease being more aggressive. From clinical trials in both age groups, the progression of β-cell dysfunction over time is the basis for deteriorating glycemia, with none of the currently available glucose-lowering agents able to halt this inexorable decline. Reflecting on β-cell mass, this is clearly reduced in people with type 2 diabetes. One basis for this is islet amyloid, which is formed from the normal β-cell secretory peptide islet amyloid polypeptide (IAPP) (or amylin). The process of amyloid formation promotes oxidative stress, inflammation, and β-cell death, creating a destructive feed-forward that exacerbates disease progression. Experimental studies demonstrate that reducing amyloid formation reduces oxidative stress, inflammation, and the loss of β-cell mass. Ultimately, preserving β-cell function and mass is critical in striving to prevent and treat type 2 diabetes. Future tactics have to deviate from the current approaches if we are going to be successful in reducing the deleterious effects of a dysfunctional β-cell in type 2 diabetes.