Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential; understanding the mechanisms that underlie this functional heterogeneity might make it possible to develop new regenerative approaches. Here we show that Fltp (also known as Flattop and Cfap126), a Wnt/planar cell polarity (PCP) effector and reporter gene acts as a marker gene that subdivides endocrine cells into two subpopulations and distinguishes proliferation-competent from mature β-cells with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that endocrine subpopulations from Fltp-negative and -positive lineages react differently to physiological and pathological changes. The expression of Fltp increases when endocrine cells cluster together to form polarized and mature 3D islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger β-cell maturation. By contrast, the Wnt/PCP effector Fltp is not necessary for β-cell development, proliferation or maturation. We conclude that 3D architecture and Wnt/PCP signalling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a marker for endocrine subpopulations sheds light on the molecular underpinnings of islet cell heterogeneity and plasticity and might enable targeting of endocrine subpopulations for the regeneration of functional β-cell mass in diabetic patients.

Emerging insulin resistance is normally compensated by increased insulin production of pancreatic β-cells, thereby maintaining normoglycemia. However, it is unclear whether this is achieved by adaptation of β-cell function, mass, or both. Most importantly, it is still unknown which of these adaptive mechanisms fail when type 2 diabetes develops. We performed longitudinal in vivo imaging of β-cell calcium dynamics and islet mass of transplanted islets of Langerhans throughout diet-induced progression from normal glucose homeostasis, through compensation of insulin resistance, to prediabetes. The results show that compensation of insulin resistance is predominated by alterations of β-cell function, while islet mass only gradually expands. Hereby, functional adaptation is mediated by increased calcium efficacy, which involves Epac signaling. Prior to prediabetes, β-cell function displays decreased stimulated calcium dynamics, whereas islet mass continues to increase through prediabetes onset. Thus, our data reveal a predominant role of islet function with distinct contributions of triggering and amplifying pathway in the in vivo processes preceding diabetes onset. These findings support protection and recovery of β-cell function as primary goals for prevention and treatment of diabetes and provide insight into potential therapeutic targets.