Jing W. Hughes

In the pancreatic islet, serotonin (5-HT) functions basally to modulate glucagon secretion, but its contribution to beta-cell signaling and function remains unclear. Here, we demonstrate that the Gs-coupled serotonin receptor 6 (5-HT6), previously thought to be expressed almost exclusively in the brain, localizes to the primary cilium and plasma membrane of islet cells and augments insulin secretion. Utilizing a transgenic model of beta-cell cilia loss, along with approaches to perturb cilia-specific 5-HT6 function without disrupting the native cilium architecture, we show that 5-HT6 action in beta cells is dependent on the primary cilium. Critically, the plasma membrane pool of 5-HT6 cannot stimulate insulin release when the cilium is absent, representing an instance of whole-cell regulation by a cilia-localized GPCR. These findings establish subcellular localization as a determinant of GPCR function in beta cells and identify ciliary 5-HT6 signaling as a distinct pathway for modulating insulin secretion.

Pancreatic β-cells couple nutrient and hormone sensing to insulin release. Prevailing models depict the β-cell as a homogeneous metabolic unit, overlooking specialized subcellular compartments like the primary cilium. Primary cilia are sensory organelles that function as critical signaling hubs in pancreatic β-cells. Disrupting primary cilia causes diabetes, but the underlying mechanisms remain unclear. In this review, we critically assess evidence supporting the cilium’s role in β-cells, including functional studies that implicate cilia in the control of cytosolic Ca ²⁺ dynamics and exocytosis, molecular studies that identify key hormone receptors on β-cell cilia, and genetic data linking cilia gene perturbations with diabetes in humans and rodents. We argue that the evidence for an acute function in stimulus-secretion coupling is insufficient and outline the missing links required to define the cilium’s precise signaling role, focusing on how it might detect glucose and hormonal inputs, generate an outgoing signal, and relay this information to the cell body to control insulin secretion. Resolving these questions will not only clarify a fundamental aspect of β-cell biology but may reveal principles of subcellular signaling relevant to physiology and disease in other organ systems.

Pancreatic islets maintain glucose homeostasis through the coordinated secretion of hormones and, notably, neurotransmitters. While islet innervation has long been recognized as essential for development and function, the source of these neuromodulators is variable and so is their signaling. Islet α and β cells express a broad repertoire of receptors for neurotransmitters such as acetylcholine, glutamate, GABA, and catecholamines. Emerging evidence reveals an additional layer of regulatory complexity, as a subset of these receptors localize to the primary cilium, a sensory organelle that functions as a specialized signaling hub. Disruption of primary cilia on β cells impairs glucose homeostasis in mice, and human ciliopathies commonly feature metabolic dysfunction. In this review, we synthesize recent findings on neurotransmitter signaling within the islet, with a focus on pathways that converge on the primary cilium. We discuss how compartmentalized signaling via cilia-enriched receptors represents a new dimension of islet cell regulation and offer a perspective on how targeting these ciliary pathways may provide future research directions for modulating α- and β-cell function in diabetes.

Primary cilia are antenna-like sensory and signaling organelles present on most mammalian cells, including glucose-sensing pancreatic β-cells. Here, we show that the local energetic demands of primary cilia require the ATP-producing enzyme pyruvate kinase, with loss of PKm1, but not PKm2, impairing ciliary glycolytic flux. While the entire glycolytic machinery localizes to cilia, our data indicate that mitochondria are a critical source of phosphoenolpyruvate (PEP), the high-energy glycolytic intermediate that drives the pyruvate kinase reaction. Abolishing PCK2, the mitochondrial enzyme that generates PEP, prevents cilia from sensing not only glucose but also the amino acids glutamine and leucine. Finally, by mislocalizing glycolysis, we demonstrate that primary cilia can utilize ATP generated within the cell body when glucose is limiting. These findings indicate that primary cilia, while possessing the capacity for local ATP generation, leverage a ciliary-mitochondrial signaling axis to meet their bioenergetic needs.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are mainstay therapies for diabetes and obesity, acting in part by enhancing glucose-dependent insulin secretion. While the primary cilium is a known signaling compartment for certain G-protein coupled receptors (GPCRs), its role in the β-cell response to incretins remains undefined. Here, we show that primary cilia are essential for GLP-1R signaling. Loss of β-cell cilia in mouse and human islets severely impaired GLP-1-potentiated insulin secretion, an effect preceded by blunted whole-cell cAMP and Ca²⁺ responses. Immunofluorescence and immunogold scanning electron microscopy revealed endogenous GLP-1R localized to the primary cilium. Critically, disrupting ciliary GPCR trafficking via Tulp3 knockdown – while preserving cilia structure – recapitulated the signaling and secretory deficits, demonstrating a specific requirement for the ciliary receptor pool. These findings establish the primary cilium as a non-redundant signaling compartment for GLP-1R and uncover a new layer of subcellular organization in incretin action in β cells.

Lee J, et al. J Korean Med Sci. 2025 Dec;41:e44. https://doi.org/10.3346/jkms.2026.41.e44

Recent advances in genome-wide approaches, the availability of isolated human islets for research and the evaluation of novel incretin mimetics in large clinical trials have brought about remarkable progress in our understanding of the role of the pancreatic beta cell in type 2 diabetes. Here, we review key developments in type 2 diabetes initiation, progression and remission, focusing mostly on human studies published in the last 5 years. Progress in multi-omics technologies has enabled researchers to identify links between type 2 diabetes risk variants and gene regulatory networks in islet endocrine cells that control beta cell development, function and stress resilience. These studies support the notion that early abnormalities in insulin secretion, rather than a reduction in beta cell mass, play a fundamental and primary role in early type 2 diabetes pathogenesis. Contributing to these intrinsic beta cell defects are various pathogenic signals from other (endocrine and non-endocrine) islet cells, the exocrine pancreas, the gut and insulin-sensitive tissues. It has also become apparent that beta cells comprise a heterogeneous population that responds differently to stress situations and that sex-related differences in beta cell responses should not be underestimated. Finally, human clinical trials have clearly demonstrated that diabetes remission can be achieved using glucose-lowering therapies and particularly strategies focused on weight loss, including bariatric surgery and, more recently, the use of highly efficient new drugs targeting the incretin system. While progress in the last 5 years has been significant, much remains to be uncovered to bring these advances to the clinic and thereby alleviate the dramatic consequences of type 2 diabetes complications for the hundreds of millions of people who live with this disease. Graphical Abstract

Primary cilia are essential sensory organelles whose structural complexity has challenged detailed imaging analysis. Ultrastructure expansion microscopy (U‐ExM) offers a promising approach by physically enlarging specimens in hydrogels, enabling nanoscale protein mapping. Here, we apply U‐ExM to pancreatic islet cilia and demonstrate the conserved presence of all four axonemal dynein subtypes, including prominent localization of the intermediate chain DNAI1 in both primary cilia and centrioles. These findings suggest that U‐ExM is a robust tool for ciliary studies and provide evidence that primary cilia may possess motor capabilities that could reshape our understanding of their function.