Intrinsic β cell circadian clocks are important regulators of insulin secretion and overall glucose homeostasis. Whether the circadian clock in β cells is perturbed following exposure to pro-diabetogenic stressors such as pro-inflammatory cytokines, and whether these perturbations are featured during the development of diabetes, remains unknown. To address this, we examined the effects of cytokine-mediated inflammation common to the pathophysiology of diabetes, on the physiological and molecular regulation of the β cell circadian clock. Specifically, we provide evidence that the key diabetogenic cytokine IL-1β disrupts functionality of the β cell circadian clock and impairs circadian regulation of glucose-stimulated insulin secretion. The deleterious effects of IL-1β on the circadian clock were attributed to impaired expression of key circadian transcription factor Bmal1, and its regulator, the NAD-dependent deacetylase, Sirtuin 1 (Sirt1). Moreover, we also identified that Type 2 diabetes in humans is associated with reduced immunoreactivity of β cell BMAL1 and SIRT1, suggestive of a potential causative link between islet inflammation, circadian clock disruption, and β cell failure. These data suggest that the circadian clock in β cells is perturbed following exposure to pro-inflammatory stressors and highlights the potential for therapeutic targeting of the circadian system for treatment β cell failure in diabetes.

Obesity is associated with several chronic comorbidities, one of which is type 2 diabetes mellitus (T2DM). The pathogenesis of obesity and T2DM is influenced by alterations in diet macronutrient composition, which regulate energy expenditure, metabolic function, glucose homeostasis, and pancreatic islet cell biology. Recent studies suggest that increased intake of dietary carbohydrates plays a previously underappreciated role in the promotion of obesity and consequent metabolic dysfunction. Thus, in this study, we utilized mouse models to test the hypothesis that dietary carbohydrates modulate energetic, metabolic, and islet adaptions to high-fat diets. To address this, we exposed C57BL/6J mice to 12 wk of 3 eucaloric high-fat diets (>60% calories from fat) with varying total carbohydrate (1–20%) and sucrose (0–20%) content. Our results show that severe restriction of dietary carbohydrates characteristic of ketogenic diets reduces body fat accumulation, enhances energy expenditure, and reduces prevailing glycemia and insulin resistance compared with carbohydrate-rich, high-fat diets. Moreover, severe restriction of dietary carbohydrates also results in functional, morphological, and molecular changes in pancreatic islets highlighted by restricted capacity for β-cell mass expansion and alterations in insulin secretory response. These studies support the hypothesis that low-carbohydrate/high-fat diets provide antiobesogenic benefits and suggest further evaluation of the effects of these diets on β-cell biology in humans.

SUMMARY Coordinated communication among pancreatic islet cells is necessary for maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β cell stress. We report that pro-inflammatory β cell small EVs (cytokine-exposed EVs [cytoEVs]) induce β cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8 + T cells and macrophages. Proteomic analysis of cytoEVs shows enrichment of the chemokine CXCL10, with surface topological analysis depicting CXCL10 as membrane bound on cytoEVs to facilitate direct binding to CXCR3 receptors on the surface of β cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. This work implies a significant role of pro-inflammatory β cell-derived small EVs in modulating β cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.

Time-restricted feeding improves glucose homeostasis through epigenetic control of pancreatic β cell function.

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