Dietary carbohydrates modulate metabolic and ß-cell adaptation to high-fat diet-induced obesity.

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 ß-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 ß-cell biology in humans.

Circadian Disruption across Lifespan Impairs Glucose Homeostasis and Insulin Sensitivity in Adult Mice.

Circadian rhythm disruption is associated with impaired glucose homeostasis and type 2 diabetes. For example, night shift work is associated with an increased risk of gestational diabetes. However, the effects of chronic circadian disruption since early life on adult metabolic health trajectory remain unknown. Here, using the "Short Day" (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was used to disrupt mouse circadian rhythms across the lifespan, we investigated glucose homeostasis in adult mice. Adult SD mice were fully entrained into the 8 h/8 h LD cycle, and control mice were entrained into the 12 h/12 h LD cycle. Under a normal chow diet, female and male SD mice displayed a normal body weight trajectory. However, female but not male SD mice under a normal chow diet displayed glucose intolerance and insulin resistance, which are associated with impaired insulin signaling/AKT in the skeletal muscle and liver. Under high-fat diet (HFD) challenges, male but not female SD mice demonstrated increased body weight gain compared to controls. Both male and female SD mice developed glucose intolerance under HFD. Taken together, these results demonstrate that environmental disruption of circadian rhythms contributes to obesity in a sexually dimorphic manner but increases the risk of glucose intolerance and insulin resistance in both males and females.

Pro-inflammatory ß cell small extracellular vesicles induce ß cell failure through activation of the CXCL10/CXCR3 axis in diabetes.

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 ß cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to ß cell stress. We report that pro-inflammatory ß cell small EVs (cytokine-exposed EVs [cytoEVs]) induce ß 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 ß cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated ß cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. This work implies a significant role of pro-inflammatory ß cell-derived small EVs in modulating ß cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.

Time-restricted feeding prevents deleterious metabolic effects of circadian disruption through epigenetic control of ß cell function.

Circadian rhythm disruption (CD) is associated with impaired glucose homeostasis and type 2 diabetes mellitus (T2DM). While the link between CD and T2DM remains unclear, there is accumulating evidence that disruption of fasting/feeding cycles mediates metabolic dysfunction. Here, we used an approach encompassing analysis of behavioral, physiological, transcriptomic, and epigenomic effects of CD and consequences of restoring fasting/feeding cycles through time-restricted feeding (tRF) in mice. Results show that CD perturbs glucose homeostasis through disruption of pancreatic ß cell function and loss of circadian transcriptional and epigenetic identity. In contrast, restoration of fasting/feeding cycle prevented CD-mediated dysfunction by reestablishing circadian regulation of glucose tolerance, ß cell function, transcriptional profile, and reestablishment of proline and acidic amino acid­rich basic leucine zipper (PAR bZIP) transcription factor DBP expression/activity. This study provides mechanistic insights into circadian regulation of ß cell function and corresponding beneficial effects of tRF in prevention of T2DM.

Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic ß cell function in type 2 diabetes.

Pancreatic ß cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the ß cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in ß cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM ß cells contributes to ß cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in ß cells of patients with T2DM and demonstrated that its expression was associated with loss of ß cell transcriptional identity, intracellular alkalinization, and ß cell dysfunction. In addition, we generated a ß cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and ß cell dysfunction. Importantly, improved glucose tolerance and enhanced ß cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating ß cell identity and function. These results suggest that increased ß cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of ß cell failure and should be considered as a potential therapeutic target.