Single cell technologies permit interrogation of the molecular underpinnings of heterogeneity, addressing two fundamental questions: Do functionally distinct subpopulations of β-cells exist? Can accounting for heterogeneity improve diabetic therapy? Several research groups have proposed subpopulations based on clustering analysis using single cell RNA sequencing (scRNA-seq), however, there is little agreement among studies 12– 15. ![]() Improving endogenous β-cell function in diabetes is complicated by cellular heterogeneity, because individual β-cells vary significantly in function, gene expression, protein level, and stress response 11. This requires understanding how and why β-cells become dysfunctional in obesity. There is urgent need for therapies that improve endogenous β-cell function. Differentiating induced pluripotent stem cells into insulin secreting cells may alleviate this bottleneck, but current methods fail to recapitulate fine-tuned glucose sensing and insulin secretion in vivo 9, 10. Currently, transplantation of cadaveric islets is the only method for restoring β-cell mass in diabetes but is severely limited by donor availability and requires lifelong immunosuppressant therapy 7, 8. Without sufficient β-cell mass and insulin production, sustained hyperglycemia increases risk for deadly metabolic diseases 4– 6. Obesity initially promotes β-cell expansion, but prolonged glycemic stress and inflammation drive β-cell death and dysfunction, resulting in type 2 diabetes 1– 3. Proper insulin secretion from pancreatic β-cells is required to maintain glycemic control. In sum, this study uses a novel data integration method to explore how β-cells respond to obesity and glycemic stress, helping to define the relationship between β-cell heterogeneity and diabetes, and shedding light on novel genetic pathways with therapeutic potential. We identify subtype-specific expression of Pdyn and Fam151a as candidate regulators of genetic pathways associated with β-cell function in obesity. Network analysis identifies fatty acid metabolism and β-cell physiology gene expression modules associated with the hyperglycemic-obese state. Relative proportions of these cells are influenced by age, sex, and diet. We identify 4 β-cell subpopulations associated with insulin secretion, hypoxia response, cell polarity, and stress response. Previous studies have shown that high-fat fed SM/J mice resolve glycemic dysfunction between 20 and 30wks. Here, we integrate pancreatic islet single-cell and bulk RNA sequencing data to identify β-cell subpopulations based on gene expression and characterize genetic networks associated with β-cell function in high- and low-fat fed male and female SM/J mice at 20 and 30wks of age. Standard single-cell RNA sequencing analysis illuminates some genetic underpinnings driving heterogeneity, but new strategies are required to capture information lost due to technical limitations. Whereas with the Miracell system, the bacteria are able to receive the necessary air naturally through the atmosphere.īy design Miracell has the ability to decrease its capacity in times of lower flow rates via bypassing unused compartments and routing wastewater to the last modular unit to conserve energy costs.Īnother important feature is the ability to increase capacity by simply adding disks or modular compartments.Understanding how heterogeneous β-cell function and stress response impact diabetic etiology is imperative for therapy development. With conventional activated sludge systems a constant flow of air needs to be pumped through aerators by blowers in order to stimulate bacterial growth. The Miracell which operates on the RBC principle has many advantages over other package wastewater treatment systems that operate on the activated sludge principle. These organisms receive the necessary oxygen from the air during the rotation of the disks, consume the pollutants existing in the wastewater and convert them to carbon dioxide and water in a totally natural way. ![]() As a result of this repetitive process, organisms accumulate on the disks in the course of time. The disks which first submerge in the wastewater are then contacted with air. The system is designed such that 40% of the disks remain submerged in the wastewater. ![]() Miracell is a fully automatic Rotating Biological Contactor (RBC) wastewater treatment systemĪ unique feature allows the disks connected to a shaft to rotate at a very low speed by means of a motor which is equipped with a reduction gear.
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