Aim of this research is to understand why endocrine ?-cells in the pancreas of diabetic patients fail, with an eye toward identifying new genetic, biochemical, and cellular pathways that can be exploited as therapeutic targets to prevent and reverse this disease process. This grant has supported several original and widely reproduced discoveries, identifying a homeostatic loop orchestrated by Foxo transcription factors that integrates disparate hormonal and nutrient signals into a gene expression program intended to preserve ?-cell function and identity. Signal achievements of this work have been the demonstration that ?-cell failure can be due to ?-cell dedifferentiation into an endocrine progenitor-like state, and their partial conversion into other pancreatic cell types. Since the last competing renewal, this grant has supported five major new findings: (i) metabolic inflexibility (i.e., a curtailment of the ability to transition from lipids to glucose as energy source) is a hallmark of early b-cell dysfunction; (ii) ?-cell mass is genetically programmed by the number of endocrine progenitor cells in the developing pancreas; (iii) increasing ?-cell mass does not necessarily improve function, as proliferating ?-cells display reduced insulin secretion; (iv) ?-cell dedifferentiation, initially described in experimental animals models of diabetes, occurs also in humans with type 2 diabetes; and finally (v) identification of aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) as a marker of failing murine and human ?-cells that allows the pursuit of genes involved in the transition from a metabolically inflexible to a dedifferentiated ?-cell. The PI proposes to extend this work with the following specific aims:
In Aim 1, to develop mouse models of ALDH1A3 gain- and loss-of-function and test whether ALDH1A3 affects ?-cell mitochondrial function or differentiation, and to investigate the different patterns of ALDH1A3 expression in human and rodent islets using single-cell transcriptome analyses.
In Aim 2, the PI identified cytochrome b5 reductase isoform 3 (Cyb5r3), as a candidate contributor to ?-cell failure. Cyb5r3 is involved in mitochondrial function and FA synthesis. In this aim, they will test the involvement of Cyb5r3 in ?-cell dysfunction by developing mouse models of loss-of-function. In addition, they will address the role of Cyb5r3 in ?-cell mitochondrial respiration and fatty acid synthesis.
In Aim 3 the PI shows, using genome-wide histone acetylation analyses, that Foxo ablation in ?-cells results in an enrichment of active enhancers containing Hnf4a motifs, indicating a mechanistic relationship between these two transcription factors. Using a newly developed in vivo reporter of real-time Foxo1 activity, they will combine epigenetic and cell biological analyses to understand how Foxo cooperate with other important ?-cell transcription factors, starting with Hnf4a, with the goal of identifying shared pathways mediating ?-cell failure.
?-cell dysfunction is a key factor in the progression of type 2 diabetes, as well as an unmet treatment need. Studies supported by this grant have led to a reassessment of mechanisms of ?-cell failure, and suggested novel alternative approaches to its treatment. Key advances in the last cycle, including the prevention of ?-cell dedifferentiation, the concept of metabolic inflexibility as an early stage of ?-cell failure, and the identification of markers of failing ?-cells, offer hope that the disease can be reversed and prompt a strategic reassessment of drug discovery.
|Accili, Domenico (2018) Insulin Action Research and the Future of Diabetes Treatment: The 2017 Banting Medal for Scientific Achievement Lecture. Diabetes 67:1701-1709|
|Haeusler, Rebecca A; McGraw, Timothy E; Accili, Domenico (2018) Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 19:31-44|
|Kitamoto, Takumi; Sakurai, Kenichi; Lee, Eun Young et al. (2018) Distinct roles of systemic and local actions of insulin on pancreatic ?-cells. Metabolism 82:100-110|
|Langlet, Fanny; Haeusler, Rebecca A; Lindén, Daniel et al. (2017) Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling. Cell 171:824-835.e18|
|Ishida, Emi; Kim-Muller, Ja Young; Accili, Domenico (2017) Pair Feeding, but Not Insulin, Phloridzin, or Rosiglitazone Treatment, Curtails Markers of ?-Cell Dedifferentiation in db/db Mice. Diabetes 66:2092-2101|
|Kim-Muller, Ja Young; Fan, Jason; Kim, Young Jung R et al. (2016) Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic ? cells in diabetic mice. Nat Commun 7:12631|
|Kim-Muller, Ja Young; Kim, Young Jung R; Fan, Jason et al. (2016) FoxO1 Deacetylation Decreases Fatty Acid Oxidation in ?-Cells and Sustains Insulin Secretion in Diabetes. J Biol Chem 291:10162-72|
|Cinti, Francesca; Bouchi, Ryotaro; Kim-Muller, Ja Young et al. (2016) Evidence of ?-Cell Dedifferentiation in Human Type 2 Diabetes. J Clin Endocrinol Metab 101:1044-54|
|Accili, D; Talchai, S C; Kim-Muller, J Y et al. (2016) When ?-cells fail: lessons from dedifferentiation. Diabetes Obes Metab 18 Suppl 1:117-22|
|Kuo, Taiyi; Kim-Muller, Ja Young; McGraw, Timothy E et al. (2016) Altered Plasma Profile of Antioxidant Proteins as an Early Correlate of Pancreatic ? Cell Dysfunction. J Biol Chem 291:9648-56|
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