a-collection-of-novel-techniques-to-study-diabetes-and-obesity

A Collection Of Novel Techniques to Study Diabetes and Obesity

ARTICLES DISCUSSED:
McCarthy, E., Rowe, C. J., Crowley-Perry, M., Connaughton, V. P. Alternate immersion in glucose to produce prolonged hyperglycemia in ...

Marquette University

Alström syndrome (OMIM #203800) is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early-onset type 2 diabetes mellitus (T2DM). To investigate the underlying mechanisms of T2DM phenotypes, we generated a loss-of-function deletion of alms1 in the zebrafish. We demonstrate conservation of hallmark clinical characteristics alongside metabolic syndrome phenotypes, including a propensity for obesity and fatty livers, hyperinsulinemia and glucose response defects. Gene expression changes in β-cells isolated from alms1-/- mutants revealed changes consistent with insulin hypersecretion and glucose sensing failure, which were corroborated in cultured murine β-cells lacking Alms1. We also found evidence of defects in peripheral glucose uptake and concomitant hyperinsulinemia in the alms1-/- animals. We propose a model in which hyperinsulinemia is the primary and causative defect underlying generation of T2DM associated with alms1 deficiency. These observations support the alms1 loss-of-function zebrafish mutant as a monogenic model for mechanistic interrogation of T2DM phenotypes.

Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes.

A primary challenge in type 2 diabetes (T2D) is the preservation of a functional population of β-cells, which play a central role in regulating blood glucose levels. Two congenital disorders, Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS), can serve as useful models to understand how β-cells are normally produced and regenerated. Both are characterized by obesity, loss of β-cells, and defects in primary cilia - the sensory center of cells. Primary cilia are cellular protrusions present in almost every vertebrate cell. This antenna-like organelle plays a crucial role in regulating several signaling pathways that direct proper development, proliferation, and homeostasis. Mutations in genes expressing ciliary proteins or proteins present at or near the base of the cilium lead to disorders, collectively called ciliopathies. BBS and Alström syndrome are such disorders. Though both BBS and Alström patients are obese, their childhood diabetes rates are vastly different, suggesting distinct pathogenesis underlying these two ciliopathies. Clinical studies suggest that BBS patients are protected against early onset diabetes by sustained or enhanced β-cell function. In contrast, Alström patients are more prone to develop diabetes. They have hyperinsulinemia, yet their β-cells fail to sense glucose and to regulate insulin secretion accordingly. These data suggest a potential role for primary cilia in maintaining a functional β-cell population and that defects in cilia or in ciliary proteins impair development and function of β-cells. Identifying the respective roles of primary cilia and ciliary proteins, such as BBS and ALMS1 may shed light on β-cell biology and uncover potentially novel targets for diabetes therapy.

Primary Cilium, An Unsung Hero in Maintaining Functional β-cell Population.

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

Article	Year
Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes. Human molecular genetics\| PubMed ID: 31220269
Primary Cilium, An Unsung Hero in Maintaining Functional β-cell Population. The Yale journal of biology and medicine\| PubMed ID: 31543709
TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell. Metabolites\| PubMed ID: 34436454	2021

Sukanya Lodh

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