Research Article: High-fat diet impacts more changes in beta-cell compared to alpha-cell transcriptome

Date Published: March 8, 2019

Publisher: Public Library of Science

Author(s): Rodolphe Dusaulcy, Sandra Handgraaf, Florian Visentin, Cedric Howald, Emmanouil T. Dermitzakis, Jacques Philippe, Yvan Gosmain, David A. Buchner.


Characterization of endocrine-cell functions and associated molecular signatures in diabetes is crucial to better understand why and by which mechanisms alpha and beta cells cause and perpetuate metabolic abnormalities. The now recognized role of glucagon in diabetes control is a major incentive to have a better understanding of dysfunctional alpha cells. To characterize molecular alterations of alpha cells in diabetes, we analyzed alpha-cell transcriptome from control and diabetic mice using diet-induced obesity model. To this aim, we quantified the expression levels of total mRNAs from sorted alpha and beta cells of low-fat and high-fat diet-treated mice through RNAseq experiments, using a transgenic mouse strain allowing collections of pancreatic alpha- and beta-cells after 16 weeks of diet. We now report that pancreatic alpha cells from obese hyperglycemic mice displayed minor variations of their transcriptome compared to controls. Depending on analyses, we identified 11 to 39 differentially expressed genes including non-alpha cell markers mainly due to minor cell contamination during purification process. From these analyses, we identified three new target genes altered in diabetic alpha cells and potently involved in cellular stress and exocytosis (Upk3a, Adcy1 and Dpp6). By contrast, analysis of the beta-cell transcriptome from control and diabetic mice revealed major alterations of specific genes coding for proteins involved in proliferation and secretion. We conclude that alpha cell transcriptome is less reactive to HFD diet compared to beta cells and display adaptations to cellular stress and exocytosis.

Partial Text

Obesity is associated with insulin resistance and an increased type 2 diabetes (T2D) risk [1]. When insulin resistance is accompanied by dysfunction of pancreatic islet cells, hyperglycemia results [2]. The disrupted coordination of glucagon and insulin secretion observed in type 2 diabetes is characterized by impaired and delayed insulin secretion as well as basal hyperglucagonemia and non-suppressed glucagon secretion in response to glucose [3, 4]. A large number of studies have examined the consequences of diabetes on pancreatic islets using different animal models among them diet-induced obese mice (DIO) [5]. High-fat diet (HFD) fed mice exhibit impaired glucose tolerance and insulin resistance leading to hyperglycemia, hyperinsulinemia and dysregulated glucagon secretion [6]. Glucagon, produced by pancreatic alpha-cells, shows dysregulated secretion in both type 1 and type 2 diabetes and contributes to hyperglycemia [3, 7–10]. The consequences of increased glucagon during fasting and unsuppressed glucagon secretion in response to meals are an increased rate of hepatic glucose production contributing to hyperglycemia.

Characterization of endocrine-cell functions and their transcriptomes in diabetes is critical to better understand how and by which mechanisms alpha and beta cells may dysfunction.




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