**1. Introduction**

An analysis of the National Health and Nutrition Examination Survey database revealed that the crude prevalence of prediabetes and diabetes in the US exceeds 50% [1]. Cardiovascular consequences, including stroke, myocardial infarction, and mortality, increase even as blood glucose rises in the prediabetic phase [2]. Type 2 diabetes (T2D) has been increasing in incidence in the USA in a manner that has tracked closely with the increasing prevalence of abdominal obesity [3]. Notably, across the spectrum from obesity to T2D, insulin resistance appears to be a common feature, and as such, insulin-producing islet β cells are considered central determinants in the transition from normoglycemia to dysglycemia. The gradual or sudden failure to secrete sufficient insulin heralds rising glucose levels [4]. Precisely how and why β cells fail have been the subjects of intense investigation in recent years. One point of view posits that the increased demand for insulin secretion in the setting of insulin resistance overwhelms the capacity of β cells to produce insulin, largely as a result of the incapacity of the endoplasmic reticulum to accommodate protein throughput [5]. Another perspective suggests that excessive circulating proinflammatory cytokines or free fatty acids trigger intracellular signaling cascades that lead to β-cell inflammation, oxidative stress, and possibly cell death [6]. Finally, recent data have suggested the provocative hypothesis that secretory failure and apoptosis may only represent minor components, and the dedifferentiation of β cells to a precursor-like state effectively leads to reduced functional β-cell mass [7]. Regardless of the primary pathology, a better understanding of the molecular processes occurring in the β cell during early obesity and dysglycemia might permit targeted therapeutic interventions that allow for disease modification.

With the advent of single-cell RNA sequencing (sc-RNAseq) technologies [8], important new insights have been emerging about the nature of cells in the pancreatic islet. For example, it was shown that α cells and β cells of the adult human islet exist in multiple subpopulations, and some of those from adults with T2D exhibit features similar to those of children, supporting the dedifferentiation hypothesis [9]. Data of this sort both illuminate the potential to extract information that would be masked using bulk sequencing strategies and emphasize the heterogeneity that exists within the islet endocrine cell pool and how specific populations might have broader implications for emerging metabolic phenotypes in an organism. In light of these and other findings, in this study, we asked if alterations in islet cell gene expression patterns occur in the earliest phases of obesity and dysglycemia in a mouse model of evolving obesity and specifically how these changes might have the ability to portend future functional alterations that give rise to overt T2D. Our data show that early changes in β-cell gene expression reflect an ability of distinct β-cell populations to respond to the metabolic challenges during high-fat-diet (HFD) feeding.
