**1. Introduction**

Beta cells are dynamic and respond to fluctuating demands for insulin. Inflammation contributes to the pathogenesis and is an underlying mechanism of several metabolic diseases. Developmental programming (hereafter programming) through a nutritional insult, such as maintenance on a high-fat diet (HFD) during fetal and early neonatal life, alters growth and developmental trajectories at the organ (e.g., pancreas), micro-organ (e.g., islets), and cellular (e.g., beta cell) levels that trigger the pathogenesis of metabolic diseases. In beta cells, high-fat programming (i.e., maintenance on a diet of ≥40% mainly saturated fat as energy during critical developmental windows) induces beta cell hypoplasia and hypotrophy (altered beta cell structure) that diminishes beta cell function (altered beta cell physiology) evident by impaired glucose-stimulated insulin secretion (GSIS) resulting in insu fficient insulin release that results in and exacerbates hyperglycemia, as demonstrated in neonatal, weanling, and adult progeny [1–9]. High-fat programming also induces an altered metabolism of the substrates. For example, non-esterified fatty acids (NEFA) derived from fat metabolism have di fferent profiles in circulation and organs that are dependent on the timing and duration of programming [10,11]. Chronic hyperglycemia contributes to further deterioration of beta cell function and to worsening insulin resistance, reflecting glucotoxicity. Chronic exposure to elevated circulating saturated fatty acids through high-fat programming induces lipotoxicity that similarly contributes to diminishing beta cell integrity and physiology and insulin resistance. Gluco- and lipo-toxicity typically co-exist as glucolipotoxicity. This article describes programming, glucolipotoxicity, and islet inflammation that precede and provoke beta cell inflammation and discusses their impact on beta cell physiology and dysfunction in the pathogenesis of diabetes.

## **2. Islet Inflammation**

Macrophages are integral for inducing islet inflammation. In diabetes, intra-islet macrophage hyperplasia is the primary source of intra-islet proinflammatory cytokines [12]. Proinflammatory M1 macrophages produce and secrete interleukin 1 beta (IL1β), interleukin 6 (IL6), and tumor necrosis factor alpha (TNFα) to trigger inflammation [13], with IL1β central in islet inflammation, initiation and amplification [12]. In islets (in vitro and in vivo), M1 macrophages are the source of IL1β [12,14] and modulate beta cells' adaptive (i.e., compensatory) response to impaired function [15], characterized by beta cell dysfunction and failure. Physiologically, resident macrophages and cytokines maintain homeostasis in beta cell development and function [16]. However, metabolic diseases are often associated with chronic systemic inflammation [16] with islet and subsequent beta cell inflammation intrinsically linked to diabetes. In islet inflammation (insulitis), proinflammatory macrophage hyperplasia concomitant with elevated cytokine and chemokine concentrations contribute to impaired islet and beta cell function [16].

#### **3. Programming and Islet Inflammation**

Programming refers to a stimulus or insult during critical developmental transitions that induces alterations in offspring anatomy, physiology, and metabolism that may be transient or durable, and sometimes reversible. Nutrition, through a HFD, is one way to initiate programming. Pregnant HFD-fed C57/BL6J mice were obese with increased adiposity but not overtly diabetic [17]. However, a maternal HFD during gestation and lactation induced hepatic steatosis, adipose tissue inflammation, insulin resistance, and glucose intolerance [17]. In the islets of male progeny, there was increased oxidative stress concomitant with insulin resistance and worsening beta cell dysfunction after maintenance on a HFD from conception to weaning [17]. In pancreata from juvenile Japanese macaques (Macaca fuscata) maintained on a HFD during fetal life until to 13 months of age (high fat programmed primates), there was an increase in IL6 gene expression that correlated with a blunted first-phase insulin response reflecting early beta cell dysfunction [18]. In male progeny, there was increased pancreatic IL1β gene expression and fasting glucose concentrations [18]. Furthermore, in the juvenile primate pancreas, there was islet-associated macrophage hyperplasia concomitant with an increase in proinflammatory mediators that demonstrated that innate immune infiltration occurs prior to overt obesity or glucose dysregulation [18]. These metabolic derangements manifested prior to glucose dysregulation, revealing early events in the pathogenesis of diabetes.

In non-obese diabetic mice exposed to hyperglycemia in utero, the protective compensatory factor in response to islet stress, regenerating islet-derived protein 3 gamma (Reg3g), was decreased with a high fold change [19,20] that was deleterious for postnatal islet formation and/or maturation, thereby diminishing islet cell viability and function [21]. Furthermore, many upregulated genes were associated with pathways of inflammation and cell death [21]. As systemic inflammation was absent in progeny, the enhanced inflammation did not primarily induce islet dysfunction [21]. However, the increase in the inflammatory pathway enriched transcriptome in progeny exposed to hyperglycemia during late gestation was stimulated by greater islet cell susceptibility to death [21]. Programming with hyperglycemia therefore prompts beta cell stress, death, and inflammation. Thus, beta cell inflammation is a strong inducer of beta cell death, dysfunction, and failure, and is a predictor for developing diabetes.

Obesity is associated with immune cell hyperplasia [22–28] and inflammation. In humans and rodents with obese pregnancies, various cytokines and chemokines were elevated viz. IL1β, IL6, IL10, TNF, interferon gamma (IFNγ) and monocyte chemoattractant protein 1 (MCP1/CCL2) [29–32], and obesity-associated maternal cytokines likely access the fetus via the placenta [33,34]. Further, maternal inflammation can initiate placental inflammation [35–38]; thus, the placenta is integral for conferring maternal obesity pathology to the fetus [39]. Therefore, obesity especially during pregnancy (maternal obesity) presents a major risk for progeny, as undesirable metabolic sequelae associated with obesity such as inflammation and hyperglycemia are conferred to progeny by their mothers.

This snapshot of the influence of programming through a HFD, hyperglycemia, and maternal obesity (often due to progeny exposed to a glucolipotoxic milieu during critical developmental phases) reveals the metabolic derangements that programming confers to progeny, e.g., hepatic steatosis, inflammation (adipose tissue, placenta and islets, and immune cell hyperplasia), insulin resistance, glucose intolerance, oxidative stress, and diminished islet and beta cell viability and function.
