Abstract
Stimuli or insults during critical developmental transitions induce alterations in progeny anatomy, physiology, and metabolism that may be transient, sometimes reversible, but often durable, which defines programming. Glucolipotoxicity is the combined, synergistic, deleterious effect of simultaneously elevated glucose (chronic hyperglycemia) and saturated fatty acids (derived from high-fat diet overconsumption and subsequent metabolism) that are harmful to organs, micro-organs, and cells. Glucolipotoxicity induces beta cell death, dysfunction, and failure through endoplasmic reticulum and oxidative stress and inflammation. In beta cells, the misfolding of pro/insulin proteins beyond the cellular threshold triggers the unfolded protein response and endoplasmic reticulum stress. Consequentially there is incomplete and inadequate pro/insulin biosynthesis and impaired insulin secretion. Cellular stress triggers cellular inflammation, where immune cells migrate to, infiltrate, and amplify in beta cells, leading to beta cell inflammation. Endoplasmic reticulum stress reciprocally induces beta cell inflammation, whereas beta cell inflammation can self-activate and further exacerbate its inflammation. These metabolic sequelae reflect the vicious cycle of beta cell stress and inflammation in the pathophysiology of diabetes.
Highlights
Beta cells are dynamic and respond to fluctuating demands for insulin
Obesity especially during pregnancy 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 high-fat diet (HFD), hyperglycemia, and maternal obesity reveals the metabolic derangements that programming confers to progeny, e.g., hepatic steatosis, inflammation, insulin resistance, glucose intolerance, oxidative stress, and diminished islet and beta cell viability and function
Summary
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. High-fat programming induces an altered metabolism of the substrates. Chronic exposure to elevated circulating saturated fatty acids through high-fat programming induces lipotoxicity that contributes to diminishing beta cell integrity and physiology and insulin resistance. 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
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