Abstract. The insulin gene is expressed exclusively in the beta cells of the islet of Langerhans. The release of this polypeptide hormone into the bloodstream, ...
2. Transcriptional Regulation of Insulin Gene Expression Isabella Artner and Roland Stein
Summary. The insulin gene is expressed exclusively in the beta cells of the islet of Langerhans. The release of this polypeptide hormone into the bloodstream, principally in response to elevated glucose levels, is essential for controlling carbohydrate metabolism in peripheral tissues. A fundamental cause of diabetes, a disease that affects millions of people and is a major cause of morbidity and mortality, is the inability of beta cells to produce sufficient amounts of insulin, resulting in hyperglycemia. A large effort is underway to identify and characterize the transcriptional regulators of genes, like insulin, that are important in islet beta cell function. It is hoped that this knowledge will provide information into how beta cell function is disrupted in type 2 diabetic individuals, and to provide a foundation for cell-based therapies that may be effective in diabetes treatment. Many of the cis-acting sequences, essential in directing both selective and glucose-inducible transcription within the 5′-flanking region of the insulin gene, have been defined and several of the key trans-activators isolated, including PAX-6, PDX-1, MafA, and BETA2/NeuroD1. In addition, the inactivation of genes encoding these regulatory proteins in mice has established that most play a role in islet cell differentiation during pancreas development. In this review, the regulatory role of the islet-enriched transcription factors of the insulin gene will be discussed, with a focus on their role in adult beta cell function.
Introduction Insulin is a powerful regulator of metabolism. This hormone, which is produced by the beta cells of the endocrine pancreas, increases the storage of glucose, fatty acids, and amino acids by its actions on liver, adipose tissue, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 723 Light Hall, Nashville, TN 37232, USA
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and muscle. The endocrine pancreas is comprised of discrete cellular islands (termed the islets of Langerhans), which are dispersed throughout the larger mass of the exocrine pancreas. The islets of rodents are mainly composed of beta cells, but at their periphery contain four other endocrine cell types, alpha, delta, epsilon, and pancreatic polypeptide (PP) that synthesize the hormones glucagon, somatostatin, ghrelin, and PP, respectively. The primary regulator of insulin expression in pancreatic beta cells is the concentration of blood glucose. The phosphorylation of glucose by glucokinase, which exhibits a high Km for glucose, appears to function as the glucose sensor by adjusting the metabolic flux through glycolysis to the extracellular glucose concentration [1]. Glucose metabolism in beta cells generates intracellular signals which stimulate insulin secretion, insulin mRNA translation, and insulin gene transcription (reviewed in [2]). Diabetes mellitus, the primary human disease affecting the endocrine pancreas, results either from the autoimmune destruction of beta cells (type 1 diabetes) or from defects in the production of insulin and/or sensing of this hormone by peripheral tissues (type 2 diabetes). Because of reduced insulin action, blood glucose levels remain elevated and cause early morbidity and mortality. Despite insulin’s availability and advances in bioengineering that have led to improved technologies for insulin administration, the available systems incompletely mimic the beta cell’s ability to sense and reduce circulating glucose levels sufficiently to prevent the severe complications associated with the disease, which predominately targets the kidney, vasculature, and eye. Type 2 is the most common form of diabetes mellitus and largely afflicts middle-aged individuals. Genetic studies suggest a major genetic component, but few susceptibility genes have been identified [3], except in maturity onset diabetes of the young (MODY). MODY, an autosomal dominant form of type 2 diabetes, is characterized by early-onset (usually
