The discovery of insulin changed the landscape of diabetes treatment and research. The name insulin(e)—which came from the Latin word “insula” with reference to a hypothetical molecule that was secreted by the Islets of Langerhans—was coined by Jean de Meyer and Edward Albert Sharpey-Schafer, before the isolation of the peptide hormone by Banting and Best. Since its discovery, much effort has been expanded in understanding the synthesis and release of insulin in health and disease in order to allow us to understand better its role in the regulation of blood glucose concentrations and through this understanding, to allow us to develop better treatment for diabetes. In this chapter, we will review published data on the regulation of insulin biosynthesis and release in rodent and human pancreatic β-cells and discuss how the concerted regulation of these processes contributes to systemic glucose homeostasis.
Type 1 diabetes (T1D) results from a progressive loss of islet beta cell function. It is now divided into three stages—Stage 1, when there are two or more islet cell antibodies but there is still normoglycemia; Stage 2, when there is also dysglycemia but not diabetes-range glycemia; and Stage 3, when there is diabetes-range glycemia and/or symptoms of diabetes. It is now possible to predict progression of disease to development of Stage 3. There are immune interventions being tested to either abort the progress to Stage 3 T1D or to preserve residual beta cell function in Stage 3. Treatment approaches now include automated insulin delivery guided by continuous glucose monitoring. There are ongoing studies of replacing beta cell function with islets derived from stem cells.
Insulin resistance—defined as a reduced biological action of insulin—is implicated in the etiopathogenesis and progression of a range of prevalent cardiometabolic disorders. In contract, syndromes of severe insulin resistance, which may be inherited or acquired, are rarely encountered by most clinicians. These syndromes have provided clinical investigators with valuable mechanistic insights into the more common disorders that are associated with impaired insulin action. This chapter reviews the concept of insulin resistance in human disease and considers the methods for quantifying insulin action in vivo. The range of recognized syndromes of severe insulin resistance is described. Shared features and unique aspects of these heterogeneous disorders are detailed together with an outline of approaches to management.
Aside from its classic metabolic actions, insulin has been reported to exert cellular effects on many tissues. In this review, we will focus on insulin’s physiological and pathophysiological actions on vascular cells, mainly in endothelial cells and vascular smooth muscle cells (VSMC), as well as their effects on atherogenesis, mitogenesis, restenosis, and blood flow. In vascular cells, insulin’s actions are mediated chiefly by two pathways: The insulin receptor substrate1/2 and phosphoinositide-3 kinase/Akt pathway and the Src/mitogen-activated protein kinase pathway. Insulin also exerts direct actions on the vessel wall, endothelial cells, VSMC, and the basement membrane, which are critical for the transporting of nutrients, cytokines, hormones, and other signaling molecules. Chronic upregulation or downregulation of these pathways can trigger a cascade of downstream cellular signals and ultimately contribute to the development of vascular complications in diabetes, making these pathways potential targets for future therapies.
This chapter provides an overview of the role of insulin resistance in human disease. The genetics and the pathophysiology of insulin action in the liver, fat, and muscle are discussed. In obesity and type 2 diabetes, the ability of insulin to suppress adipocyte lipolysis, hepatic gluconeogenesis, and glycogenolysis, whereas insulin-mediated stimulation of glucose uptake by skeletal muscle is reduced. The current data point to a functional defect in hepatic glucokinase activity as a key driver of hepatic insulin resistance. The role of glucagon in the regulation of glucose metabolism is also considered. These pathophysiological insights provide the basis for nonpharmacological and pharmacological therapeutic interventions.
