Handbook of Diabetes. Rudy Bilous

Chapter 5 Normal physiology of insulin secretion and action, and the incretin effect

       KEY POINTS

       Islets of Langerhans in the endocrine pancreas contain β (insulin‐producing) and α (glucagon‐producing) cells that regulate glucose homeostasis. Pancreatic β cells may change in size, number, and function during normal ageing and development.

       Insulin secretion is biphasic: an acute first phase response that lasts a few minutes followed by a more gradual sustained second phase. Glucose is the main stimulator of insulin secretion, but other hormones, nutrients and neurotransmitters play an important role in the regulation of insulin secretion.

       The so‐called incretin effect (meal‐stimulated augmentation of insulin secretion) is diminished in type 2 diabetes, mainly because of reduced GLP‐1 secretion. The discovery, characterisation and clinical development of glucagon‐like peptides has been a major success over the last 30 years.

       Insulin receptor signalling in key tissues (skeletal muscle, fat and liver) is complex, resulting in various biological effects of insulin on glucose, lipid and protein metabolism.

Islet structure and function

Insulin is synthesised in and secreted from the β cells within the islets of Langerhans in the pancreas. The normal pancreas has about 1 million islets, which are derived embryologically from endodermal outgrowths of the foetal gut. The islets can be identified easily with various histological stains with which the cells react less intensely than does the surrounding exocrine tissue (Figure 5.1). Pancreatic islets vary in size from having a few dozen to several thousands of cells and they are scattered irregularly throughout the exocrine pancreas.

The main cell types of the pancreatic islets are β‐cells that produce insulin, α‐cells that secrete glucagon, δ‐cells that produce somatostatin and PP‐cells that produce pancreatic polypeptide. Different islet cell types can be identified by various immunostaining techniques. β‐cells are the most numerous cell type and are located mainly in the core of the islet, while α and δ cells are located in the periphery (Figure 5.2).

Islet cells interact with each other through direct physical contact and through paracrine effects of their hormone products (e.g. glucagon stimulates insulin secretion and somatostatin inhibits insulin and glucagon secretion) (Figure 5.3). The blood flow within the islets is organised centrifugally so that the different cell types are supplied in the sequence β → α → δ. Insulin also has an ‘autocrine’ (self‐regulating) effect that alters the transcription of insulin and glucokinase genes in the β cell.

Figure 5.1 A section of normal pancreas stained with haematoxylin and eosin. As observed by Paul Langerhans, the islet in the centre is identified easily by its distinct morphology and lighter staining than that of the surrounding exocrine tissue (original magnification ×350).

Figure 5.2 The localisation of pancreatic hormones in human islets. (a) Insulin immunostained in the majority of cells that form the core of the islet (peroxidase–antiperoxidase immunostain with haematoxylin counterstain). (b) Insulin mRNA localised by in situ hybridization with a digoxigenin‐labelled sequence of rat insulin cRNA (which cross‐reacts fully with human insulin mRNA). (c) Peripherally located α cells immunostained with antibodies to pancreatic glucagon using the same method as for (a). (d) Weakly immunoreactive PP cells in the epithelium of a duct in the ventral portion of the pancreatic head. Magnifications approximately ×150.

Figure 5.3 Potential interactions between the secretory products of the major islet cell types. Black arrows indicate paracrine stimulation or inhibition. The direction of blood flow within the islet is indicated by the red arrows.

Pancreatic islets are densely innervated with autonomic and peptidergic nerve fibres (Figure 5.4). Parasympathetic innervation from the vagus stimulates insulin release, while adrenergic sympathetic nerves inhibit insulin and stimulate glucagon secretion. Other nerve fibres that supply the pancreas release peptides which also regulate pancreatic function, e.g vasoactive intestinal peptide (VIP) stimulates the release of all islet hormones and neuropeptide Y (NPY) inhibits insulin secretion. Neural pathways are important in the regulation of pancreatic function.

Pancreatic β‐cells may change in size, number, and function during normal aging and development (Figure 5.5). β cell mass is determined by the net effect of four independent mechanisms: (i) β cell replication (i.e. division of existing β cells), (ii) β cell size, (iii) β cell neogenesis (i.e. emergence of new β cells from pancreatic ductal epithelial cells), and (iv) β cell apoptosis. The contribution made by each of these processes is variable and may change at different stages of life.

Figure 5.4 Structure of a pancreatic islet, showing the anatomical relationships between the four major endocrine cell types. NPY, neuropeptide Y; VIP, vasoactive intestinal polypeptide.

Figure 5.5 A hypothetical model for postnatal pancreatic β cell growth in humans.

      Adapted from Rhodes et al. Science 2005; 307: 380–384.

Insulin synthesis and insulin polypeptide structure

Insulin consists of two polypeptide chains linked by disulphide bridges; the A‐chain contains 21 amino acids and the B‐chain contains 30 amino acids (Figure 5.6). In the circulation, insulin exists as a monomer of 6000 Da molecular weight. The tertiary (three‐dimensional) structure of