Islet anatomy

A typical mammalian islet comprises ~1000 endocrine cells including the insulin- expressing β cells (~60% of adult human islet cells), glucagon- expressing α cells (20–30%), somatostatin- expressing δ cells (~10%), and cells expressing pancreatic polypeptide (<5%) ), ghrelin, and peptide YY (<1%). The anatomical arrangement of islet cells varies between species. In rodents, the majority β- cell population forms a central core surrounded by a mantle of α and δ cells (Figure 1a), but human islets show less well- defined organization, with α and δ cells also being located throughout the islet (Figure1b). Advances in high- throughput functional and molecular phenotyping have demonstrated that human islets show considerable molecular, anatomical, and functional heterogeneity, which may be important in the islet dysfunction associated with the development of type 2 diabetes.

Fig1. Anatomy of the islet of Langerhans. (a) Mouse islet. The image shows a section through a mouse pancreas in which insulin and glucagon are identified by red and green immunofluorescence, respectively, demonstrating the typical β- cell core surrounded by a thin mantle of α cells. In mouse islets, β cells comprise ~80% of the endocrine cell mass. Scale bar is 10 μm. (b) Human islet. The image shows a section through a human pancreas in which insulin and glucagon are identified by red and green immunofluorescence, respectively, demonstrating the less organized structure of the human islet when compared with mouse islets. In human islets, β cells comprise ~50–60% of the endocrine cell mass. Scale bar is 10 μm. (c) Transmission electron micrograph of human islet cells. The image shows a transmission electron micrograph of several cells within a human islet. The two cells at the top with the electron- dense secretory granules surrounded by a clear halo are β cells. The cells in the lower part of the micrograph are α cells. Scale bar is 2 μm. Source: Authors’ unpublished data.

Islets are highly vascularized and receive up to 15% of the pancreatic blood supply, despite accounting for only 2–3% of the total pancreatic mass. Each islet is served by an arteriolar blood supply that penetrates the mantle to form a capillary bed in the islet core. Earlier studies using vascular casts of rodent islets suggested that the major route of blood flow through an islet was from the inner β cells to the outer α and δ cells, but later studies using optical imaging of fluorescent markers to follow islet blood flow in vivo revealed more complex patterns of both inner- to- outer and top- to- bottom blood flow through the rodent islet. Imaging studies in human islets suggest that most β cells are in direct contact with capillaries and are structurally polarized to target insulin secretion towards the capillary bed.

Islets are well supplied by autonomic nerve fibres and terminals containing the classic neurotransmitters acetylcholine and norepinephrine, along with a variety of biologically active neuropeptides. Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase- activating polypeptide (PACAP) are localized with acetylcholine to parasympathetic nerves, where they may be involved in mediating prandial insulin secretion and the α- cell response to hypoglycaemia. Other neuropeptides, such as galanin and neuropeptide Y (NPY), are found with norepinephrine in sympathetic nerves, where they may have a role in the sympathetic inhibition of insulin secretion, although there are marked inter- species differences in the expression of these neuropeptides.

Intra- islet interactions

The anatomical organization of the islet has a profound influence on the ability of the β cells to recognize and respond to physiological signals, and numerous studies have demonstrated important roles for islet α cells and δ cells in the regulation of human β- cell function. Islet cells have the potential to communicate through several mechanisms, although their relative importance is still uncertain. Islet cells are functionally coupled through a network of gap junctions, and gene deletion studies in mice have highlighted the importance of gap- junctional coupling via connexin 36 in the regulation of insulin secretory responses. Cell- to- cell con tact through cell- surface adhesion molecules in localized micro- domains offers an alternative communication mechanism [16], and interactions mediated by E- cadherin or ephrins have been implicated in the regulation of β- cell function. Components of the intra- islet extracellular matrix, which is predominantly synthesized by islet endothelial cells and pericytes [20], influence β- cell gene expression , proliferation, survival, and function via inter actions with integrins on the β- cell surface. A further important level of control is exerted via numerous intra- islet paracrine and autocrine effects in which a biologically active substance released by one islet cell can influence the functional status of a neighbouring cell (paracrine), or of itself (autocrine). Figure.2 shows some of the molecules that have been implicated in this type of intra- islet cell–cell communication. Thus, islet cells can interact with each other via the classic islet hormones: insulin, glucagon, and somatostatin; via other products secreted by the endocrine cells, including neurotransmitters, peptides such as kisspeptin, glucagon- like peptide 1 (GLP- 1), and urocortin3 (Ucn3), and adenine nucleotides and divalent cations that are co- released with insulin ; and via other less well- known mechanisms, including the generation of gaseous signals such as nitric oxide and carbon monoxide. This plethora of potential intra- islet interactions may reflect the requirement for coordinating the secretory responses of many individual islet cells to generate the rate and pattern of hormone secretion appropriate to the prevailing physiological conditions. However, much of the experimental evidence is derived from isolated islets in vitro, which, lacking a microcirculation, may not be an appropriate model for the in vivo situation.

Fig2. Intra- islet autocrine–paracrine interactions. The heterogeneous nature and complex anatomy of the islet permit numerous interactions between islet cells that are mediated by the release of biologically active molecules.

Insulin biosynthesis and storage

The ability to release insulin rapidly in response to metabolic demand, coupled with the relatively slow process of producing poly peptide hormones, means that β cells are highly specialized for the production and storage of insulin, to the extent that insulin comprises ~10% (~10 pg/cell) of the total β- cell protein.

Biosynthesis of insulin

In humans, the gene encoding pre- proinsulin, the precursor of insulin, is located on the short arm of chromosome 11. It is 1355 base pairs in length and its coding region comprises three exons: the first encodes the signal peptide at the N- terminus of pre- proinsulin, the second the B- chain and part of the C- (connecting)- peptide, and the third the rest of the C- peptide and the A- chain (Figure 3). Transcription and splicing to remove the sequences encoded by the introns yield a messenger RNA of 600 nucleotides, translation of which gives rise to pre- proinsulin, an 11.5- kDa poly peptide. The cellular processes and approximate timescales involved in insulin biosynthesis, processing, and storage are summarized in Figure 4.

Fig3. Structure of the human insulin gene. The coding region of the human insulin (INS) gene comprises three exons, which encode the signal peptide (SP), B- chain, C- peptide, and A- chain. The exons are separated by two introns (In1 and In2). Beyond the 5′ untranslated region (5′UT), upstream of the coding sequence, lies a hypervariable region in which three alleles (classes I, II, and III) can be distinguished by their size. IGF- II, insulin- like growth factor II; PTH, parathyroid hormone.

Fig4. The intracellular pathways of proinsulin biosynthesis, processing, and storage. The molecular folding of the proinsulin molecule, its conversion to insulin, and the subsequent arrangement of the insulin hexamers into a regular pattern are shown on the left. The time course of the various processes and the organelles involved are also shown.

Pre- proinsulin is rapidly ( <1 minute) discharged into the cisternal space of the rough endoplasmic reticulum, where proteolytic enzymes immediately cleave the signal peptide, generating proinsulin. Proinsulin is a 9- kDa peptide, containing the A- and B- chains of insulin (21 and 30 amino acid residues, respectively) joined by the C- peptide (30–35 amino acids). The structural con formations of proinsulin and insulin are very similar, and a major function of the C- peptide is to align the disulfide bridges that link the A- and B- chains so that the molecule is correctly folded for cleavage (Figure 5). Proinsulin is transported in microvesicles to the Golgi apparatus, where it is packaged into membrane- bound vesicles known as secretory granules. The conversion of proinsulin to insulin is initiated in the Golgi complex and continues within the maturing secretory granule through the sequential action of two endopeptidases (prohormone convertases 2 and 3) and carboxy peptidase H , which remove the C- peptide chain, liberating two cleavage dipeptides and finally yielding insulin (Figure 5). Insulin and C- peptide are stored together in the secretory granules and are ultimately released in equimolar amounts by a process of regulated exocytosis. Under normal conditions, >95% of the secreted product is insulin (and C- peptide) and < 5% is released as proinsulin. However, the secretion of incompletely processed insulin precursors (proinsulin and its split products; Figure 5) is increased in some individuals with type 2 diabetes.

Fig5. Insulin biosynthesis and processing. Proinsulin is cleaved on the C- terminal side of two dipeptides, namely Arg³¹- Arg³² (by prohormone convertase 3) and Lys⁶⁴- Arg⁶⁵ (prohormone convertase 2). The cleavage dipeptides are liberated, so yielding the ‘split’ proinsulin products and ultimately insulin and C- peptide.

The β cell responds to increases in the circulating concentrations of nutrients by increasing insulin production in addition to increasing insulin secretion, thus maintaining insulin stores. Acute (<2 hours) increases in the extracellular concentration of glucose and other nutrients result in a rapid and dramatic increase in the transcription of pre- proinsulin mRNA and in the rate of proinsulin synthesis. There is a sigmoidal relationship between glucose concentrations and biosynthetic activity, with a threshold glucose level of 2–4 mmol/l. This is slightly lower than the threshold for the stimulation of insulin secretion (~5 mmol/l), which ensures an adequate reserve of insulin within β cells.

Storage and release of insulin

The insulin secretory granule has a typical appearance in electron micrographs, with a wide space between the crystalline electron- opaque core and its limiting membrane (Figure 1c). The major protein constituents of the granules are insulin and C- peptide, which account for ~80% of granule protein, with numerous minor components including peptidases, peptide hormones, and a variety of (potentially) biologically active peptides of uncertain function. Insulin secretory granules also contain high concentrations of divalent cations, such as zinc (~20 mmol/l), which is important in the crystallization and stabilization of insulin within the granule. Zinc is transported into the insulin secretory granules by the islet- specific zinc transporter ZnT8, where it binds to insulin to form a crystalline lattice of insoluble hexamers. Polymorphisms in the SLC30A8 gene encoding ZnT8, in which a single nucleotide polymorphism (SNP) generates a ZnT8 variant with lower Zn2+ transporting activity, are associated with increased risk of type 2 diabetes. However, deletion of SLC30A8 in a number of transgenic mouse models produces only modest effects on insulin storage and secretion, and on whole- body glucose homeostasis, so the mechanistic link between SLC30A8 polymorphisms and type 2 diabetes risk remains unclear. The intragranular functions of calcium (~120 mmol/l) and magnesium (~70 mmol/l) are uncertain, but they are co- released with insulin on exocytosis of the secretory granule contents, so they may have extracellular signalling roles via the cell- surface calcium- sensing receptor. Similarly, the adenine nucleotides found in insulin secretory gran ules (~10 mmol/l) may have a signalling role when they are released into the extracellular space.

The generation of physiologically appropriate insulin secretory responses requires complex mechanisms for moving secretory granules from their storage sites within the cell to the specialized sites for exocytosis on the inner surface of the plasma membrane, and the role of cytoskeletal elements, notably microtubules and microfilaments, in the intracellular translocation of insulin storage granules has been studied extensively. Microtubules are formed by the polymerization of tubulin subunits and normally form a network radiating outwards from the perinuclear region. The microtubular network is in a process of continual remodelling and the dynamic turnover of tubulin, rather than the total number of microtubules, is an important regulator of insulin secretion. Recent studies have implicated the microtubule- associated protein tau as a key player in the glucose- induced remodelling of β- cell microtubules, and hence insulin secretion.

The microtubule framework may provide the pathway for the secretory granules, but microtubules do not provide the motive force so other contractile proteins are likely to be involved. Actin is the constituent protein of microfilaments and exists in cells as a globular form of 43 kDa and as a filamentous form (F- actin), which associates to form microfilaments. F- actin remodelling in β cells is regulated by agents that alter rates of insulin secretion, and the pharmacological disruption of microfilament formation inhibits insulin secretion. Myosin light and heavy chains are expressed at high concentrations in β cells, suggesting that actin and myosin may interact to propel granules along the microtubular network, and a myosin- and Rab- interacting protein (MyRIP) has been implicated in cyclic adenosine monophosphate (cAMP)– dependent insulin secretion through interaction with the motor protein MyoVa . It is likely that other molecular motors, including myosin 5a, kinesins, and dynein, are also involved in the movement of secretory granules, and perhaps other organelles, in β cells.

Insulin is released from secretory granules by exocytosis, a process in which the granule membrane and plasma membrane fuse together, releasing the granule contents into the interstitial space. Much of our knowledge of the molecular mechanisms of exocytosis is derived from studies of neurotransmitter release from nerve cells, and similar mechanisms operate in β cells, although some proteins implicated in synaptic vesicle exocytosis are not required for release of β- cell secretory granules. The docking of the granules at the inner surface of the plasma membrane is via the formation of a multimeric complex of proteins known as the SNARE (soluble N- ethylmaleimide- sensitive factor attachment protein receptor) complex, which comprises proteins associated with secretory granules and the plasma membrane, and soluble fusion proteins. The docked granules will fuse with the membrane and release their contents only in the presence of elevated intracellular calcium levels, which are sensed by synaptotagmins, a class of calcium- binding granule proteins . Secretory granules are distributed throughout the β- cell cytoplasm (Figure 1c), and it is likely that the transport of granules from distant sites to the plasma membrane is regulated independently from the final secretory process, with a reservoir of pre- docked granules available at the inner surface of the plasma membrane. Fusion of this readily releasable pool of granules may account for the rapid first- phase release of insulin in response to glucose stimulation, and direct electrophysiological measurements have demonstrated that the β- cell exocytotic response comprises a short- lived first phase with a very rapid rate of granule exocytosis from the readily releasable pool, followed by a sustained second phase with a slower rate of exocytosis, from a reserve pool. A key role for the regulatory protein Munc18c in the β- cell secretory granule fusion complex was identified in experiments where its knockdown in human β cells led to significant reductions in exocytosis of granules of both the readily releasable and reserve pools.

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مواضيع ذات صلة

Glucagon actions in the liver: amino acid metabolism and the hepatic–α- cell axis

Glucagon actions in the liver: glucose and lipid metabolism

Regulation of α- cell secretion

Regulation of insulin secretion by non- nutrients

Regulation of insulin secretion

الجلوكاجون Glucagon

هرمون الانسولين

المرض السكري (Diabetes Mellitus)

الغدة البنكرياسيةThe Pancreas