The Pancreas And Insulin Secretion
A 21-year-old male student, HB, was referred to the Diabetic Clinic of his local hospital. He had been feeling unwell for about 4 weeks, noticing a marked increase in thirst, passage of large volumes of urine both during the day and at night. He felt generally tired and unwell and had lost about 6 kg in weight over the preceding month. Physical examination was normal. A diagnosis of Type 1 diabetes was made on the basis of a random blood glucose of 25 mmol/L and the presence of glucose and ketones in the urine. HB was started on insulin therapy and subsequently managed with a ‘basal-bolus’ regimen, taking an injection of short-acting insulin 30 minutes before meals and intermediate-acting insulin at bedtime. His symptoms improved over the next few weeks and he attended the clinic for dietary advice and education about testing his own blood glucose, managing hypoglycaemic attacks and monitoring for complications.
Type 1 diabetes is an autoimmune condition causing destruction of the pancreatic β cells (see below). Treatment of Type 1 DM is with insulin, administered as subcutaneous injections by the patient. Therapy is tailored to the individual patient and is commonly given as biphasic insulin containing short and intermediate acting insulins and administered twice daily or as a ‘basal-bolus’ regimen with intermediate insulin given at bedtime supplemented by short-acting insulin before meals. Patients monitor their blood glucose concentrations using capillary blood glucose testing strips and a portable glucometer.
Glycated haemoglobin reflects diabetic control over a period of weeks to months, reflecting erythrocyte lifespan (120 days) and is used to assess glycaemic control in patients with diabetes. The most commonly reported fraction is haemoglobin A1c (HbA1c), which is increased in diabetes by covalent bonding of glucose. The rate of formation of HbA1c is directly proportional to blood glucose concentrations.
The pancreas lies closely adjacent to the duodenum (Fig. 38a) and consists of two major tissue types, namely the acini, which secrete digestive juices into the duodenum, and the islets of Langerhans, which secrete insulin and glucagon directly into the bloodstream, and are therefore truly endocrine. The human pancreas has between 1 and 2 million islets, each organized around small capillaries into which the hormones are secreted. The islet cells can be distinguished into four types: α, β, δ (also called A, B and D) and F (Fig. 38b). The β cells, which constitute about 60% of the islet cells, lie towards the middle of the islet and secrete insulin. The α cells secrete glucagon and the δ cells secrete somatostatin. The other cell type, the F cell, secretes pancreatic polypeptide. A physiological role for pan- creatic polypeptide has not yet been identified with certainty.
In humans, the gene coding for insulin is located on the short arm of chromosome 11. Insulin is secreted by the β cells of the islets of Langerhans. It is a protein consisting of two chains, an A-chain of 21 amino acids, and a B-chain of 30 amino acids, linked by two disulphide bridges (A7B7 and A20B19; Fig. 38c). Another disulphide bridge links A6A11 on the A-chain. Insulin can exist as a monomer (molecular weight of 6 kDa), the form in which it predominantly circulates. It can dimerize to form a dimer of molecular weight of 12 kDa, and three dimers can aggregate in the presence of two zinc atoms to form a hexamer of molecular weight 36 kDa.
Biosynthesis. Insulin is cleaved from proinsulin. Proinsulin is derived from a larger precursor, preproinsulin, which is synthesized in the rough endoplasmic reticulum. Proinsulin is a continuous chain which starts at the N-terminal end of the B-chain and terminates at the C-terminal end of the A-chain. A connecting peptide (C-peptide; Fig. 38c) is interposed between the C-terminal end of the B-chain and the N-terminal end of the A-chain. In the Golgi apparatus and the storage granules, a converting enzyme cleaves proinsulin to yield insulin.
Secretion of insulin. Insulin synthesis and secretion is stimulated by glucose (Fig. 38d), which stimulates the β cell to take up extracellular calcium (Ca2+). The cation appears to trigger a contractile mechanism, whereby the microtubules participate in the movement of insulin-containing granules towards the cell membrane, where granules fuse and the granule contents are released into the extracellular space by exocytosis. Insulin secretion in response to a sudden rise in circulating glucose occurs in a biphasic fashion: there is an immediate release of stored insulin, lasting less than a minute, followed by a more sustained release of both stored and newly synthesized insulin. A great many other substances stimulate insulin release, but not all elicit a biphasic release pattern. Carbohydrates, most amino acids and, to a lesser extent, fatty acids and ketones, all stimulate insulin release. Although a number of gut hormones can stimu- late insulin release, the physiological significance of this, if any, is unknown. Glucagon, which is synthesized in the pancreatic α cells, stimulates insulin release by direct action on the β cells. Insulin release is also affected by the nervous system and by neurotransmitters. Acetylcholine stimulates insulin release, as does epinephrine, acting on β-receptors. Stimulation of α- receptors, on the other hand, causes an inhibition of insulin release. Stimulation of different areas of the hypothalamus in experimental animals has different effects on insulin release. For example electrical stimulation of the ventrolateral region stimulates insulin release, while electrical stimulation of the ventromedial region inhibits insulin release. The basal secretion of insulin is also affected by neurotransmitters. Drugs which block adrenergic α-receptors increase basal insulin tone, while drugs which block β-receptors reduce basal insulin tone.
Insulin metabolism. Insulin circulates as a monomer, unbound to plasma proteins. It is filtered by the glomeruli, but is almost completely reabsorbed in the proximal tubules, and is degraded by the kidneys. The liver removes half the hepatic portal insulin that passes through it. The half-life of insulin in plasma is about 5 minutes. Proinsulin, which is also released with insulin, has a longer half-life (about 20 minutes). Proinsulin is not cleaved to insulin in the plasma. Although the liver and kidneys are the major sites of insulin degradation, virtually all the tissues of the body can break down the hormone. Insulin can be degraded extracellularly, and also intracellularly, after it has bound to its receptor and become internalized in the cell.