The human pancreas is an unpaired gland of the alimentary tract with mixed endocrine-exocrine function. It is composed of four functionally different, but interrelated components, the exocrine tissue, the ducts, the endocrine cells and the connective tissue (Islam et al., 2010). The pancreas has 2 functions, firstly to secrete molecules into the intestine to facilitate digestion and secondly the peptides secreted by its islet cells signal to other organs involved in metabolism (Suckale and Solimena, 2008).
The human pancreas is a retroperitoneal organ of the upper abdomen that, on average weighs in the range of 100 - 150 g and measures 15 - 25 cm in length. Anatomically the pancreas is connected with the other abdominal organs including the spleen, stomach, duodenum and colon. Structurally, the pancreas is divided into head, body, neck and tail. The head region of the pancreas is relatively flat and suited within the first loop of the duodenum. The tail region is in close vicinity to the hilum of the spleen, the only part of the pancreas that contains the pancreatic polypeptide (PP) cells (Islam et al., 2010). The body region of the pancreas has a shape that resembles a prism page 3 (Leung, 2010). The pancreas is composed of small lobules measuring 1 - 10 mm in diameter and microscopically, the lobules are formed by a mixture of ductules and well-vascularised epithelial cell clusters that reflect the two main functions of the pancreas, digestion and glucose homeostasis (Islam et al., 2010). Structurally, the head lies in the C - curve of the duodenum, to which it is firmly adherent, and sends out the small uncinate process, which hooks posterior to the superior mesenteric vessels as these travels from behind the pancreas into the root of the mesentery. Posteriorly, lie the inferior vena cava, the commencement of the portal vein, aorta, superior mesenteric vessels, the crura of diaphragm, coeliac plexus, the left kidney and suprarenal gland. The tortuous splenic artery runs along the upper border of the pancreas. The splenic vein runs behind the gland, receives the inferior mesenteric vein and joins the superior mesenteric to form the portal vein behind the pancreatic duct. Blood is supplied to the pancreas from the splenic artery, and the superior and inferior pancreaticoduodenal arteries; the corresponding veins drain into the portal system (Harold, 2007).
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Figure 1: Frontal view of the pancreas. The head of the pancreas is tucked into the curvature of the duodenum, overlapping somewhat both in front and behind. The main pancreatic duct (MPD) comes to lie to the left of the common bile duct (CBD) in the head. The right hepatic duct (RHD) and left hepatic duct (LHD) unite after exiting from the liver to form the common hepatic duct (CHD), which in turn unites with the cystic duct (CD) to form the common bile duct, which is transmitted towards the pancreas and duodenum through the lesser omentum. An extension of the head, the uncinate process, is extended behind the emerging superior mesenteric vein and artery (SMV A). APD, Accessory pancreatic duct. Adapted from (Go et al., 1993)
The exocrine pancreas:
The enzyme - secreting units in the exocrine pancreas are traditionally referred to as acini composed of epithelial cells bordering a common luminal space (Go et al., 1993). About 80 % of the pancreas is dedicated to produce and deliver digestive enzymes and hydrogen carbonate (HCO3-). Hydrogen carbonate is a basic chemical which neutralise the hydrochloric acid (HCl) produced in the stomach. Digestive proteases, nucleases, and lipases are synthesised by the acinar cells of the pancreas to break down nutrients (Suckale and Solimena, 2008). Pancreatic acinar cells secrete three major categories of digestive enzymes, α - amylase, lipase and protease which are responsible for the hydrolysis of carbohydrates, fats and proteins respectively (Leung and Ip, 2006). Most pancreatic zymogens are synthesised in their catalytically inactive form by ribosomes on the endoplasmic reticulum from where they are inserted into the ER lumen and translocate to the Golgi network. Here they segregate into condensing vacuoles and thereafter remain confined within membrane bound cellular compartments. Mature secretory granules of exocrine pancreatic acinar cells are exclusively found at the cellular apex. Under physiological conditions the content of the zymogen granules is secreted following secretagogues stimulation of acinar cells and activation of zymogens is initiated only when they reach the gut by a proteolytic cleavage of its propeptides (Weiss et al., 2008). Acinar cells secretion is primarily induced by the ingestion of food, which initiates multiple endocrine, neurocrine and paracrine pathways that regulate the release of appropriate amounts of acinar digestive enzymes (Leung and Ip, 2006).
The Acinar cell:
Islets of Langerhans:
Always on Time
Marked to Standard
The islet is a complex structure (Ashcroft and Rorsman, 1989) which contains five different endocrine cell types as summarised in Table 1. Each endocrine cell type is characterised by its own typical secretory granule morphology, different peptide hormone content, and specific endocrine, paracrine, and neuronal interactions (Islam et al., 2010). The pancreatic islet of Langerhans consists of four types of cells; insulin - releasing beta (β) - cells, glucagon - producing alpha (α) - cells; somatostatin - containing delta (ï¤) - cells, and PP - secreting cell (Table2). Islet cells can influence one another by both paracrine effects and via gap junctions which exist both between cells of the same type and between different types of islet cells (Meda et al., 1986).
Cell population (%)
Beta cells (β-cells)
60 - 90 %
Produces insulin and amylin
Alpha cells (α-cells)
15 - 20 %
Delta cells (ï¤-cells)
3 - 10 %
Pancreatic polypeptide-containing cells (PP cells)
Produces pancreatic polypeptide
Produces ghrelin (Prado et al., 2004)
Table1: Cell types in the pancreatic islet of Langerhans. Islets of Langerhans contain the endocrine cells of the pancreas which produce hormones that are secreted directly into the blood.
The adult human islet of Langerhans has a mean diameter of 140 µm and varies in size and range from small clusters of only a few cells to large aggregates of many thousands of cells (Islam et al., 2010). Approximately one million islets are distributed throughout a healthy adult human pancreas, representing 1 and 2 % of the total mass of the organ (Quesada et al., 2008). The cytoarchitecture of the human islet, where most of the β - cells shows associations with other endocrine cells, suggest unique paracrine interactions. Most of the β -, α -, and ï¤ - cells in the human islets are aligned along blood vessels with no particular order or arrangement (Cabrera et al., 2006). In most rodents, β - cells compose the core of the islets and the non - β cells, including α -, ï¤ -, and PP - cells, form the mantle region (Cabrera et al., 2006). In type 1 diabetic patients, where β - cells are lost, α - cells comprise approximately 75 % of the total cell number, although the absolute mass of the α -, ï¤ -, and PP cells does not appear to be altered (Rahier et al., 1983).
In addition to nutrients and paracrine signals, islet function is further regulated by sympathetic, parasympathetic and sensory nerves that go deeply into the islet, suggesting that multiple regulation levels determine hormone release from pancreatic islets (Ahrén, 2000). The principal levels of control on glycaemia by the islet of Langerhans depends largely on the coordinated secretion of glucagon and insulin by α - and β - cells respectively. Both cell types respond oppositely to changes in blood glucose concentration. Whereas α - cells release the hyperglycaemic hormone glucagon when extracellular glucose concentrations become low, pancreatic β - cells secrete insulin in response to high concentrations of sugar to restore normal levels (Kanno et al., 2002, Quesada et al., 2006b).
α - cells
β - cells
ï¤ - cells
PP - cells
Number of amino acids
Table 2: Cell types in the adult human endocrine pancreas. Table summarising the peptide hormones produced by different cells of the islet of Langerhans. Adapted from (Islam et al., 2010).
Pancreatic alpha (α) cells were discovered in 1907 as histologically distinct from the β - cells of the (Lane, 1907). The α - cells are one of four polypeptide - secreting islet cells which secrete glucagon (Gromada et al., 2007). The number of α - cells is estimated at 15 - 20 % (Rahier et al., 1983), and are most prominent in the dorsally derived part of the pancreas and virtually absent in the ventrally derived part (Islam et al., 2010).
Glucagon: Glucagon, like other polypeptide hormones, is encoded by a prepro gene. The preproglucagon gene has six exons, one of which encodes a glucagon precursor and two of which encode the precursors for glucagon - like peptide (GLP) - 1 and GLP - 2, respectively (Mojsov et al., 1986). The primary structures of glucagon, GLP - 1 and GLP - 2 are highly conserved across mammals, suggesting preservation of critical biological activity (Taborsky, 2010). Glucagon is a 29 - amino acid peptide with hyperglycaemic action. The peptide is derived from proglucagon (180 amino acids) through proteolytic cleavage (Jiang and Zhang, 2003). Proglucagon is expressed in various tissues (brain, pancreas and intestine) and is proteolytically processed into multiple peptide hormones in a tissue specific fashion (Jiang and Zhang, 2003). Glucagon is stored in secretory granules that have a typical morphology with an electrodense core and a grayish peripheral mantle (Deconinck et al., 1972). Glucagon acts via a seven - transmembrane G protein - coupled receptor consisting of 485 amino acids (Jelinek et al., 1993). Glucagon is released into the bloodstream when circulating glucose levels are low (Figure 2). The main physiological role of glucagon is to stimulate hepatic glucose output, thereby leading to an increase in glycaemia. This provides the major counter-regulatory mechanism for insulin in maintaining glucose homeostasis in vivo (Jiang and Zhang, 2003). Mechanisms that mediates the alpha - cell response to hypoglycaemia are: 1) a direct effect of hypoglycaemia to stimulate the pancreatic alpha cell, 2) release from suppression by the islet beta cell, and 3) autonomic stimulation of the islet alpha cell (Taborsky, 2010) as illustrated in figure 2.
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Figure 2: Mechanisms for regulation of glucagon release in response to hypoglycaemia. A. During euglycaemia, glucagon secretion may be suppressed (thin arrow) as a result of 1) the lack of autonomic stimulation, including adrenergic stimulation of α - cell; and 2) a marked paracrine inhibition by factors released by β - cells within the islet. Green arrows indicate stimulatory pathways, whereas red arrows symbolise inhibitory pathways. B. During hypoglycaemia, glucagon secretion is markedly increased (thick arrow). This may arise from a marked reduction of the paracrine inhibitory effects as well as a stimulatory action of the autonomic nervous system secondary to its activation by central hypoglycaemia. Adapted from (Gromada et al., 2007).
Pancreatic α - cells are equipped with a specific set of channels that generate action potentials of Na+ and Ca2+ in the absence or at low levels of glucose. This electrical activity triggers Ca2+ signals and glucagon secretion. Elevated glucose concentrations inhibit all these events. ATP - dependent K+ (KATP) channels play a fundamental role in α - cells, such as they do in β - cells, since they couple variations in extracellular glucose concentrations to changes in membrane potential and electrical activity (Quesada et al., 2008). At low - glucose levels, the activity of KATP channels renders a membrane potential of about -60 mV. At this voltage, T - type channels open, which depolarize the membrane potential to levels where Na+ and N - type Ca2+ channels are activated, leading to regenerative action potentials (Gromada et al., 2007). Ca2+ entry through N - type channels induces glucagon secretion. The repolarisation of action potentials is mediated by the flowing of K+ A - currents. At low - glucose concentrations, this electrical activity triggers oscillatory Ca2+ signals in human α - cells in intact islets (Quesada et al., 2006a). However, the increase in extracellular glucose levels raises the cytosolic ATP ï€¯ ADP ratio which blocks KATP channels, depolarising α - cells to a membrane potential range where the channels involved in action potentials become inactivated. As a consequence, electrical activity, Ca2+ signals and glucagon secretion is inhibited. Thus, glucagon release from α - cells is mainly supported by an intermediate KATP channel activity that maintains a membrane potential range able to sustain regenerative electrical activity (MacDonald et al., 2007).
The liver is the major site for the physiological action of glucagon. Glucagon activates the hepatic glucagon receptors which are coupled to G protein S (Gs), which activates adenylate cyclase through its alpha subunit. The resultant increase of hepatic cylase adenosine monophosphate levels activates protein kinase A, which in turn, phosphorylates the enzymes needed to activate live glycogenolysis (Taborsky, 2010).
Potassium channels are ion channels most widely distributed and found in all living organisms (Littleton and Ganetzky, 2000). These channels are selective to K+ ions over other cations such as Na+ and are found in most cell types and control a wide variety of cell functions (Illingworth and Domene, 2009). Voltage-dependent K+ channels open to allow an efflux of K+ in response to depolarisation of the membrane potential resulting in the repolarisation and a return to the resting membrane potential (Ko et al., 2008). Amongst the various K+ ion channels, ATP-sensitive channels (KATP) have been identified in many tissues and cell types, including cardiomyocytes, (Seino, 1999), pancreatic β-cells (Ashcroft, 1988), skeletal muscles (Spruce et al., 1985) and vascular smooth muscles (Cao et al., 2002), pituitary (Bernardi et al., 1993) and brain (Ashford et al., 1988). These channels permit the diffusion of K+ ions across the cell membrane and this movement is the basis of several biological processes (Bennett et al.). In the cardiac and smooth muscle KATP channels have been implicated in cell excitability, cytoprotection, and the cellular loss of K+ during ischemia (Noma, 1983), hypoxia (Jovanovic et al., 1998) or other metabolic insults (Landry and Oliver, 1992). Inhibition of KATP channels leads to impaired coronary and cerebral autoregulation (Nelson and Quayle, 1995, Hong et al., 1994).
The KATP channels exist as a hetero-octameric complex of four pore-forming (Kir6.x) and four regulatory sulphonylurea receptor (SURx) subunits (Clement et al., 1997). The channels consists of four inwardly rectifying potassium channel subunits (KIR6.1 or KIR6.2) and each KIR subunit is associated with a larger regulatory sulphonylurea receptor (SUR) (Babenko et al., 1998). The regulatory SUR subunit is encoded by two different genes, SUR1 and SUR2 (Seino, 2002). Pancreatic β-cell KATP channels consist of SUR1 and Kir6.2 (Figure 2), whereas KATP channels in cardiomyocytes and skeletal muscle comprise SUR2A and Kir6.2 (Seino et al., 2000) (Summarised in Table 3). The three-dimensional structural and functional characterisation of the KATP channel complex reveals that the channel is a compact structure, roughly 18 nm in cross-section and 13 nm in height (Mikhailov et al., 2005). Different combinations of Kir6.x and SURï‚¢s yield the tissue-specific KATP channel subtypes with different electrophysiological and pharmacological features (Inagaki et al., 1997, Inagaki et al., 1996). KATP channels couple the cellï‚¢s metabolic status to its electrical activity and play an important role in various cellular functions as sensors of intracellular ATP and ADP (Inagaki and Seino, 1998).
Vascular smooth muscle
Table 3: Types of KATP channel.
Figure 3: Predicted octameric structure of KATP channel. The functional channel consists of SUR1 or SUR2A and Kir6.2 subunit in a 1:1 stoichiometry. As shown from the top view, four Kir6.2 subunits surround and form a central pore. Adapted from (Koster, 2005).
KATP channels are inhibited by intracellular ATP and activated by intracellular nucleoside diphosphates (NDP) in the presence of Mg2+, thus coupling the metabolic state of cell to membrane electrical activity (Ashcroft, 1988, Seino, 1999). ATP closes the KATP channel by binding to Kir6.2 (Tucker et al., 1997).
Another distinguishing feature of KATP channels is the inhibition of channel activity by sulphonylurea agents (glibenclamide and tolbutamide) and as these agents are highly selective for KATP channels with affinities of these drugs for the channel in the low nmol/L to low µmol/L range (Brayden, 2002).
The ATP-sensitive K+ (KATP) channels in the pancreas are not a classical inward rectifier potassium channels as they display weak rectification (Nichols and Lederer, 1991) in comparison to the classical inward rectifier potassium channels which show strong inward rectification i.e. the inward flow of the K+ ions is greater than the outward flow for the opposite driving force (Nichols and Lopatin, 1997). The functional role of the inward rectifier channels depends critically on their degree of rectification (Nichols and Lopatin, 1997). In pancreatic β-cells, the increase in ATP/ADP ratio generated by glucose stimulation closes the KATP channels to elicit a secretion of insulin, the primary hormone of glucose homeostasis (Inagaki and Seino, 1998). Thus KATP channels are crucial in the regulation of glucose-induced insulin secretion (Inagaki and Seino, 1998).
Insulin was discovered by Dr. Frederic Banting and Dr. Charles Best in 1921 and the first patient was treated a year later in 1922 (Sonksen and Sonksen, 2000). Insulin is the only blood-glucose lowering hormone secreted by the beta cells of the pancreatic islets of Langerhans which constitute 65 - 90% of the islet cell population (Ashcroft and Rorsman, 1989).
Insulin is synthesised in the β cells of the islets of Langerhans. Insulin is a small polypeptide hormone (Molecular weight of 6000) Both the B and A chain sequences are highly conserved in mammals (Permutt et al., 1981).
The biosynthesis of insulin occurs via at least two intermediates, preproinsulin and Proinsulin and involves several organelles. The genetic information for biosynthesis is initially encoded onto an mRNA of 600 nucleotides (210 kDa), the transcript of which gives rise to Preproinsulin (11.5 kDa protein, 109 amino acids). This protein contains a hydrophobic pre-region of 23 amino acids which function to promote the association of ribosomes with the membrane of the endoplasmic reticulum (ER) ensuring the discharge of the newly synthesised precursor into the cisternal space of the rough endoplasmic reticulum. Within the endoplasmic reticulum, rapid proteolytic cleavage occurs transforming the preproinsulin into proinsulin (Howell and Bird, 1989). Proinsulin is a 9 kDa peptide of 86 amino acids, composed of an amino-terminal B chain with 30 amino acids which is joined by two disulfide bridges to the carboxy-terminal, A chain which contains 21 amino acids and a 30-35 amino acid connecting peptide segment known as the C-peptide (Dodson and Steiner, 1998, Howell and Bird, 1989). Proinsulin is synthesised on membrane bound polysomes (Permutt and Kipnis, 1972) as are other secretory peptides. The C-peptide facilitates the correct folding of the A and B chains and alignment of the disulfide bridges prior to cleavage (Howell and Bird, 1989). The vesicular transfer of proinsulin from the ER brings it to the Golgi, an aqueous environment containing zinc and calcium (Howell et al., 1978). From the Golgi complex, where the pH within the cisternae is approximately neutral, proinsulin is packaged in trans-Golgi vesicles and surrounded by a membrane containing an ATP-dependent proton pump. The conversion of proinsulin to insulin continues within the maturing secretory granule by the sequential action of proteases, which are pH dependent, are only active at low pH and possess trypsin and carboxypeptidase B-like activities. As the vesicle matures, H+ ions are transported inwards via a proton pump, decreasing pH and increasing the activity of the proteases, ensuring that insulin is only produced within the maturing secretory granule. The action of the proteases liberates the connecting C-peptide from between the A and B chains, plus two pairs of basic amino acids from either end of the C-peptide. The conversion of proinsulin to the insulin starts at the stage of vesicle formation as demonstrated from radiolabelling and electron microscopic studies (Dodson and Steiner, 1998). Removal of the C-peptide decreases the solubility of insulin, coprecipitating it with Zn2+ contained within the granule, as rhombohedral Zn2+-insulin hexameric microcystals with a ratio of 2 Zn2+ : 6 insulin (Howell et al., 1969). The advantage of retaining the hexamer is that the six insulin molecules form an oblate spheroid that readily forms close-packed arrays that favour crystal growth (Dodson and Steiner, 1998). The biological advantage of the formation of crystals may well be to protect insulin from further proteolysis by converting enzymes (Dodson and Steiner, 1998). Insulin and C-peptide are stored together in the granule sac and secreted in equimolar amounts. In normal conditions 95% of the hormone is secreted as insulin, and less than 5% as proinsulin (Howell and Bird, 1989).
C-peptide is released into the blood in equimolar quantities to that of insulin and measurements of the release of C-peptide has proved useful as an independent measure of insulin secretory rate in humans, in vivo (Rubenstein et al., 1969).
Ultra-structural studies have shown that a single beta-cell contains more than 10,000 secretory granules (Olofsson et al., 2002). Quantitatively, pancreatic insulin secretion in the basal state varies from 0.25 to 1.5 U/h in normal human subjects and accounts for 50% or more of the 24 - hour integrated insulin secretion (Scheen, 2004).
Electrophysiology of the beta cell:
An increase in extracellular glucose concentration leads to the induction of electrical activity (Ashcroft and Rorsman, 1989). Over the physiological range of glucose concentrations, this electrical activity consists of oscillations in membrane potential between depolarised plateaux, on which bursts of action potentials are superimposed, separated by repolarised electrically silent intervals. The periods of electrical activity are accompanied by changes in the cytoplasmic Ca2+ concentration ([Ca2+]i) (Valdeolmillos et al., 1989) which in turn drive pulsatile insulin secretion (Bergsten, 1995). Glucose produces a concentration-dependent increase in electrical activity and at glucose concentrations over 20 mmol/L, uninterrupted action potential firing is observed (Ashcroft and Rorsman, 1989). In intact islet, every beta cell responds to glucose in a graded fashion. Although glucose also exerts an effect on downstream steps in the secretory process, it is not able to elicit insulin release if electrical activity and the accompanying Ca2+-influx are prevented. Thus, the progressive increase in beta cell activity is a key element in the series of reactions culminating in glucose-induced insulin secretion (Rorsman and Renström, 2003).
Two types of ion channels are important for the initiation of insulin secretion, ATP-regulated K+-channels (KATP channels) and voltage gated Ca2+ channels
Figure: Stimulus-secretion coupling in pancreatic beta cell. Scheme illustrating the stimulus-secretion coupling in a pancreatic beta cell in which two types of ion channels, KATP channels and voltage gated Ca2+ channels are particularly important for the initiation of insulin secretion. Glut2: Glucose transporter, KATP channel: ATP-dependent K+ channel, Ca2+ channel: Voltage gated calcium channel, ï™: Membrane potential, ATP: Adenosine triphosphate, ADP: Adenosine diphosphate, SG: Secretory granules, + and - sign indicate stimulation and inhibition respectively, whereas the ï‚ and ï‚¯ arrows indicate an increase or decrease of the indicated parameter respectively. Adapted from (Rorsman and Renström, 2003).
Insulin has two classes of action, 1) excitatory, for example stimulating glucose uptake and lipid synthesis and 2) inhibitory, for example inhibiting lipolysis, proteolysis, glycogenolysis, gluconeogenesis and ketogenesis
Within the storage vesicle, the insulin hexamer in the crystalline form is very stable, but however, on the release into the serum the insulin microcrystals experience a jump in pH from ~5.5 to pH 7.4 (Dodson and Steiner, 1998).
Figure: Diverse biological effects of insulin. When insulin binds to its receptor, resultant activation of the insulin signalling cascade leads to multiple effects on several biological processes. These biological processes include, glucose transport, glycogen synthesis, lipid metabolism, protein synthesis, gene expression, mitogenesis, cell growth, division and survival Adapted from (Rhodes and White, 2002).
The term diabetes mellitus encompasses a group of metabolic disorders characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both (Association, 2010). Diabetes mellitus has reached epidemic proportions and affects more than 346 million individuals worldwide (2006). The vast majority of cases of diabetes fall into two broad etiopathogenic categories. Type 1 diabetes (T1D) is caused by an absolute deficiency of insulin secretion which accounts for 5 - 10 % of all the global cases of diabetes. Type 2 diabetes (T2D) or non - insulin dependent diabetes is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response and accounts for ~ 90 - 95 % of diabetic individuals (Association, 2010). The chronic hyperglycaemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels (2002).
Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the β - cells of the pancreas with consequent insulin deficiency to abnormalities that result in the resistance to insulin action. Diabetes mellitus is diagnosed on the basis of world health organisation (WHO) recommendations from 1999, incorporating both fasting and 2 hour after glucose load (75 g) criteria into a predictable diagnostic classification (2006).
Table: Disorders of glycemia: etiological types and stages.
Type 1 (Insulin - dependent) diabetes:
Type 1 (Insulin dependent) diabetes mellitus (T1D, MIM 222100) is a chronic autoimmune disease associated with selective destruction of insulin - producing pancreatic β - cells. T1D is characterised by absolute insulin deficiency, an abrupt onset of symptoms, proneness to ketosis and dependency on exogenous insulin to sustain life (Pociot and McDermott, 2002). T1D is understood to have an autosomal recessive inheritance and an autoimmune pathogenesis, exhibited by lymphocytic insulitis (inflammation of the islet). Type 1 diabetes is one of the most common chronic childhood illnesses, affecting 18 to 20 per 100,000 children a year in the United Kingdom (Onkamo et al., 1999). Two forms of type 1 diabetes are identified and the American Diabetes committee recommends the term type 1A diabetes for immune mediated diabetes with its destruction of the islet β - cells of the pancreas (2002) and non-immune mediated diabetes with severe insulin deficiency is termed type 1B. Type 1B is far less frequent, has no known cause, and occurs mostly in individuals of Asian or African descent, who have varying degrees of insulin deficiency between sporadic episodes of ketoacidosis (Abiru et al., 2002). The interplay between genetic susceptibility and environmental factors may account for the pathogenesis of type 1 diabetes (Devendra et al., 2004).
Although type 1 diabetes accounts for only 5 - 10 % of all those with diabetes, it remains a serious chronic disorder, usually beginning earlier in life than type 2 diabetes, but with important short-term and long-term consequences (Daneman, 2006). T1D is the most common form of diabetes among children and young adults in populations of Caucasoid origin, where the prevalence is approximately 0.4 % (Pociot and McDermott, 2002). T1D affects approximately 350,000 people in the UK and up to 20 million people globally (Thrower and Bingley, 2010). The overall age - adjusted incidence of T1D varies from 0.1 / 100,000 per year in China and Venezuela to 36 / 100,000 per year in Sardinia and Finland (Karvonen et al., 2000). There is a marked geographic variation in incidence, with a child in Finland being about 400 times more likely than a child in Venezuela to acquire the disease (Gillespie, 2006). The incidence of T1D shows a trend towards earlier onset, with cases rapidly increasing in specific regions and is highly variable among different ethnic populations (Atkinson and Eisenbarth, 2001, Devendra et al., 2004). The geographic variation in the annual incidence of type 1 diabetes is illustrated in figure 1, adapted from (Gillespie, 2006). The incidence of type 1 diabetes seems to be increasing in almost all populations, with the increase particularly high in nations with a low incidence of this disease (Onkamo et al., 1999).
Figure 1: Global variation in annual incidence in type 1 diabetes mellitus. There is a marked geographic variation in incidence of T1D which reflects the global distribution of major ethnic populations, which demonstrates a different degree of genetic susceptibility to diabetes among populations. This wide global variation in incidence between and within major ethnic groups suggests that environmental factors are significant in the etiology of type 1 diabetes (Karvonen et al., 2000). Adapted from (Gillespie, 2006).
Figure: The development of type 1 diabetes: There is a gradual destruction of β - cells by inflammatory cell infiltration of the islets (Imagawa et al., 1999). Metabolic progression of T1D is marked by a loss of the first - phase insulin response to intravenous glucose, oral glucose tolerance and stimulated C - peptide levels also decline over a period of at least 2 years before the classical symptoms of hyperglycaemia become apparent (Sosenko et al., 2006). By the time of diagnosis, 80 - 90 % of β - cells have been destroyed (Atkinson, 2005). Adapted from (Thrower and Bingley, 2009).
Individuals with diabetes (millions)
Individuals with diabetes (millions)
Table: Countries with the highest estimated numbers of cases of diabetes in 2000 and 2030 (Forouhi and Wareham, 2006)