To ensure that circulating levels of insulin are appropriate for the prevailing metabolic status, β cells are equipped with mechanisms to detect changes in circulating nutrients and hormone levels, and in the activity of the autonomic nervous system. Moreover, β cells have fail- safe mechanisms for coordinating this afferent information and responding with an appropriate secretion of insulin. The major physiological determinant of insulin secretion in humans is the circulating concentration of glucose and other nutrients, including amino acids and fatty acids. These nutrients possess the ability to initiate an insulin secretory response: when nutrients are absorbed from the gastrointestinal system, the β cell detects the changes in circulating nutrients and releases insulin to enable their uptake and metabolism or storage by the target tissues. The consequent decrease in circulating nutrients is detected by the β cells, which switch off insulin secretion to prevent hypoglycaemia. The β- cell responses to nutrient initiators of insulin secretion can be modified by various hormones and neurotransmitters, which act to amplify, or occasionally inhibit, the nutrient- induced responses (Table 1). Under normoglycaemic conditions, these agents have little or no effect on insulin secretion, a mechanism that prevents inappropriate secretion of insulin, which would result in potentially harmful hypoglycaemia. These agents are often referred to as potentiators of insulin secretion to distinguish them from nutrients that initiate the secretory response. The overall insulin output depends on the relative input from initiators and potentiators at the level of individual β cells, on the synchronization of secretory activity between β cells in individual islets, and on the coordination of secretion between the hundreds of thousands of islets in a human pancreas. This section considers the mechanisms employed by β cells to recognize and respond to nutrient initiators and non- nutrient potentiators of insulin secretion.

Table1. Key non- nutrient regulators of insulin secretion.

Nutrient- induced insulin secretion

Nutrient metabolism

Islet β cells respond to small changes in extracellular glucose concentrations within a narrow physiological range and the mechanisms through which β cells couple changes in nutrient metabolism to regulated exocytosis of insulin are becoming increasingly well understood. Glucose is transported into β cells via high- capacity glucose transporters (GLUT; GLUT 2 in rodents, GLUT 1, 2, and 3 in humans), enabling rapid equilibration of extracellular and intracellular glucose concentrations. Once inside the β cell, glucose is phosphorylated by glucokinase, which acts as the glucose sensor, coupling insulin secretion to the prevailing glucose level, although evidence is accumulating of other metabolic amplifiers of insulin secretion, notably the anaplerotic flux of pyruvate to oxaloacetate and beyond. The dose–response curve of glucose- induced insulin secretion from isolated islets is sigmoidal (Figure 1) and is determined primarily by the activity of glucokinase. Glucose concentrations below 5 mmol/l do not affect rates of insulin release, and the rate of secretion increases progressively at extracellular glucose levels between 5 and ~15 mmol/l, with half- maximal stimulation at ~8 mmol/l. The time course of the insulin secretory response to elevated glucose is characterized by a rapidly rising but transient first phase, followed by a maintained and prolonged second phase, as shown in Figure 2. This profile of insulin secretion is obtained whether insulin levels are measured following a glucose load in vivo, or whether the secretory output from the perfused pancreas or isolated islets is assessed, suggesting that the characteristic biphasic secretion pattern is an intrinsic property of the islets.

Fig1. Glucose- induced insulin secretion from islets of Langerhans. No stimulation is seen below a threshold value of ~5 mmol/l glucose. Potentiators amplify insulin secretion at stimulatory concentrations of glucose, but are ineffective at subthreshold glucose levels.

Fig.  Glucose- induced insulin release in vitro. The image shows the pattern of glucose- induced insulin secretion from perfused pancreas, in response to an increase in the glucose concentration. An acute first phase, lasting a few minutes, is followed by a sustained second phase of secretion that persists for the duration of the high- glucose stimulus. A similar biphasic pattern of glucose- induced insulin secretion is seen in isolated rodent and human islets, suggesting that this characteristic pattern of insulin secretion is an intrinsic property of the islets.

ATP- sensitive potassium channels and membrane depolarization

In the absence of extracellular glucose, the β- cell membrane potential is maintained close to the potassium equilibrium potential by the efflux of potassium ions through inwardly rectifying potassium channels. These channels were called ATP- sensitive potassium (KATP) channels, because application of adenosine triphosphate (ATP) to the cytosolic surface of β- cell membrane patches resulted in rapid, reversible inhibition of resting membrane permeability to potassium ions. This property of the KATP channel is pivotal in linking glucose metabolism to insulin secretion. Thus, ATP generation following glucose metabolism, in conjunction with concomitant lowering of adenosine diphosphate (ADP) levels, leads to closure of β- cell KATP channels. Channel closure and the subsequent reduction in potassium efflux promote depolarization of the β- cell membrane and influx of calcium ions through voltage- dependent L- type calcium channels. The resultant increase in cytosolic Ca2+ triggers the exocytosis of insulin secretory granules, thus initiating the insulin secretory response (Figure 3).

Fig3. Intracellular mechanisms through which glucose stimulates insulin secretion. Glucose is metabolized within the β cell to generate adenosine triphosphate (ATP), which closes ATP- sensitive potassium channels in the cell membrane. This prevents potassium ions from leaving the cell, causing membrane depolarization, which in turn opens voltage- gated calcium channels in the membrane and allows calcium ions to enter the cell. The increase in cytosolic calcium initiates granule exocytosis. Sulfonylureas act downstream of glucose metabolism, by binding to the SUR1 component of the KATP channel (inset). GLUT, glucose transporter.

At around the time that the KATP channels were established as the link between the metabolic and electrophysiological effects of glucose, they were also identified as the cellular target for sulfonylureas. The capacity of sulfonylureas to close KATP channels explains their effectiveness in type 2 diabetes where the β cells no longer respond adequately to glucose, as the usual pathway for coupling glucose metabolism to insulin secretion is bypassed. The β- cell KATP channel is a hetero- octamer formed from four potassium channel subunits (termed Kir6.2) and four sulfonylurea receptor subunits (SUR1). The Kir6.2 subunits form the pore through which potassium ions flow and these are surrounded by the SUR1 subunits, which have a regulatory role (Figure3). ATP and sulfonylureas induce channel closure by binding to Kir6.2 and SUR1 subunits, respectively, while ADP activates the channels by binding to a nucleotide- binding domain on the SUR1 subunit. Diazoxide, an inhibitor of insulin secretion, also binds to the SUR1 subunit to open the channels. The central role of KATP channels in β- cell glucose recognition makes them obvious candidates for β- cell dysfunction in type 2 diabetes. Early studies in people with type 2 diabetes, maturity- onset diabetes of the young (MODY), or gestational diabetes failed to detect any Kir6.2 gene mutations that com promised channel function. Since then, larger- scale studies of variants in genes encoding Kir6.2 and SUR1 have demonstrated polymorphisms associated with increased risk of type 2 diabetes. Similarly, activating mutations in the Kir6.2 gene are causal for cases of permanent neonatal diabetes (PNDM), which has enabled individuals with insulin- dependent PNDM to achieve nor mal glucose levels with sulfonylurea treatment alone. In contrast, loss of β- cell functional KATP channel activity has been implicated in the pathogenesis of congenital hyperinsulinism, a condition characterized by hypersecretion of insulin. Numerous mutations in both the Kir6.2 and SUR1 subunits have been identified in people with congenital hyperinsulinism and these are responsible for the severe impairment in glucose homeostasis in these individuals.

Calcium and other intracellular effectors

Intracellular calcium is a principal effector of the nutrient- induced insulin secretory response, linking depolarization with exocytosis of insulin secretory granules (Figure 3). A large electrochemical concentration gradient (~10 000- fold) of calcium is maintained across the β- cell plasma membrane by a combination of membrane- associated calcium extruding systems and active calcium sequestration within intracellular organelles. The major route through which calcium is elevated in β cells is by influx of extracellular calcium through voltage- dependent L- type calcium channels that open in response to β- cell depolarization, and it has been estimated that each β cell contains about 500 L- type channels.

Studies with permeabilized β cells have demonstrated that elevations in intracellular calcium are alone sufficient to initiate insulin secretion, and conditions that elevate intracellular calcium usually stimulate insulin release. An increase in cytosolic calcium is essential for the initiation of insulin secretion by glucose and other nutrients: preventing calcium influx by removal of extracellular calcium or by pharmacological blockade of voltage- dependent calcium channels abolishes nutrient- induced insulin secretion. Glucose and other nutrients also induce a calcium- dependent activation of β- cell phospholipase C (PLC), leading to the generation of inositol 1,4,5- trisphosphate (IP3) and diacylglycerol (DAG), both of which serve second- messenger functions in β cells. The generation of IP3 leads to the rapid mobilization of intracellular calcium, but the significance of this in secretory responses to nutrients is uncertain, and it is likely to have little more than a modulatory role, amplifying the elevations in cytosolic calcium concentration induced by the influx of extracellular calcium.

The elevations in intracellular calcium are transduced into the regulated secretion of insulin by intracellular calcium- sensing systems within β cells. Important among these are the calcium- dependent protein kinases, which include myosin light- chain kinases, the calcium/phospholipid- dependent kinases, and the calcium/calmodulin- dependent kinases (CaMKs). CaMKs are protein kinases that are activated in the presence of calcium and the calcium- binding protein calmodulin, and several studies have implicated CaMK II in insulin secretory responses. It has been proposed that CaMK II activation is responsible for the initiation of insulin secretion in response to glucose and other nutrients, and for enhancing nutrient- induced secretion in response to receptor agonists that elevate intracellular calcium. Cytosolic PLA2 (cPLA2) is another β- cell calcium- sensitive enzyme. It is activated by concentrations of calcium that are achieved in stimulated β cells, and it generates arachidonic acid by the hydrolysis of membrane phosphatidylcholine. Arachidonic acid is capable of stimulating insulin secretion in a glucose- and calcium- independent manner, and it is further metabolized in islets by the cyclooxygenase (COX) path ways to produce prostaglandins and thromboxanes, and by the lipoxygenase (LOX) pathways to generate hydroperoxyeicosa tetraenoic acids (HPETES), hydroxyeicosatetraenoic acids (HETES), and leukotrienes.

The precise roles of arachidonic acid derivatives in islet function remain uncertain because experimental investigations have relied on COX and LOX inhibitors of poor specificity, and although prostaglandin E2 is largely inhibitory in rodent islets, it has stimulatory effects on insulin secretion from human islets. Calcium sensors are also important at the later stages of the secretory path way, where the calcium- sensitive synaptotagmin proteins are involved in the formation of the exocytotic SNARE complex, to confer calcium sensitivity on the initiation and rate of exocytotic release of insulin secretory granules.

The elevations in intracellular calcium induced by nutrients activate other effector systems in β cells, including PLC and cPLA2, and calcium- sensitive adenylate cyclase isoforms, which generate cAMP from ATP. Although these signalling systems are of undoubted importance in the regulation of β cells by non- nutrients, their role in nutrient- induced insulin secretion is still uncertain. Thus, DAG generated by glucose- induced PLC activation has the potential to activate some protein kinase C (PKC) isoforms. PKC was first identified as a calcium- and phospholipid- sensitive, DAG- activated protein kinase, but some isoforms of PKC require neither calcium nor DAG for activation. The isoforms are classified into three groups:

• Calcium and DAG sensitive (conventional).

 • Calcium independent, DAG sensitive (novel).

• Calcium and DAG independent (atypical).

β cells contain conventional, atypical, and novel PKC iso forms. The early literature on the role of PKC in nutrient- induced insulin secretion is confusing, but several studies have shown that glucose- induced insulin secretion is maintained under conditions where DAG- sensitive PKC isoforms are depleted, suggesting that conventional and novel PKC isoforms are not required for insulin secretion in response to glucose.

The role of cAMP in the insulin secretory response to nutrients is similarly unclear. cAMP has the potential to influence insulin secretion by the activation of cAMP- dependent protein kinase A (PKA), or via the cAMP- regulated guanine nucleotide exchange factors known as exchange proteins activated by cAMP (EPACs). However, elevations in β- cell cyclic AMP do not stimulate insulin secretion at substimulatory glucose concentrations, and the secretagogue effects of glucose can be maintained in the presence of competitive antagonists of cAMP binding to PKA or EPACs. These observations suggest that cAMP does not act as a primary trigger of nutrient- stimulated β- cell secretory function, but observations linking glucose- induced oscillations in β- cell cAMP to oscillations in insulin secretion suggest that a role for this messenger system in nutrient- induced insulin secretion cannot be ruled out.

K_ATP channel- independent pathways

 Since the early reports linking KATP channel closure to the exocytotic release of insulin, it has become apparent that β cells also possess a KATP channel- independent stimulus–secretion coupling pathway: this is termed the amplifying pathway to distinguish it from the triggering pathway that is activated by KATP channel closure. Studies in which β- cell calcium is elevated by depolarization and KATP channels are maintained in the open state by diazoxide have indicated that glucose, at concentrations as low as 1–6 mmol/l, is still capable of stimulating insulin secretion. The triggering and amplifying pathways are both physiologically relevant for the first and second phases of glucose- induced insulin secretion, but the mechanisms by which glucose stimulates insulin secretion in a KATP channel- independent manner remain debated, although adenine nucleotides have been implicated. However, it is clear that glucose must be metabolized and various potential metabolic amplifiers of glucose- induced insulin secretion have been identified in experimental studies, with the suggestion that perturbations in these pathways may be involved in β- cell failure in type 2 diabetes.

Amino acids

 Several amino acids stimulate insulin secretion in vivo and in vitro. Most require stimulatory concentrations of glucose, but some, such as leucine, lysine, and arginine, can stimulate insulin secretion in the absence of glucose, and therefore qualify as initiators of secretion. Leucine enters islets by a sodium- independent transport system and stimulates a biphasic increase in insulin release. The effects of leucine on β- cell membrane potential, ion fluxes, and insulin secretion are similar to, but smaller than, those of glucose. Thus, metabolism of leucine within β cells decreases the potassium permeability, causing depolarization and activation of L- type calcium channels through which calcium enters the β cells and initiates insulin secretion. Leucine also activates the amplifying pathway of insulin secretion in a KATP channel- independent manner, as described already for glucose. The charged amino acids lysine and arginine cross the β- cell plasma membrane via a transport system specific for cationic amino acids. It is generally believed that the accumulation of these positively charged molecules directly depolarizes the β- cell membrane, leading to calcium influx.

Regulation of insulin secretion by non- nutrients

 The complex mechanisms that have evolved to enable changes in extracellular nutrients to initiate an exocytotic secretory response are confined to islet β cells, and perhaps to a subset of hypothalamic neurons. However, the mechanisms that β cells use to recognize and respond to non- nutrient potentiators of secretion are ubiquitous in mammalian cells, and so are covered only briefly in this section, followed by a review of the physiologically relevant non- nutrient regulators of β- cell function.

Most, if not all, non- nutrient modulators of insulin secretion influence β cells by binding to and activating specific receptors on the extracellular surface. Because of their central role in coordinating whole- body fuel homeostasis, β cells express receptors for a wide range of biologically active peptides, glycoproteins, and neurotransmitters (Table 1), and quantitative reverse transcriptase polymerase chain reaction (RT- PCR) analysis has indicated that human islets express 293 different G- protein- coupled receptors. However, receptor occupancy generally results in the activation of a limited number of intracellular effector systems, which were introduced in the section ‘Nutrient- Induced Insulin Secretion’ (Figures 4 and 5).

Fig4. Adenylate cyclase and the regulation of insulin secretion. Some receptor agonists (e.g. glucagon, glucagon- like peptide- 1, pituitary adenylate cyclase- activating polypeptide) bind to cell- surface receptors that are coupled to adenylate cyclase (AC) via the heterotrimeric GTP- binding protein Gs. Adenylate cyclase hydrolyses adenosine triphosphate (ATP) to generate adenosine 5′ cyclic monophosphate (cAMP), which activates protein kinase A (PKA) and exchange proteins activated by cAMP (EPACs). Both of these pathways potentiate glucose- stimulated insulin secretion. Glucose also activates adenylate cyclase, but increases in intracellular cyclic AMP levels in response to glucose are generally smaller than those obtained with receptor agonists. Some inhibitory agonists (e.g. norepinephrine, somatostatin) bind to receptors that are coupled to adenylate cyclase via the inhibitory GTP- binding protein Gi, resulting in reduced adenylate cyclase activity and a decrease in intracellular cAMP.

Fig5. Phospholipase C and the regulation of insulin secretion. Some receptor agonists (e.g. acetylcholine, cholecystokinin) bind to cell- surface receptors that are coupled to phospholipase C (PLC) via the heterotrimeric GTP- binding protein Gq. Phospholipase C hydrolyses phosphatidylinositol bisphosphate (PIP2), an integral component of the membrane, to generate inositol 1,4,5- trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes calcium from the endoplasmic reticulum and DAG activates protein kinase C (PKC), both of which enhance insulin secretion. Nutrients also activate PLC in a calcium- dependent manner, but the importance of IP3 and DAG in nutrient- induced insulin secretion is uncertain.

اخر الاخبار

اخبار العتبة العباسية المقدسة

شعبة الخطابة الحسينية النسوية تُقيم مسابقة حفظ الخطب الثلاث لطالبات الدورات الصيفية في كربلاء

وفد العتبة العباسية المقدسة يشارك في مهرجان الصحة النفسية بجامعة كربلاء

أمناء العتبات المقدسة يناقشون أهمية مشاريع التوسعة وبناء صحون جديدة لاستيعاب أعداد الزائرين

قسم الشؤون الفكرية يصدر الجزأين الخامس والسادس من دليل الأطاريح والرسائل الجامعية لعام 2025م

المزيد

الآخبار الصحية

أول إرشادات غذائية قائمة على الأدلة لمعالجة الإمساك المزمن

صباح بلا إفطار؟.. صحتك في خطر!

هل يمكن للجلد أن يكشف عن صحتك العقلية؟.. دراسة حديثة تجيب

السر في مطبخك.. 6 أطعمة تمنح عظامك قوة الشباب

المزيد

الآخبار التكنلوجية

ناسا تكشف: كوكب الأرض أصبح أقل لمعانا خلال العقود الماضية

دراسة: الوقت الذي تستخدم فيه هاتفك قد يفضح حالتك النفسية

الهنغاري لاسلو كراسناهوركاي يفوز بجائزة نوبل للآداب 2025

رسميا.. إعلان الفائز بجائزة نوبل للسلام لعام 2025

المزيد

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

Islet structure and function

الجلوكاجون Glucagon

هرمون الانسولين

المرض السكري (Diabetes Mellitus)

الغدة البنكرياسيةThe Pancreas