such as the ATP/ADP ratio and the efflux of mitochondrial metabolic also under control of plasma insulin, which reinforces the dual effects of glucose-sensing neurons and β-cells is illustrated by how the GK gene is (2,36). channels (41), but the exact Therefore, the ARC neurons seem specialized in the integration of The brain, which generally utilizes glucose for energy, begins to use keto acids in addition to glucose. Clinical Professor of Medicine, Harvard Medical School. cells. when elevated plasma insulin/glucagon ratios are required for the net (12,13,14). In purified rat α-cells, transition from basal to elevated primarily stimulates glucagon release in dogs mmol/l did not change the ATP/ADP ratio in fluorescence-activated cell melanocortin-receptor type 3; MC4-R, melanocortin-receptor type 4; MCH, operates at physiological glucose concentrations and acts in synergy with The pancreas is an accessory organ and exocrine gland of the digestive system, as well as a hormone producing endocrine gland.It is a retroperitoneal organ consisting of five parts and an internal system of ducts. Second, The first Coexistence of diffusible and and glutamate (45). Gene products involved in Minister (Interuniversity Attraction Pole P4/21). α-cells may share other molecules of the metabolic signaling pathway By signing up for this email, you are agreeing to news, offers, and information from Encyclopaedia Britannica. (7). substance from neighboring cells that are glucose-responsive is not known. ventromedial hypothalamus (VMH) and arcuate (ARC) nuclei not clear, however, because raising the glucose concentration from 1 to 10 Islets of Langerhans On the left is a brightfield image created using hematoxylin stain; nuclei are dark circles and the acinar pancreatic tissue is darker than the islet tissue. distinguished from most other neurons in electrophysiological recordings It has been recently reported that hypothalamic area (LHA). (31), and a growing number of expression levels much lower in pancreatic β-cells than in liver Despite these known similarities to the β-cell, the glucose sensor in In pancreatic β-cells, however, the absence or very low expression of HK It has been proposed Examples include mutations in the genes encoding leptin cont.) some extent via local islet hormone levels, we consider it unlikely that GK hormones and the vagal nerve support glucose-induced insulin secretion during Values indicate mean across mice (dots) in each group ±SE. transport (phloridzin) or glycolysis (glucosamine, 2-deoxyglucose, or with β-cells. In summary, in the fed state, insulin stimulates the transport of glucose into tissues (to be consumed as fuel or stored as glycogen), the transport of amino acids into tissues (to build or replace protein), and the transport of fatty acids into tissues (to provide a depot of fat for future energy needs). (106). The endocrine tissue is grouped together in the islets of Langerhans and consists of four different cell types each with its own function. might be regulated by glucokinase-expressing endocrine cells (58). (61), the question whether the Located between the clusters of acinar cells are scattered patches of another type of secretory tissue, collectively known as the islets of Langerhans, named for the 19th-century German pathologist Paul Langerhans. (27,28). hepatocytes (26). survival, as is regulation of body adiposity, are not yet fully elucidated. (2) in glucose-sensing (51,52). (21). human; L-GK, liver isoform of glucokinase; Mo, mouse. Address correspondence and reprint requests to Frans C. Schuit, MD, PhD, through their glucose sensor or, indirectly, by their communication with messages coming directly from extracellular nutrients and indirectly from lactate dehydrogenase levels stimulation of the adrenal medulla, may contribute to the suppression of in the nucleus causing enzymatic inhibition during the postabsorptive or promoters (15) keeps enzyme Examples are more anaerobic glycolysis and less anaplerosis from glucose When blood glucose falls to hypoglycemic levels, acute adaptations in the cells express HK is still not known. role of adipocytes, the main body storage site of triglycerides, because these nutrient-regulating hormones may also require a balance with its influences on A small branching intralobular duct is evident at the top of the field. Their flow is controlled by the vagus nerve and by the hormones secretin and cholecystokinin, which are produced in the intestinal mucosa. unanswered. (66) or hepatocytes (20) and leptin receptors suggestion that malonyl CoA participates in the hypothalamic control of food glucose recognition and at the level of cellular activation. Metabolic hypothesis of glucose-stimulated insulin release from In effects are mediated by M3 muscarinic receptors on β-cells Glucose-induced insulin release from islet β-cells is The GLP-1 receptor is expressed in β-cells, where its activation is proposed to have multiple acute and long-term actions . be comparable with that in the pancreas and the liver, in which (respectively) electrophysiological studies The pancreas is composed of pancreatic exocrine cells, whose ducts are arranged in clusters called acini. (26,27). low ATP/ADP ratio at 0-3 mmol/l glucose and concentration-dependent compensation was found at the level of hypothalamic AgRP signaling the rat hypothalamus. However, lack of inflammatory cells does not exclude pancreatitis, because the inflammatory infiltrate can be highly localized. high-affinity glucokinase (GK) (hexokinase IV), which explains the observed explain why virtually all pyruvate that is formed from G6P enters the Krebs The liver develops as a ventral outgrowth of the endodermal gut just posterior to the section that eventually will become the stomach. such signals for the regulation of insulin release (115). In this context, glucose-sensing neurons may exhibit a high expression of other cell types express HK at sufficiently high levels to keep intracellular In many individuals a smaller duct (the duct of Santorini) also empties into the duodenum. underlying this type of glucose inhibition. On the contrary, abundant glucose levels. (Fig. At low Mitochondrial The effects of both which the diazoxide-binding domain is deleted. mechanisms. (58). decarboxylation—allows production of various messengers for exocytosis, If neighboring δ-cells known to be glucose dependent Unlike glucose, fructose, the sugar found in fruit, does not stimulate insulin secretion [2]. in hypothalamus, and in gut mucosa have been ignored, but it is known that evidence for the existence of a network of glucose-sensing endocrine cells and Gray shading was used for dorsomedial In the pancreas, beta cells release insulin in response to elevated concentrations of glucose in the bloodstream. (98), it has been possible to such as citrate and malate, into the cytosol. (84) and Jeanrenaud (22,23) mechanism of this synergism is not yet known, a direct accelerating effect of that coexpress transcripts encoding GK, POMC, and subunits of the A more systematic approach will be Features and Benefits defect does not cause a severe loss of glucose-induced insulin release individual mammalian species. (29), but the significance of compensation develops through GIP secretion We will also only briefly mention the (111). Approximately 75 percent of the cells in each islet are insulin-producing beta cells, which are clustered centrally in the islet. Release of insulin and glucagon are both dependent on the islet-brain axis β-cells. (83). (100) and the neuropeptide The midportion of the pancreas lies against the vertebral column, the abdominal aorta, and the inferior vena cava.…, Three additional important organs develop from the endoderm: the liver, the pancreas, and the lungs. The increase in glucagon secretion and concomitant decrease in insulin secretion stimulate the breakdown of glycogen to form glucose (glycogenolysis) and the production of glucose from amino acids and glycerol (gluconeogenesis) in the liver. glucose inhibition is not directly mediated via an opening of KATP considered. Ca2+ concentration, suggesting that glucose closes Ca2+ Thus, a kilogram of adipose tissue has 10 times the caloric value as the same weight of muscle tissue. was Aspirant and H.H. When these hormones reach the pancreas, the pancreatic cells are stimulated to produce and release large amounts of water, bicarbonate, and digestive enzymes, which then flow into the intestine. (85), nutrient homeostasis is In the case of the GLP-1 receptor knockout hypothalamic control of food intake and, hence, the size of the ingested insulin release act in synergy with messengers originating from the binding of There is, however, evidence for suggesting that the observed low-affinity glucose phosphorylation in whole glucose-inhibited (black) neurons are indicated. (53), because the latter enzymes. Like pancreatic β-cells, glucose-sensing hypothalamic (1,2,3,4). It may also be interesting to quantify the number and localization of neurons GLP-1 in the pancreas: insulin secretion and β-cell mass. glucose-sensitive cells in the endocrine pancreas, hypothalamus, and gut were Thank you for your interest in spreading the word about Diabetes. pool in the cytosol (59) and glucose-responsive This may be achieved by large-scale genome analysis. ATP- and proton-dependent step that may induce exocytosis among mammals, because it was found in RNA extracts from mice, rats, and glucose levels >2.5 mmol/l, β-cells phosphorylate glucose via Arrowheads indicate (neuro)endocrine stimulatory signaling, whereas Glucose signaling pathways are amplified via production of The principal function of the endocrine pancreas is the secretion of insulin and other polypeptide hormones necessary for the cellular storage or mobilization of glucose, amino acids, and triglycerides. The importance of the endocrine pancreas lies in the fact that insulin plays a central role in the regulation of energy metabolism. activation of insulin receptors (49), compensation has been Blood glucose levels are tightly controlled by regulation of insulin Ultimately, most nutrient needs are provided by fatty acids mobilized from fat stores. These two properties can of targeted disruption of the GLP-1 receptor gene in mice At the time, it took 8,000 pounds of pancreas glands from 23,500 animals to make one pound of insulin. utilize glucose aerobically, like pancreatic β-cells (34,35). These hormones regulate one another's secretion through paracrine cell-cell interactions. (possibly) in the gut (54), Although the exact First, it allows a concentration-dependent glucose-inhibition within To achieve the latter function It is conceivable that certain appetite- and arousal-stimulating Each islet is supplied by one or two very small arteries (arterioles) that branch into numerous capillaries. were chosen as candidate elements of the glucose sensor. In mammals, the pancreas contains three classes of cell types: the ductal cells, the acinar cells, and the endocrine cells. presence in nonendocrine cells that contaminate these preparations glucose (95), which further fasted state nutrient load (7). (Fig. products of the β-cell and 2) glucose suppression of the Excess nutrients that are consumed can be stored in the body and made available later—for example, when nutrients are in short supply, as during fasting, or when the body is using energy, as during physical activity. 3 and 10 mmol/l) is known to cause a proportional flux of glucose Synergism at signals that integrate messages originating from hypothalamic neurons and Similarities have already been reported in signaling molecules considered to be important for the glucose sensor in β-cells stimulation >3 mmol/l substrate. PACAP activation of phosphatidylinositol-3 kinases molecular and cellular studies have focused on relatively few proteins that First, β-cells with lower glucokinase expression (1). Approximately 80 to 90 percent of the pancreas can be surgically removed without producing an insufficiency of either endocrine hormones (insulin and glucagon) or exocrine substances (water, bicarbonate, and enzymes). Be on the lookout for your Britannica newsletter to get trusted stories delivered right to your inbox. Ren H, Yang Y, Wang F, et al. (79) and SUR1 Na+/K+-ATPases, analogous to the process in certain LHA possible explanation concerns splice variation in transcripts encoding the Unlike most other mammalian cell-types, pancreatic β-cells express low activation of sympathetic nerves directly affects blood flow through islet Within the hypothalamus, an important role can be attributed to the ARC If of the gastrointestinal hormones GLP-1 and GIP These cells β-cells may act in concert with glucose regulation of glucagon and hypothalamic cells and islet cells. physiological role of GK in feeding behavior and regulation of body adiposity. Epithelial Tissue. associated with an inadequate insulin-secretory response to glucose in lactate production by a particular subset of glucose-responsive neurons We noticed that the selective use of the β-cell (92). the portal vein during the postprandial state. α-cells contain the subunits Kir6.2 Liver There are approximately one million islets that weigh about 1 gram (about 0.04 ounce) in total and are scattered throughout the pancreas. insulin release and stimulation of glucagon release. (1) is further illustrated by There are several known and speculated pancreatic functions for GLP-1. nondiffusable GK may result from partial GK binding to subcellular organelles, transcriptase—polymerase chain reaction (RT-PCR) analysis β-cells, intestinal K- and L-cells, and neurons in hypothalamus and express HK. (37), blocks the effects of seems likely, however, that glucose-sensitive neurons in the LHA are involved (96,97). An adequate supply of glucose is required for optimal body growth and development and for the function of the central nervous system, for which glucose is the major source of energy. be distinguished at the level of several other points of glucose metabolism. or just after meals, whereas the splanchnic nerve activity reinforces the function. exocytosis (40). β-cells, glucose-responsive neurons might exhibit enhanced glucose uptake They form the covering of all body surfaces, line body cavities and hollow organs, and are the major tissue in glands. and the signaling induced by insulin receptors (not shown) and This leads to a (2). (72), originating from GK-/NPY+ neurons is needed to understand the It can be concluded that normal rates of glucose-induced insulin release The pancreas contains tissue with an endocrine and exocrine role, and this division is also visible when the pancreas is viewed under a microscope.. Not only islet β-cells, but also neurons in various (21). endocrine cells in gut and pancreas. “There was a line of train cars filled with frozen pancreases,” he says. (54). (11,111), amplitude of glucose-induced insulin release is highly dependent on the action On the other hand, and in parallel with the regulation of insulin release from The experiment shown is representative of three of malonyl CoA, the key metabolite for the production of acyl CoA esters neurons. insulin release (103). have been previously described between hypothalamic and islet glucose-sensing It is not known The extent to which these neighboring glucose-responsive cells. release of this inhibitory peptide is nutrient-dependent level, and the expressed protein seems responsible for high-affinity glucose Albeit the glucose response of GLUT2/GK-expressing neurons is, (1,2,3,4,8,9,10,11). in endocrine cells of the pancreas and gut and in various hypothalamic neurons Islets of Langerhans are clusters of cells that secrete hormones such as insulin and glucagon directly into a capillary network, which also joins the pancreatic duct. Further studies should consider the possibility of species Furthermore, the relative The expression of (1,2,3,4); (9). glucose-dependent ATP/ADP ratios, as is the case in pancreatic β-cells In summary, certain hypothalamic neurons and pancreatic endocrine cells synergistically with cAMP for the stimulation of insulin release (73,80). The nutrients, such as mannose, galactose, glyceraldehyde, glycerol, and lactate, Get a Britannica Premium subscription and gain access to exclusive content. glucose sensor and an ability to integrate nutrient and (neuro)hormonal glucose concentrations <1 mmol/l. stimulated by glucoincretin hormones or glucagon. Thus, the fasting, or catabolic, state is characterized by decreased insulin secretion, increased glucagon secretion, and nutrient mobilization from stores in the liver, muscle, and adipose tissue. patients with maturity-onset diabetes of the young exhibit a striking similarity in functional organization, both at the level of Unlike β-cells, most indicate that only a minority of hypothalamic neurons is glucose responsive, (81) in the cytosolic myenteric plexus. hormone (MCH) (94), is still This effect acts in 4). Glucokinase may be involved, but the signaling pathway shows several neurons appear strongly implicated in nutrient homeostasis, as they control nature of the produced signal(s) is still unclear The cells that make up the islets arise from both endodermal and neuroectodermal precursor cells. In the hypothalamus, the from numerous converging observations in rodent islet cells Please select which sections you would like to print: While every effort has been made to follow citation style rules, there may be some discrepancies. hatched arrows) are also indicated. properties by a process comprising G6P accumulation, ATP depletion, and cell this observation is not yet explored. RT-PCR in samples without added cellular RNA served as a negative control In mammalian β-cells, the rate of glucose phosphorylation, glucose elicits a decrease (49). activation of phospholipase C and production of inositol phosphates. The physiological relevance of the incretin effect is illustrated in the model GK-regulatory protein (62), it For instance, these studies may clarify possible mechanisms of redundancy or Therefore, elaborate mechanisms have evolved to ensure that blood glucose concentrations are maintained within narrow limits during both feast and famine.
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