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Hormonal control of metabolism: regulation of plasma glucose
PHYSIOLOGY
Hormonal control of metabolism: regulation of plasma glucose
Learning objectives After reading this article, you should be able to: C understand the physiological regulatory processes contributing to the maintenance of steady state glucose homeostasis C appreciate the role and underlying mechanisms responsible for the pancreatic insulin-glucagon and external modulator response to fluctuations in blood glucose levels C recognize the complex and dynamic interplay between islet and brain-centred glycoregulatory systems in effecting normal glycaemic control
Niroshini Nirmalan Mahesh Nirmalan
Abstract Blood glucose concentrations are required to be maintained within a narrow therapeutic range in order to ensure the normal functioning of the body. This is accomplished through a complex, interactive, finely coordinated neuro-endocrine regulatory process. Hormonal control through the opposing actions of insulin and glucagon secreted by the islet cells of the pancreas serve as the primary response mechanism to avert post-prandial hyperglycaemia and fasting hypoglycaemia. In addition to this basic response, a range of endocrine mediators concurrently intervene, to enable the fine modulation of the process through a range of insulin-dependent and insulin-independent processes, which ultimately achieve glycaemic control by influencing tissue glucose uptake, glycolysis, glycogenesis, glycogenolysis and gluconeogenesis. More recent evidence supports a central, predominantly hypothalamic role initiated through nutrient (glucose, fatty acid) and hormonal (insulin, leptin, glucagon-like peptide-1) stimuli that influences glucose regulation by direct or indirect effects on skeletal muscle glucose uptake, islet cell insulin/glucagon secretion and hepatic glucose production.
endogenous glucose synthesis (gluconeogenesis). Glucose exits the blood when utilised by many organs and tissue, especially the brain, muscle and adipose tissues. The net effect of the influx and efflux mechanisms result in the maintenance of arterial blood glucose concentrations between 3.5 mmol/litre (after exercise) to 9 mmol/litre (following a meal), while post-prandial levels are confined within a narrow range of 4e5.5 mmol/litre. Glucose homeostasis is primarily driven by the concurrent, opposing actions of a range of hormone. Insulin promotes the lowering of plasma glucose concentrations and its subsequent conversion to glycogen, while glucagon acts as the main opposing hormone to increase plasma glucose levels by promoting glucose release from the liver through glycogen breakdown. The dynamic interplay between the insulin-glucagon interaction, together with the permissive role of several other hormones (e.g. growth hormone, glucagon-like peptide-1 (GLP1), leptin, c-peptide etc.), non-glucose fuels (e.g. free fatty acids (FFAs)) and catecholamines, provides the complex modulatory framework requisite for maintaining glucose homeostasis. In spite of these complex interactions, the generic framework of ‘normality’ being a dynamic balance between forces that tend to increase the value of a given variable and opposing forces that tend to decrease the value of that variable concurrently, very much holds true when applied to glucose homeostasis. The versatility of the regulatory mechanisms is reflected in its ability to respond to the widely varying carbohydrate concentrations that occur after a heavy meal or prolonged fasting, in addition to being able to deliver the immediate energy requirements of intense exercise or survival responses (e.g. flight or fight response). Glucose is the primary source of energy for most tissues, particularly the nervous system, red blood cells, renal medulla and skeletal muscles. A failure in the regulation of this nutrient can result in hypoglycaemia and hyperglycaemia, with dire clinical consequences including death. It is in fact established that the brain may suffer irreversible damage even after a very brief period of energy depletion, a concern of great importance in anaesthetized or unconscious subjects.
Keywords Brain-islet axis; glucagon; gluconeogenesis; glucose homeostasis; glycogenolysis; insulin; neuro-hormonal regulation Royal College of Anaesthetists CPD Matrix: 1A01
Introduction Glucose, an essential nutrient for living organisms, functions not only as rich source of potential energy, but also as a precursor for a wide array of metabolic intermediates in biosynthetic pathways. Plasma glucose levels are required to be maintained within a narrow range to ensure the normal functioning of organs and tissues. The complex regulation of glucose metabolism is effected by a sophisticated network of hormones and neuropeptides released primarily from the pancreas, liver, intestines, brain, muscle and adipose tissue. Glucose enters the blood stream via the liver through a range of routes including carbohydrate absorption from the intestines, the breakdown of glycogen (glycogenolysis) or
Niroshini Nirmalan MBBS PhD is a Senior Lecturer in the School of Life Sciences, University of Salford, Manchester, UK. Conflicts of interest: none declared.
Absorption and transport of glucose The entry of glucose into cells is by facilitated diffusion via transmembrane glucose transporters (GLUT). GLUT-1, the commonest isoform is ubiquitously present in many cells and is primarily responsible for ensuring the basal glucose needs of the
Mahesh Nirmalan MBBS FRCA PhD is a Consultant in Intensive Care at the Manchester Royal Infirmary and Professor in Medical Education at the Faculty of Biology, Medicine and Health, University of Manchester, UK. Conflicts of interest: none declared.
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PHYSIOLOGY
through exocytosis. Following glucose stimulation, the insulin precursor proinsulin is cleaved to form equal amounts of insulin and connecting peptide (C-peptide). Although the role of Cpeptide is as yet unclear, there is evidence to suggest that it might influence glucose uptake in skeletal muscles in a dose dependent manner. Furthermore, plasma C-peptide levels are often monitored as a surrogate marker of glucose stimulated insulin secretion. Insulin release from b-cells is biphasic, with a major peak within the first 5 minutes of a glucose stimulus follow by a slower smaller peak. Insulin promotes glucose uptake in tissues, particularly the skeletal muscles, liver and adipose tissues. The transport of glucose molecules across the sarcolemma of skeletal muscles which account for approximately 40% of the body mass, therefore, play a crucial role in regulating blood glucose levels. While both GLUT-1 and GLUT-4 mediate the facilitated diffusion of glucose molecules in an insulin sensitive manner, the latter has emerged the dominant isoform in the process, particularly during periods of increased insulin sensitivity, as is the case after following active muscular exercise. However, not all tissues are insulin sensitive. In the liver and pancreas for example, glucose transport is also mediated through GLUT-2 receptors which do not respond to changes in insulin levels. Similarly, glucose uptake in the brain is mediated through GLUT-2 which does not translocate to the plasma membrane in an insulin sensitive manner. Indeed, such an insulin-independent mechanism is key to for glucose homeostatic control outside the function of fuel utilisation, including glucose sensing and maintenance of basal glucose levels. The plasma membrane of hepatocytes is freely permeable to glucose transport permitting a rapid response to any perturbations of blood glucose levels. Increases in insulin levels trigger a signalling pathway which entails the binding of insulin to the insulin receptor and the activation of the canonical insulin receptor substrate (IRS)-phosphatidylinositol 3-OH (PI3K)-Akt pathway. This results in the suppression of hepatic glucose production (HGP) by the inhibition glycogenolysis (the breakdown of glycogen to glucose) and the stimulation of hepatic gluconeogenesis (the synthesis of new glucose from noncarbohydrate carbon substrates). In addition, glycolysis and glycogenesis are triggered within hepatocytes, further aiding the shifting of the glucose load from the plasma into the hepatocytes either for oxidation or for storage as glycogen. A second pancreatic hormone, somatostatin, released by the d cells of the pancreatic islets in response to high plasma glucose, amino acids and fatty acids, contributes to glucose homeostasis by acting as an inhibitor of insulin secretion. Accurate glycaemic control by the islets is very much dependent on the opposing arm of the regulation involving a second hormone glucagon. In contrast to insulin, glucagon release by a cells of the pancreatic islets is triggered by a reduction in blood glucose levels. Glucagon opposes hypoglycaemia by mobilizing glucose into the plasma through increased glycogenolysis and gluconeogenesis. In addition, the simultaneous inhibition of the intra-hepatic glycolysis and glycogenesis impedes further glucose uptake by hepatocytes (Figure 1). The islet centred model for glycaemic control proposes that the regulatory process is initiated primarily by the effect of high levels of blood glucose.
cells. This form of transport is dependent on a concentration gradient and the rapid metabolism of glucose ensures that intracellular levels are relatively lower than plasma concentrations. The human genome encodes for 12 passive glucose transporters. GLUT-2 is primarily responsible for the transport of glucose out of hepatocytes when breakdown of glycogen occurs. GLUT-4 is a transporter found in adipose tissues, skeletal and cardiac muscles and its activity is regulated by insulin. The GLUT-4 isoform translocates to the plasma membrane from an intracellular compartment in response to insulin and muscle contractions, resulting in increased glucose uptake in response to high blood glucose concentrations.
Pancreatic regulation of glucose metabolism The pancreas plays a dominant role in the regulation of glucose metabolism by secreting the two key opposing hormones, insulin and glucagon, which are responsible for lowering and increasing glucose levels respectively. The major portion of the pancreas is formed from acinar or exocrine cells which secrete digestive hormones into the duodenum, via the pancreatic and accessory pancreatic ducts. The endocrine function of the pancreas relates to cell clusters called the islets of Langerhans which reside within the exocrine tissue and account for 1e2% of the organ by mass. Five distinct endocrine cell populations reside within the islets of Langerhans and produce varying hormones (Table 1). Insulin is a polypeptide hormone secreted by the b-cells of the islets in response to high blood glucose levels. Glucose uptake by b-cells is through facilitated diffusion using the transporter GLUT-2 located on the cell surface. Within the cells the glucose undergoes glycolysis with ATP generation, which in turn results in closure of the ATP-sensitive Kþ channels (KATP channels). The resultant decrease in the outward movement of Kþ elicits depolarization of the cell membrane and the opening of voltage-dependent Caþþ channels (VDCCs). Insulin is stored in large core-dense vesicles within the b-cells. Increased intracellular Caþþ levels are detected by a family of sensorproteins, synaptotagmins, which in turn form a complex with synaptosomal-associated receptor proteins (SNAREs) to trigger the fusion of the insulin vesicles with the plasma membrane and the release of the hormone into the extracellular environment
Cell populations in the islets of Langerhans, hormones and functions
acells bcells gcells dcells ε-cells
% islet cells
Endocrine hormone
Function
15e35
Glucagon
Increases blood glucose levels
55e80
Insulin
Decreases blood glucose levels
3e5 3e10
Pancreatic polypeptide Somatostatin
<1
Ghrelin
Regulates exocrine and endocrine function of the pancreas Inhibits insulin and glucagon release Regulates apetite
Table 1
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Schematic representation of the traditional islet-centred insulin-glucagon homeostatic mechanism that operates in response to changes in normal blood glucose levels Stimulates glucose uptake by cells Insulin Stimulates glycogen formation
Pancreas
Tissue cells Blood glucose falls to normal range Glucose Glycogen
Liver Stimulus: rising blood glucose level
Imb
ala
nce
Homeostasis: normal blood glucose level about 90 mg/100 ml)
Imb
ala
nce
Stimulus: declining blood glucose level
Blood glucose rises to normal range Pancreas Stimulates glycogen breakdown
Glycogen Glucose
Glucagon
Liver Figure 1
few minutes of a meal. The initial release is followed by a sharp decline in secretion to prevent progression to hypoglycaemia. GLP-1 is also known to down-regulate glucagon secretion by a cells. The decretins in contrast limostatin and neuromedin U (NmU), are secreted in response to fasting and result in the suppression of insulin. Insulin growth factor 1 (IGF-1, also called somatomedin-c), an insulin-mimetic peptide regulated by growth hormone, is primarily produced in the liver and to a lesser extent in the skeletal muscles and adipose tissues. Though structurally similar, it is less potent than insulin, it enables glucose disposal in concert with insulin, the two hormones thus having as additive effect.
External modulation of pancreatic hormone secretion While the primary control of glucose homeostasis is reliant on the coordinated regulatory balance between insulin and glucagon, a great variety of modulators, either potentiate or inhibit the process (Table 2). In the gut, glucose triggers the releases incretin hormones including GLP-1 and glucose-dependent insulinotropic peptide (GIP) by the entero-endocrine L and K cells respectively, which potentiate glucose-induced insulin secretion by binding to specific G-protein coupled receptors in pancreatic b-cells. This in turn triggers the cAMP signalling pathway where by intracellular Caþþ concentration is increased by mobilizing internal ryanodine sensitive stores and triggering voltage-dependent Caþþ channels. The potentiation of insulin release is through the resultant increase and exocytosis of the highly Caþþ sensitive insulin-containing granules as described previously. GLP-1 and GIP may account for approximately 50% of the insulin released by the islets. GLP-1 constitutes the first line of defence against hyperglycaemia and is released within a
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Neural modulation of glucose homeostasis The link between the central nervous system (CNS) and glucose homeostasis was proposed in the 19th century, following observations by Claude Bernard that punctures in the floor of the fourth ventricle triggered the occurrence of glycosuria. The
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PHYSIOLOGY
Phases of glucose homeostasis in relation to nutritional status Phase I
Phase II
Phase III
Phase IV
Nutritional status Primary source of glucose
Well fed Exogenous
Early fasting Hepatic gluconeogenesis Renal gluconeogenesis
Prolonged fasting Renal gluconeogenesis Hepatic gluconeogenesis
Tissue glucose uptake
All tissues
Post-absorption Hepatic glucose production e Glycogenolysis e Gluconeogenesis All (exception of the liver)
RBC normal, brain diminished
Primary fuel source
Glucose
Glucose
Mainly brain and red blood cells (RBCs) Glucose Ketone bodies
Ketone bodies Glucose
Table 2
century that followed focused much of its research on discerning the role of the pancreatic islets in glucose homeostasis. More recently however, a growing body of evidence indicates that the brain, particularly the hypothalamus, has the ability to directly sense and control hormones and nutrients involved in the homeostatic process, thus supporting the existence of a parallel, brain-centred glycoregulatory system (BCGS). Although the islet and brain-centred systems are distinct and well defined, the eventual control of blood glucose is heavily dependent on the dynamic, cooperative, and compensatory interplay between the two regulatory systems. The resulting redundancy, clearly acts as the much needed safety net to ensure that the body’s primary fuel source is tightly regulated. Presumably, failure of both systems is requisite to allow for the development and progression of diseases like diabetes or more importantly life-threatening hypoglycaemia. Glucose is the primary source of fuel for many cells and tissues in the human body and the sole energy substrate for the brain. Hence the discovery of hormone and nutrient sensing mechanisms in the brain that regulate glucose homeostasis is hardly a surprise. A surge in research over the past two decades has provided a clearer understanding of the molecular mechanisms underpinning the orchestration of this neural pathway. The CNS is sensitive to a range of regulatory hormones including insulin, leptin, GLP-1 as well nutrients like glucose and fatty acids. Interestingly, in addition to a peripheral role on the islets, both insulin and GLP-1 act on the CNS centrally to regulate peripheral glucose levels. Many recent studies have documented the glycol-regulatory nature of therapeutic interventions targeting certain areas of the brain, particularly the hypothalamus and the brain stem. A decrease in blood glucose levels and an accompanying increase in hepatic insulin sensitivity results as a response to the injection of insulin or glucose in defined hypothalamic sites. In contrast, deletion of hypothalamic insulin or leptin receptors results in glucose intolerance and systemic insulin resistance. In mice models of uncontrolled diabetes, the intra-cerebro-ventricular (ICV) administration of pharmacological doses of the adipocyte hormone leptin resulted in normalizing of elevated blood glucose levels through increasing tissue uptake and normalizing HGP. Since the latter was effected in a background of low insulin levels, the observed central leptin-induced normalization of HGP is likely to be mediated by a mechanism other than increased
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hepatic insulin sensitivity. More recent data from the Shulman laboratory support the involvement of the hypothalamicpituitary-adrenal (HPA) axis for mediating the ICV leptin effects in uncontrolled diabetes. Recent studies have also confirmed the presence of hypothalamic glucose sensing neurons which react through ‘excitation’ or ‘inhibition’ in response to fluctuations in ambient blood glucose and nutrient levels. High levels of post-prandial circulating nutrients (glucose, fatty acids, amino acids etc.) trigger the rich intestinal network comprised of sympathetic and parasympathetic primary visceral afferent nerve fibres, which in turn project the impulses to the central areas of the brain, primarily the hind brain and hypothalamic regions. In addition central impulses are relayed through secretions from intestinal neuroendocrine cells which release a series of peptide hormones including ghrelin, cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and GLP-1. These hormones can have CNS effect by either acting locally through the afferent autonomic fibres or enter the circulation and mediate direct central effects. In addition to its previously described peripheral role on the pancreas, a central role for GLP-1 is postulated whereby centrally administered ICV infusions of GLP-1 improve glucose tolerance and pharmacological antagonist of GLP-1 receptors reverse the effect. High intestinal fatty acid levels stimulate the secretion of CCK from duodenal I-cells which results in activation of specific CCK receptors of vagal afferents and ultimately suppress HGP. The critical role of CCK is exemplified in non-insulin dependent diabetes mellitus. Here, reduced plasma levels of CCK impair homeostatic control mechanisms, resulting in post-prandial hyperglycaemia. The complex neuro-endocrine regulatory system enables the fine coordination of the gut-brain-pancreas-liver axis, effecting changes in the circulating glucose levels to enable tight homeostatic control of the body’s vital fuel source (Figure 2). A significant body of evidence suggests that in addition to insulindependent glycaemic control, the brain, in coordination with neuro-endocrine signals emanating from the gut, can cause significant suppression of blood glucose levels through insulinindependent mechanisms. Recent work on the role of the CNS in glycaemic control has highlighted a potential overlap of central circuits overseeing energy regulation and body weight. The arcuate nucleus in the hypothalamus where glucose-sensing neurons have been identified is also known to house the NPY
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PHYSIOLOGY
Interactive model of brain and islet-centred glucose regulatory mechanisms BCGS
Adipose tissue
Leptin
Glucose, nutrients Insulin
Pancreas
FGF19 Vagal afferents
–
–
Hepatic glucose production
+
+
Insulin-dependent glucose uptake
+
Gastrointestinal tract
Insulin-independent glucose disposal
Blood glucose
BCGS, brain-centred glycoregulatory system. Figure 2
neurons that stimulate appetite and POMC neurons that suppress appetite. Leptin, the primary adipokine secreted by adipocytes has a dual role in modulating insulin release as well as acting on receptors in the hypothalamic arcuate nucleus to inhibit food intake. In the pancreatic islets, leptins suppress insulin secretion through activation of the KATP channels which decrease Caþþ influx. Central control of glucose homeostasis is undoubtedly complex, but is clearly of great clinical relevance in attempting to understand how diseases that predominantly affect the CNS can be associated with conditions such as obesity and type 2 diabetes. While it is now an established concept, the extent of its contribution towards maintaining physiological blood glucose levels and the detailed mechanisms by which its effects are delivered, is less defined.
which catalyses the final step of the gluconeogenesis and glycogenolysis pathways hydrolysing glucose-6-phosphate into free glucose and a phosphate group. With the exception of the liver and the kidneys, other tissues do not contribute to a direct increase in blood glucose levels. Hypoglycaemic states trigger a range of hormonal responses including the secretion of catecholamines, glucagon, cortisol and somatostatin. Glucagon counteracts fasting induced hypoglycaemia by promoting gluconeogenesis and glycogenolysis through enhancing the activity of G6Pase and other enzymes the two pathways and concurrently suppressing skeletal muscle uptake of glucose and glycolysis. A similar mechanism is also employed by catecholamines and stress hormones (somatostatin and steroids) to enable a rapid increase of blood glucose levels in response to stress situations (severe exercise, flight or fright reaction). They act by increasing blood glucose and fatty acid levels through a range of metabolic affects. In addition, somatostatin minimizes glucose usage by inhibiting general metabolic activity through suppressing thyroid-stimulating hormone. While the hormones do not contribute significantly to the regulation of fuel metabolism in a resting phase, they are very important modulators in times of stress, injury and critical illness. In prolonged fasting states, the renal gluconeogenic response, producing glucose from glutamine, could account for as much as 50% of the blood glucose needs. Epinephrine
Homeostatic responses to hypoglycaemia Factors affecting normal glycaemic control have been discussed above. The pathological consequences for acute or sustained fluctuations in blood glucose levels outside the normal physiological range can be dire. In patients without diabetes, a hypoglycaemic state can be precipitated due to fasting or prolonged exercise and is usually accompanied by depletion of cellular glycogen stores. The dominant response to this situation is mediated by the liver, the primary source of non-dietary glucose because of the presence of glucose-6-phosphatase (G6Pase),
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continues to unravel with increasing research activity in the area. While the islet-based insulin-glucagon modulatory axis performs the primary and pivotal role of modulating and responding to gross changes in the normal fluctuations of blood glucose levels, a myriad of neuro-hormonal inputs enable the finer regulation of the process to ensure sustained glycaemic control within the narrow therapeutic limits required to ensure health. A
augments renal gluconeogenesis while insulin has an opposing effect. Type 1 diabetics display an impaired ability to respond to hypoglycaemia due to reduced glucagon levels. Such patients are heavily reliant on renal gluconeogenesis to counteract effects of hypoglycaemia. In prolonged fasting (carbohydrate stress), fatty acid mobilization as an alternate fuel source is initiated through glucagon signalling, resulting in activation of hormone-sensitive lipase in adipose tissues and suppression of acetyl-CoA carboxylase activity in the liver. Ketones produced from excess fatty acid oxidation provide an alternate fuel source to glucose, initially in skeletal muscles, but eventually in the brain as well. The different phases of glucose homeostasis in response to host nutritional status are summarized in Table 2. The compensatory homeostatic changes are reversed after feeding, when the glucose and glycogen stores are replete.
FURTHER READING Lin HV, Accili D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab 2011; 14: 9e19. Morton GJ, Schwartz MW. Leptin and the central nervous system control of glucose metabolism. Physiol Rev 2011; 91: 389e411. Osundiji MA, Evans ML. Brain control of insulin and glucagon secretion. Endocrinol Metab Clin North Am 2013; 42: 1e14. € der PV, Wu B, Liu Y, Han Y. Pancreatic regulation of glucose Ro homeostasis. Exp Mol Med 2016; 48: e219. http://dx.doi.org/10. 1038/emm.2016.6. Sandoval D, Cota D, Seeley RJ. The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol 2008; 70: 513e35. € p MH, et al. Cooperation between Schwartz MW, Seeley RJ, Tscho brain and islet in glucose homeostasis and diabetes. Nature 2013; 503: 59e66.
Conclusion Glucose is the primary metabolic substrate and fuel source for all mammalian cells and tissues. The obligatory use of glucose as a fuel source by the brain and red blood cells means that any perturbation the blood glucose levels outside its narrow therapeutic range, can result in severe pathological consequences, even death. The complexity of the glucose homeostatic response
ANAESTHESIA AND INTENSIVE CARE MEDICINE 18:10
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Ó 2017 Published by Elsevier Ltd.
Hormonal control of metabolism: regulation of plasma glucose
Learning objectives After reading this article, you should be able to: C understand the physiological regulatory processes contributing to the maintenance of steady state glucose homeostasis C appreciate the role and underlying mechanisms responsible for the pancreatic insulin-glucagon and external modulator response to fluctuations in blood glucose levels C recognize the complex and dynamic interplay between islet and brain-centred glycoregulatory systems in effecting normal glycaemic control
Niroshini Nirmalan Mahesh Nirmalan
Abstract Blood glucose concentrations are required to be maintained within a narrow therapeutic range in order to ensure the normal functioning of the body. This is accomplished through a complex, interactive, finely coordinated neuro-endocrine regulatory process. Hormonal control through the opposing actions of insulin and glucagon secreted by the islet cells of the pancreas serve as the primary response mechanism to avert post-prandial hyperglycaemia and fasting hypoglycaemia. In addition to this basic response, a range of endocrine mediators concurrently intervene, to enable the fine modulation of the process through a range of insulin-dependent and insulin-independent processes, which ultimately achieve glycaemic control by influencing tissue glucose uptake, glycolysis, glycogenesis, glycogenolysis and gluconeogenesis. More recent evidence supports a central, predominantly hypothalamic role initiated through nutrient (glucose, fatty acid) and hormonal (insulin, leptin, glucagon-like peptide-1) stimuli that influences glucose regulation by direct or indirect effects on skeletal muscle glucose uptake, islet cell insulin/glucagon secretion and hepatic glucose production.
endogenous glucose synthesis (gluconeogenesis). Glucose exits the blood when utilised by many organs and tissue, especially the brain, muscle and adipose tissues. The net effect of the influx and efflux mechanisms result in the maintenance of arterial blood glucose concentrations between 3.5 mmol/litre (after exercise) to 9 mmol/litre (following a meal), while post-prandial levels are confined within a narrow range of 4e5.5 mmol/litre. Glucose homeostasis is primarily driven by the concurrent, opposing actions of a range of hormone. Insulin promotes the lowering of plasma glucose concentrations and its subsequent conversion to glycogen, while glucagon acts as the main opposing hormone to increase plasma glucose levels by promoting glucose release from the liver through glycogen breakdown. The dynamic interplay between the insulin-glucagon interaction, together with the permissive role of several other hormones (e.g. growth hormone, glucagon-like peptide-1 (GLP1), leptin, c-peptide etc.), non-glucose fuels (e.g. free fatty acids (FFAs)) and catecholamines, provides the complex modulatory framework requisite for maintaining glucose homeostasis. In spite of these complex interactions, the generic framework of ‘normality’ being a dynamic balance between forces that tend to increase the value of a given variable and opposing forces that tend to decrease the value of that variable concurrently, very much holds true when applied to glucose homeostasis. The versatility of the regulatory mechanisms is reflected in its ability to respond to the widely varying carbohydrate concentrations that occur after a heavy meal or prolonged fasting, in addition to being able to deliver the immediate energy requirements of intense exercise or survival responses (e.g. flight or fight response). Glucose is the primary source of energy for most tissues, particularly the nervous system, red blood cells, renal medulla and skeletal muscles. A failure in the regulation of this nutrient can result in hypoglycaemia and hyperglycaemia, with dire clinical consequences including death. It is in fact established that the brain may suffer irreversible damage even after a very brief period of energy depletion, a concern of great importance in anaesthetized or unconscious subjects.
Keywords Brain-islet axis; glucagon; gluconeogenesis; glucose homeostasis; glycogenolysis; insulin; neuro-hormonal regulation Royal College of Anaesthetists CPD Matrix: 1A01
Introduction Glucose, an essential nutrient for living organisms, functions not only as rich source of potential energy, but also as a precursor for a wide array of metabolic intermediates in biosynthetic pathways. Plasma glucose levels are required to be maintained within a narrow range to ensure the normal functioning of organs and tissues. The complex regulation of glucose metabolism is effected by a sophisticated network of hormones and neuropeptides released primarily from the pancreas, liver, intestines, brain, muscle and adipose tissue. Glucose enters the blood stream via the liver through a range of routes including carbohydrate absorption from the intestines, the breakdown of glycogen (glycogenolysis) or
Niroshini Nirmalan MBBS PhD is a Senior Lecturer in the School of Life Sciences, University of Salford, Manchester, UK. Conflicts of interest: none declared.
Absorption and transport of glucose The entry of glucose into cells is by facilitated diffusion via transmembrane glucose transporters (GLUT). GLUT-1, the commonest isoform is ubiquitously present in many cells and is primarily responsible for ensuring the basal glucose needs of the
Mahesh Nirmalan MBBS FRCA PhD is a Consultant in Intensive Care at the Manchester Royal Infirmary and Professor in Medical Education at the Faculty of Biology, Medicine and Health, University of Manchester, UK. Conflicts of interest: none declared.
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Ó 2017 Published by Elsevier Ltd.
PHYSIOLOGY
through exocytosis. Following glucose stimulation, the insulin precursor proinsulin is cleaved to form equal amounts of insulin and connecting peptide (C-peptide). Although the role of Cpeptide is as yet unclear, there is evidence to suggest that it might influence glucose uptake in skeletal muscles in a dose dependent manner. Furthermore, plasma C-peptide levels are often monitored as a surrogate marker of glucose stimulated insulin secretion. Insulin release from b-cells is biphasic, with a major peak within the first 5 minutes of a glucose stimulus follow by a slower smaller peak. Insulin promotes glucose uptake in tissues, particularly the skeletal muscles, liver and adipose tissues. The transport of glucose molecules across the sarcolemma of skeletal muscles which account for approximately 40% of the body mass, therefore, play a crucial role in regulating blood glucose levels. While both GLUT-1 and GLUT-4 mediate the facilitated diffusion of glucose molecules in an insulin sensitive manner, the latter has emerged the dominant isoform in the process, particularly during periods of increased insulin sensitivity, as is the case after following active muscular exercise. However, not all tissues are insulin sensitive. In the liver and pancreas for example, glucose transport is also mediated through GLUT-2 receptors which do not respond to changes in insulin levels. Similarly, glucose uptake in the brain is mediated through GLUT-2 which does not translocate to the plasma membrane in an insulin sensitive manner. Indeed, such an insulin-independent mechanism is key to for glucose homeostatic control outside the function of fuel utilisation, including glucose sensing and maintenance of basal glucose levels. The plasma membrane of hepatocytes is freely permeable to glucose transport permitting a rapid response to any perturbations of blood glucose levels. Increases in insulin levels trigger a signalling pathway which entails the binding of insulin to the insulin receptor and the activation of the canonical insulin receptor substrate (IRS)-phosphatidylinositol 3-OH (PI3K)-Akt pathway. This results in the suppression of hepatic glucose production (HGP) by the inhibition glycogenolysis (the breakdown of glycogen to glucose) and the stimulation of hepatic gluconeogenesis (the synthesis of new glucose from noncarbohydrate carbon substrates). In addition, glycolysis and glycogenesis are triggered within hepatocytes, further aiding the shifting of the glucose load from the plasma into the hepatocytes either for oxidation or for storage as glycogen. A second pancreatic hormone, somatostatin, released by the d cells of the pancreatic islets in response to high plasma glucose, amino acids and fatty acids, contributes to glucose homeostasis by acting as an inhibitor of insulin secretion. Accurate glycaemic control by the islets is very much dependent on the opposing arm of the regulation involving a second hormone glucagon. In contrast to insulin, glucagon release by a cells of the pancreatic islets is triggered by a reduction in blood glucose levels. Glucagon opposes hypoglycaemia by mobilizing glucose into the plasma through increased glycogenolysis and gluconeogenesis. In addition, the simultaneous inhibition of the intra-hepatic glycolysis and glycogenesis impedes further glucose uptake by hepatocytes (Figure 1). The islet centred model for glycaemic control proposes that the regulatory process is initiated primarily by the effect of high levels of blood glucose.
cells. This form of transport is dependent on a concentration gradient and the rapid metabolism of glucose ensures that intracellular levels are relatively lower than plasma concentrations. The human genome encodes for 12 passive glucose transporters. GLUT-2 is primarily responsible for the transport of glucose out of hepatocytes when breakdown of glycogen occurs. GLUT-4 is a transporter found in adipose tissues, skeletal and cardiac muscles and its activity is regulated by insulin. The GLUT-4 isoform translocates to the plasma membrane from an intracellular compartment in response to insulin and muscle contractions, resulting in increased glucose uptake in response to high blood glucose concentrations.
Pancreatic regulation of glucose metabolism The pancreas plays a dominant role in the regulation of glucose metabolism by secreting the two key opposing hormones, insulin and glucagon, which are responsible for lowering and increasing glucose levels respectively. The major portion of the pancreas is formed from acinar or exocrine cells which secrete digestive hormones into the duodenum, via the pancreatic and accessory pancreatic ducts. The endocrine function of the pancreas relates to cell clusters called the islets of Langerhans which reside within the exocrine tissue and account for 1e2% of the organ by mass. Five distinct endocrine cell populations reside within the islets of Langerhans and produce varying hormones (Table 1). Insulin is a polypeptide hormone secreted by the b-cells of the islets in response to high blood glucose levels. Glucose uptake by b-cells is through facilitated diffusion using the transporter GLUT-2 located on the cell surface. Within the cells the glucose undergoes glycolysis with ATP generation, which in turn results in closure of the ATP-sensitive Kþ channels (KATP channels). The resultant decrease in the outward movement of Kþ elicits depolarization of the cell membrane and the opening of voltage-dependent Caþþ channels (VDCCs). Insulin is stored in large core-dense vesicles within the b-cells. Increased intracellular Caþþ levels are detected by a family of sensorproteins, synaptotagmins, which in turn form a complex with synaptosomal-associated receptor proteins (SNAREs) to trigger the fusion of the insulin vesicles with the plasma membrane and the release of the hormone into the extracellular environment
Cell populations in the islets of Langerhans, hormones and functions
acells bcells gcells dcells ε-cells
% islet cells
Endocrine hormone
Function
15e35
Glucagon
Increases blood glucose levels
55e80
Insulin
Decreases blood glucose levels
3e5 3e10
Pancreatic polypeptide Somatostatin
<1
Ghrelin
Regulates exocrine and endocrine function of the pancreas Inhibits insulin and glucagon release Regulates apetite
Table 1
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Ó 2017 Published by Elsevier Ltd.
PHYSIOLOGY
Schematic representation of the traditional islet-centred insulin-glucagon homeostatic mechanism that operates in response to changes in normal blood glucose levels Stimulates glucose uptake by cells Insulin Stimulates glycogen formation
Pancreas
Tissue cells Blood glucose falls to normal range Glucose Glycogen
Liver Stimulus: rising blood glucose level
Imb
ala
nce
Homeostasis: normal blood glucose level about 90 mg/100 ml)
Imb
ala
nce
Stimulus: declining blood glucose level
Blood glucose rises to normal range Pancreas Stimulates glycogen breakdown
Glycogen Glucose
Glucagon
Liver Figure 1
few minutes of a meal. The initial release is followed by a sharp decline in secretion to prevent progression to hypoglycaemia. GLP-1 is also known to down-regulate glucagon secretion by a cells. The decretins in contrast limostatin and neuromedin U (NmU), are secreted in response to fasting and result in the suppression of insulin. Insulin growth factor 1 (IGF-1, also called somatomedin-c), an insulin-mimetic peptide regulated by growth hormone, is primarily produced in the liver and to a lesser extent in the skeletal muscles and adipose tissues. Though structurally similar, it is less potent than insulin, it enables glucose disposal in concert with insulin, the two hormones thus having as additive effect.
External modulation of pancreatic hormone secretion While the primary control of glucose homeostasis is reliant on the coordinated regulatory balance between insulin and glucagon, a great variety of modulators, either potentiate or inhibit the process (Table 2). In the gut, glucose triggers the releases incretin hormones including GLP-1 and glucose-dependent insulinotropic peptide (GIP) by the entero-endocrine L and K cells respectively, which potentiate glucose-induced insulin secretion by binding to specific G-protein coupled receptors in pancreatic b-cells. This in turn triggers the cAMP signalling pathway where by intracellular Caþþ concentration is increased by mobilizing internal ryanodine sensitive stores and triggering voltage-dependent Caþþ channels. The potentiation of insulin release is through the resultant increase and exocytosis of the highly Caþþ sensitive insulin-containing granules as described previously. GLP-1 and GIP may account for approximately 50% of the insulin released by the islets. GLP-1 constitutes the first line of defence against hyperglycaemia and is released within a
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Neural modulation of glucose homeostasis The link between the central nervous system (CNS) and glucose homeostasis was proposed in the 19th century, following observations by Claude Bernard that punctures in the floor of the fourth ventricle triggered the occurrence of glycosuria. The
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Phases of glucose homeostasis in relation to nutritional status Phase I
Phase II
Phase III
Phase IV
Nutritional status Primary source of glucose
Well fed Exogenous
Early fasting Hepatic gluconeogenesis Renal gluconeogenesis
Prolonged fasting Renal gluconeogenesis Hepatic gluconeogenesis
Tissue glucose uptake
All tissues
Post-absorption Hepatic glucose production e Glycogenolysis e Gluconeogenesis All (exception of the liver)
RBC normal, brain diminished
Primary fuel source
Glucose
Glucose
Mainly brain and red blood cells (RBCs) Glucose Ketone bodies
Ketone bodies Glucose
Table 2
century that followed focused much of its research on discerning the role of the pancreatic islets in glucose homeostasis. More recently however, a growing body of evidence indicates that the brain, particularly the hypothalamus, has the ability to directly sense and control hormones and nutrients involved in the homeostatic process, thus supporting the existence of a parallel, brain-centred glycoregulatory system (BCGS). Although the islet and brain-centred systems are distinct and well defined, the eventual control of blood glucose is heavily dependent on the dynamic, cooperative, and compensatory interplay between the two regulatory systems. The resulting redundancy, clearly acts as the much needed safety net to ensure that the body’s primary fuel source is tightly regulated. Presumably, failure of both systems is requisite to allow for the development and progression of diseases like diabetes or more importantly life-threatening hypoglycaemia. Glucose is the primary source of fuel for many cells and tissues in the human body and the sole energy substrate for the brain. Hence the discovery of hormone and nutrient sensing mechanisms in the brain that regulate glucose homeostasis is hardly a surprise. A surge in research over the past two decades has provided a clearer understanding of the molecular mechanisms underpinning the orchestration of this neural pathway. The CNS is sensitive to a range of regulatory hormones including insulin, leptin, GLP-1 as well nutrients like glucose and fatty acids. Interestingly, in addition to a peripheral role on the islets, both insulin and GLP-1 act on the CNS centrally to regulate peripheral glucose levels. Many recent studies have documented the glycol-regulatory nature of therapeutic interventions targeting certain areas of the brain, particularly the hypothalamus and the brain stem. A decrease in blood glucose levels and an accompanying increase in hepatic insulin sensitivity results as a response to the injection of insulin or glucose in defined hypothalamic sites. In contrast, deletion of hypothalamic insulin or leptin receptors results in glucose intolerance and systemic insulin resistance. In mice models of uncontrolled diabetes, the intra-cerebro-ventricular (ICV) administration of pharmacological doses of the adipocyte hormone leptin resulted in normalizing of elevated blood glucose levels through increasing tissue uptake and normalizing HGP. Since the latter was effected in a background of low insulin levels, the observed central leptin-induced normalization of HGP is likely to be mediated by a mechanism other than increased
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hepatic insulin sensitivity. More recent data from the Shulman laboratory support the involvement of the hypothalamicpituitary-adrenal (HPA) axis for mediating the ICV leptin effects in uncontrolled diabetes. Recent studies have also confirmed the presence of hypothalamic glucose sensing neurons which react through ‘excitation’ or ‘inhibition’ in response to fluctuations in ambient blood glucose and nutrient levels. High levels of post-prandial circulating nutrients (glucose, fatty acids, amino acids etc.) trigger the rich intestinal network comprised of sympathetic and parasympathetic primary visceral afferent nerve fibres, which in turn project the impulses to the central areas of the brain, primarily the hind brain and hypothalamic regions. In addition central impulses are relayed through secretions from intestinal neuroendocrine cells which release a series of peptide hormones including ghrelin, cholecystokinin (CCK), fibroblast growth factor 19 (FGF19) and GLP-1. These hormones can have CNS effect by either acting locally through the afferent autonomic fibres or enter the circulation and mediate direct central effects. In addition to its previously described peripheral role on the pancreas, a central role for GLP-1 is postulated whereby centrally administered ICV infusions of GLP-1 improve glucose tolerance and pharmacological antagonist of GLP-1 receptors reverse the effect. High intestinal fatty acid levels stimulate the secretion of CCK from duodenal I-cells which results in activation of specific CCK receptors of vagal afferents and ultimately suppress HGP. The critical role of CCK is exemplified in non-insulin dependent diabetes mellitus. Here, reduced plasma levels of CCK impair homeostatic control mechanisms, resulting in post-prandial hyperglycaemia. The complex neuro-endocrine regulatory system enables the fine coordination of the gut-brain-pancreas-liver axis, effecting changes in the circulating glucose levels to enable tight homeostatic control of the body’s vital fuel source (Figure 2). A significant body of evidence suggests that in addition to insulindependent glycaemic control, the brain, in coordination with neuro-endocrine signals emanating from the gut, can cause significant suppression of blood glucose levels through insulinindependent mechanisms. Recent work on the role of the CNS in glycaemic control has highlighted a potential overlap of central circuits overseeing energy regulation and body weight. The arcuate nucleus in the hypothalamus where glucose-sensing neurons have been identified is also known to house the NPY
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Interactive model of brain and islet-centred glucose regulatory mechanisms BCGS
Adipose tissue
Leptin
Glucose, nutrients Insulin
Pancreas
FGF19 Vagal afferents
–
–
Hepatic glucose production
+
+
Insulin-dependent glucose uptake
+
Gastrointestinal tract
Insulin-independent glucose disposal
Blood glucose
BCGS, brain-centred glycoregulatory system. Figure 2
neurons that stimulate appetite and POMC neurons that suppress appetite. Leptin, the primary adipokine secreted by adipocytes has a dual role in modulating insulin release as well as acting on receptors in the hypothalamic arcuate nucleus to inhibit food intake. In the pancreatic islets, leptins suppress insulin secretion through activation of the KATP channels which decrease Caþþ influx. Central control of glucose homeostasis is undoubtedly complex, but is clearly of great clinical relevance in attempting to understand how diseases that predominantly affect the CNS can be associated with conditions such as obesity and type 2 diabetes. While it is now an established concept, the extent of its contribution towards maintaining physiological blood glucose levels and the detailed mechanisms by which its effects are delivered, is less defined.
which catalyses the final step of the gluconeogenesis and glycogenolysis pathways hydrolysing glucose-6-phosphate into free glucose and a phosphate group. With the exception of the liver and the kidneys, other tissues do not contribute to a direct increase in blood glucose levels. Hypoglycaemic states trigger a range of hormonal responses including the secretion of catecholamines, glucagon, cortisol and somatostatin. Glucagon counteracts fasting induced hypoglycaemia by promoting gluconeogenesis and glycogenolysis through enhancing the activity of G6Pase and other enzymes the two pathways and concurrently suppressing skeletal muscle uptake of glucose and glycolysis. A similar mechanism is also employed by catecholamines and stress hormones (somatostatin and steroids) to enable a rapid increase of blood glucose levels in response to stress situations (severe exercise, flight or fright reaction). They act by increasing blood glucose and fatty acid levels through a range of metabolic affects. In addition, somatostatin minimizes glucose usage by inhibiting general metabolic activity through suppressing thyroid-stimulating hormone. While the hormones do not contribute significantly to the regulation of fuel metabolism in a resting phase, they are very important modulators in times of stress, injury and critical illness. In prolonged fasting states, the renal gluconeogenic response, producing glucose from glutamine, could account for as much as 50% of the blood glucose needs. Epinephrine
Homeostatic responses to hypoglycaemia Factors affecting normal glycaemic control have been discussed above. The pathological consequences for acute or sustained fluctuations in blood glucose levels outside the normal physiological range can be dire. In patients without diabetes, a hypoglycaemic state can be precipitated due to fasting or prolonged exercise and is usually accompanied by depletion of cellular glycogen stores. The dominant response to this situation is mediated by the liver, the primary source of non-dietary glucose because of the presence of glucose-6-phosphatase (G6Pase),
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continues to unravel with increasing research activity in the area. While the islet-based insulin-glucagon modulatory axis performs the primary and pivotal role of modulating and responding to gross changes in the normal fluctuations of blood glucose levels, a myriad of neuro-hormonal inputs enable the finer regulation of the process to ensure sustained glycaemic control within the narrow therapeutic limits required to ensure health. A
augments renal gluconeogenesis while insulin has an opposing effect. Type 1 diabetics display an impaired ability to respond to hypoglycaemia due to reduced glucagon levels. Such patients are heavily reliant on renal gluconeogenesis to counteract effects of hypoglycaemia. In prolonged fasting (carbohydrate stress), fatty acid mobilization as an alternate fuel source is initiated through glucagon signalling, resulting in activation of hormone-sensitive lipase in adipose tissues and suppression of acetyl-CoA carboxylase activity in the liver. Ketones produced from excess fatty acid oxidation provide an alternate fuel source to glucose, initially in skeletal muscles, but eventually in the brain as well. The different phases of glucose homeostasis in response to host nutritional status are summarized in Table 2. The compensatory homeostatic changes are reversed after feeding, when the glucose and glycogen stores are replete.
FURTHER READING Lin HV, Accili D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab 2011; 14: 9e19. Morton GJ, Schwartz MW. Leptin and the central nervous system control of glucose metabolism. Physiol Rev 2011; 91: 389e411. Osundiji MA, Evans ML. Brain control of insulin and glucagon secretion. Endocrinol Metab Clin North Am 2013; 42: 1e14. € der PV, Wu B, Liu Y, Han Y. Pancreatic regulation of glucose Ro homeostasis. Exp Mol Med 2016; 48: e219. http://dx.doi.org/10. 1038/emm.2016.6. Sandoval D, Cota D, Seeley RJ. The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol 2008; 70: 513e35. € p MH, et al. Cooperation between Schwartz MW, Seeley RJ, Tscho brain and islet in glucose homeostasis and diabetes. Nature 2013; 503: 59e66.
Conclusion Glucose is the primary metabolic substrate and fuel source for all mammalian cells and tissues. The obligatory use of glucose as a fuel source by the brain and red blood cells means that any perturbation the blood glucose levels outside its narrow therapeutic range, can result in severe pathological consequences, even death. The complexity of the glucose homeostatic response
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