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Endocrine and metabolic pharmacology: new insights into old hormones and novel approaches to treating metabolic disorders
Endocrine and metabolic pharmacology: new insights into old hormones and novel approaches to treating metabolic disorders Editorial overview Brian L Furman and Julia C Buckingham Current Opinion in Pharmacology 2004, 4:580–582 This overview comes from a themed issue on Endocrine and metabolic diseases Edited by Julia Buckingham and Brian Furman
1471-4892/$ – see front matter ß 2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2004.09.002
Brian L Furman Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Taylor Street, Glasgow G4 0NR, UK
Professor Furman is Dean of the Faculty of Science at the University of Strathclyde. His main research interests are concerned with the regulation of blood glucose and insulin secretion. Julia C Buckingham Faculty of Medicine, Imperial College London, Hammersmith campus, Du Cane Road, London W12 0NN, UK
Professor Buckingham is Professor of Pharmacology and Head of the Division of Neuroscience and Psychological Medicine at Imperial College, London. She is editor-in-chief of the Journal of Neuroendocrinology and President of the British Pharmacological Society. Her major research interests are concerned with the regulation of the function of the hypothalamo-pituitary-adrenocortical axis.
Current Opinion in Pharmacology 2004, 4:580–582
Abbreviations 11b-HSD1 11b-hydroxysteroid dehydrogenase-1 DPPIV dipteptidyl peptidase IV GH growth hormone GLP-1 glucagon like peptide 1 PYY peptide YY TRH TSH-releasing hormone UCP uncoupling protein
Separating endocrine and metabolic pharmacology from other types of pharmacology is highly arbitrary when one considers that endocrine hormones are secreted by a vast range of structures that, when the editors were students, would never have been regarded as having a classical endocrine function (e.g. in the heart, kidney and gastrointestinal tract). Moreover, the classic hormones are increasingly being found to have functions and actions not typically associated with endocrine activity. The identification of subtypes of receptors for various hormones has opened up many new therapeutic approaches, and the use of knockout mice or mice in which particular hormones, their receptors or the enzymes responsible for their inactivation are overexpressed has made important contributions to identifying therapeutic targets. The present series of reviews covers a range of endocrine pharmacology from potential new approaches to treating diabetes and obesity to new ideas concerning the fundamental pharmacology of glucocorticoids, which might lead to the holy grail of separating their antiinflammatory actions from their potentially debilitating adverse effects. Obesity and type 2 diabetes mellitus are major health challenges for the 21st century. Currently available treatments for obesity are limited, comprising agents that reduce appetite through central monoaminergic mechanisms (e.g. sibutramine) or inhibitors of intestinal lipase (e.g. orlistat), which reduce fat absorption. Obesity is an important risk factor for type 2 diabetes, which is associated with both insulin resistance and impaired insulin secretion. The review by McGowan and Bloom discusses peptide YY (PYY), one of several hormones synthesised and secreted by the gastrointestinal tract. This hormone, like glucagon like peptide 1 (GLP-1; see below), is secreted by L-cells of the intestine in response to food intake. Obese individuals appear to have reduced circulating PYY concentrations. One circulating form, PYY3-36, acutely inhibits food intake when given www.sciencedirect.com
Editorial overview Furman and Buckingham 581
peripherally to rodents and, during chronic administration, reduces both food intake and body weight gain. Interestingly, the anorectic effects have been reproduced in both normal and obese humans. The review also discusses how stress ameliorates the anorectic effects of PYY3-36, a phenomenon which could explain the difficulty that some laboratories have experienced in reproducing the anorectic actions of the peptide.
diabetic mice. 11b-HSD1 is also highly expressed in the brain, where it can amplify the negative feedback effect of cortisol on the hypothalamus. Glucocorticoids can also play a role in memory disorders and, interestingly, aged 11b-HSD1 / mice show improved ability to learn compared with wild-type mice. The development of selective inhibitors of 11b-HSD1 thus offers exciting therapeutic potential.
Several agents are available for treating type 2 diabetes; these act either by increasing insulin secretion, through inhibition of KATP channels (e.g. sulphonylureas and meglitinide analogues), or by augmenting the peripheral actions of insulin (e.g. metformin and thiazolidinediones). None provides perfect control and novel agents are needed. GLP-1 and glucose-dependent insulinotropic polypeptide, which augment glucose-induced insulin secretion through elevating b-cell cAMP levels, are incretin hormones secreted by the intestine in response to food intake. As discussed in the review by Holst and Deacon, administration of GLP-1 and its analogues has been shown to improve insulin secretion and glucose tolerance in patients with type 2 diabetes. The main problems with GLP-1 are its peptidic nature, necessitating parenteral administration, and its short half-life owing to rapid breakdown by dipteptidyl peptidase IV (DPPIV) and rapid renal excretion. Stable analogues of GLP, which are also slowly excreted, are undergoing investigation as possible treatments for type 2 diabetes. The natural peptide exendin-4 from the venom of the Gila monster is a GLP-1 mimetic and is stable against DPPIV. It is currently in a Phase III clinical trial. Another approach to exploit the incretin mechanism is to inhibit DPPIV, which results in augmentation of the natural incretins GLP-1 and glucosedependent insulinotropic polypeptide. Several orally active DPPIV inhibitors are undergoing development as potential treatments for type 2 diabetes.
Harper and Gerrits review recent information on uncoupling proteins (UCPs), which are mitochondrial transporters present in the mitochondrial inner membrane. The first to be identified, UCP2, is expressed in brown adipose tissue and is unequivocally linked to thermogenesis. Over the past seven years, at least four novel UCPs have been discovered with different tissue distributions and functions. UCP2 is expressed in several tissues, including the stomach, lung, spleen, pancreatic islet b-cells, neurons and various tumour cells. It appears to play an important role in protection from reactive oxygen species and acts as an anti-death protein in tumour cells and neurons. Indeed, protection against reactive oxygen species might also be a function of UCP3, which has a more restricted tissue expression when compared with that of UCP2. UCP3 could have an important role in muscle fatty acid oxidation and in protecting mitochondria from damage induced by fatty acid anions. Much work is needed but the intriguing observation that patients with type 2 diabetes have reduced muscle UCP3 protein levels might link UCP3 to protection from muscle lipid peroxidation and lipotoxicity, and may implicate deficiencies in UCP3 in the aetiology of type 2 diabetes. Little is known about UCP4, expressed exclusively in the brain, or UCP5, which is also abundantly expressed in the brain but at lower levels in other tissues.
Of increasing interest to those working in the fields of diabetes and obesity is the enzyme 11b-hydroxysteroid dehydrogenase-1 (11b-HSD1) which catalyses the regeneration of cortisol from cortisone. The review by Seckl focuses on this enzyme and highlights the consequences of its deficiency. Knockout mice (11b-HSD1 / ) are resistant to stress- or high-fat-induced hyperglycaemia; have reduced serum triglycerides, raised high-density lipoprotein cholesterol and lowered hepatic fibrinogen synthesis; and show reduced expression of ‘insulin resistance cytokines’ (e.g. resistin and tumour necrosis factora) in adipose tissue. Moreover, when the 11b-HSD1 / phenotype is superimposed on an obesity-prone background, the mice gain less weight on a high-fat diet despite showing relative hyperphagia. These observations indicate that 11b-HSD1 is an important therapeutic target for the ‘metabolic syndrome’; indeed, the first inhibitors of this enzyme were found to augment hepatic insulin action and to lower blood glucose in normal and www.sciencedirect.com
Pawlikowski and Mełen´-Mucha have reviewed the rapidly developing field of therapy using somatostatin analogues. Somatostatin, originally discovered as a hypothalamic hormone that inhibited growth hormone (GH) secretion, is now known to inhibit the secretion of many other hormones, decrease gastrointestinal motility and prevent the proliferation of normal and neoplastic cells. The long-acting analogues octreotide and lanreotide show selectivity for the sst2 receptor, with lower affinity for sst3 and sst5 subtypes, and are widely used to treat acromegaly, neuroendocrine tumours and many other conditions, including the control of bleeding of esophageal varices, diarrhoea due to AIDS or chemotherapy, breast cancer, Zollinger-Ellison syndrome and postgastrectomy dumping syndrome. As pharmacologists. we are usually interested in agonists that are highly selective for a single receptor subtype. However, tumours can lose expression of sst2, have mutated sst2 receptors that stimulate rather than inhibit proliferation, or express other receptor subtypes. Therefore, an agent such as SOM230 with high affinity for sst1, sst2, sst3 and sst5 might have Current Opinion in Pharmacology 2004, 4:580–582
582 Endocrine and metabolic diseases
greater therapeutic potential. Chimeric molecules such as BIM-23A387, which selectively binds to sst2 and dopamine D2 receptors, could have great potential in treating acromegaly, prolactinomas and non-functioning pituitary adenomas. There is also considerable interest in coupling somatostatin analogues to cytotoxic drugs or radioisotopes to selectively target tumours expressing high levels of somatostatin receptors. The next two reviews in the section focus on anabolic agents. The first, by Bahrke and Yesalis, discusses anabolic steroids and focuses particularly on androstenedione and dehydroepiandrosterone. Although these two agents are widely used by athletes, there is very little evidence for their effectiveness in increasing strength. The review by Vanhorebeek and Van den Berghe provides a beautiful illustration of the importance of understanding the fundamental pathophysiology of a disorder before designing a rational treatment. Prolonged critical illness results in a hypercatabolic state and a non-specific wasting syndrome with severe muscle weakness, intestinal atrophy, delayed tissue healing and immune dysfunction. Pulsatile GH secretion, which would be anabolic, is suppressed, with a resulting reduction in levels of circulating insulin-like growth factor-I and insulin-like growth factor binding protein. This appears to be a result of hypothalamic deficiency, as normal responsiveness to GH secretagogues is maintained. Other hypothalamic functions, including secretion of TSH-releasing hormone (TRH), are also depressed, leading to impaired thyroid function. However, the restoration of thyroid function requires administration of both TRH and GH secretagogues.
Current Opinion in Pharmacology 2004, 4:580–582
High dose GH administration was predicted to provide a valuable therapy for the wasting syndrome of prolonged critical illness on the basis that GH-deficiency of acute critical illness persists into the chronic phase. A large multi-centre trial showed that this regimen actually increased morbidity and mortality. The authors conclude that now is the time to initiate large-scale clinical trials to examine the effects of hypothalamic secretagogues, such as combinations of GH secretagogues and TRH. The final review by Goulding provides new insights into the molecular actions of glucocorticoids. It addresses the identification of the mechanisms through which glucocorticoids suppress inflammation in an attempt to dissociate these from the actions of glucocorticoids on other metabolic pathways. Recent research has revealed an increasing complexity of the effect of glucocorticoids in relation both to their genomic effects and to their much more rapid non-genomic actions, which also impact upon the inflammatory and immune responses. The review concludes with a temporal spatial model of glucocorticoid action and highlights novel approaches to glucocorticoid pharmacology using gene array technology and complex cluster analysis. In conclusion, we thank the authors for a series of fascinating reviews. These have provided new insights and pointed the way to important therapeutic advances; for example, in the treatment of obesity and the metabolic syndrome, in the treatment of acromegaly and neuroendocrine tumours and in the prevention of the catabolism associated with prolonged critical illness.
www.sciencedirect.com
1471-4892/$ – see front matter ß 2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2004.09.002
Brian L Furman Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Taylor Street, Glasgow G4 0NR, UK
Professor Furman is Dean of the Faculty of Science at the University of Strathclyde. His main research interests are concerned with the regulation of blood glucose and insulin secretion. Julia C Buckingham Faculty of Medicine, Imperial College London, Hammersmith campus, Du Cane Road, London W12 0NN, UK
Professor Buckingham is Professor of Pharmacology and Head of the Division of Neuroscience and Psychological Medicine at Imperial College, London. She is editor-in-chief of the Journal of Neuroendocrinology and President of the British Pharmacological Society. Her major research interests are concerned with the regulation of the function of the hypothalamo-pituitary-adrenocortical axis.
Current Opinion in Pharmacology 2004, 4:580–582
Abbreviations 11b-HSD1 11b-hydroxysteroid dehydrogenase-1 DPPIV dipteptidyl peptidase IV GH growth hormone GLP-1 glucagon like peptide 1 PYY peptide YY TRH TSH-releasing hormone UCP uncoupling protein
Separating endocrine and metabolic pharmacology from other types of pharmacology is highly arbitrary when one considers that endocrine hormones are secreted by a vast range of structures that, when the editors were students, would never have been regarded as having a classical endocrine function (e.g. in the heart, kidney and gastrointestinal tract). Moreover, the classic hormones are increasingly being found to have functions and actions not typically associated with endocrine activity. The identification of subtypes of receptors for various hormones has opened up many new therapeutic approaches, and the use of knockout mice or mice in which particular hormones, their receptors or the enzymes responsible for their inactivation are overexpressed has made important contributions to identifying therapeutic targets. The present series of reviews covers a range of endocrine pharmacology from potential new approaches to treating diabetes and obesity to new ideas concerning the fundamental pharmacology of glucocorticoids, which might lead to the holy grail of separating their antiinflammatory actions from their potentially debilitating adverse effects. Obesity and type 2 diabetes mellitus are major health challenges for the 21st century. Currently available treatments for obesity are limited, comprising agents that reduce appetite through central monoaminergic mechanisms (e.g. sibutramine) or inhibitors of intestinal lipase (e.g. orlistat), which reduce fat absorption. Obesity is an important risk factor for type 2 diabetes, which is associated with both insulin resistance and impaired insulin secretion. The review by McGowan and Bloom discusses peptide YY (PYY), one of several hormones synthesised and secreted by the gastrointestinal tract. This hormone, like glucagon like peptide 1 (GLP-1; see below), is secreted by L-cells of the intestine in response to food intake. Obese individuals appear to have reduced circulating PYY concentrations. One circulating form, PYY3-36, acutely inhibits food intake when given www.sciencedirect.com
Editorial overview Furman and Buckingham 581
peripherally to rodents and, during chronic administration, reduces both food intake and body weight gain. Interestingly, the anorectic effects have been reproduced in both normal and obese humans. The review also discusses how stress ameliorates the anorectic effects of PYY3-36, a phenomenon which could explain the difficulty that some laboratories have experienced in reproducing the anorectic actions of the peptide.
diabetic mice. 11b-HSD1 is also highly expressed in the brain, where it can amplify the negative feedback effect of cortisol on the hypothalamus. Glucocorticoids can also play a role in memory disorders and, interestingly, aged 11b-HSD1 / mice show improved ability to learn compared with wild-type mice. The development of selective inhibitors of 11b-HSD1 thus offers exciting therapeutic potential.
Several agents are available for treating type 2 diabetes; these act either by increasing insulin secretion, through inhibition of KATP channels (e.g. sulphonylureas and meglitinide analogues), or by augmenting the peripheral actions of insulin (e.g. metformin and thiazolidinediones). None provides perfect control and novel agents are needed. GLP-1 and glucose-dependent insulinotropic polypeptide, which augment glucose-induced insulin secretion through elevating b-cell cAMP levels, are incretin hormones secreted by the intestine in response to food intake. As discussed in the review by Holst and Deacon, administration of GLP-1 and its analogues has been shown to improve insulin secretion and glucose tolerance in patients with type 2 diabetes. The main problems with GLP-1 are its peptidic nature, necessitating parenteral administration, and its short half-life owing to rapid breakdown by dipteptidyl peptidase IV (DPPIV) and rapid renal excretion. Stable analogues of GLP, which are also slowly excreted, are undergoing investigation as possible treatments for type 2 diabetes. The natural peptide exendin-4 from the venom of the Gila monster is a GLP-1 mimetic and is stable against DPPIV. It is currently in a Phase III clinical trial. Another approach to exploit the incretin mechanism is to inhibit DPPIV, which results in augmentation of the natural incretins GLP-1 and glucosedependent insulinotropic polypeptide. Several orally active DPPIV inhibitors are undergoing development as potential treatments for type 2 diabetes.
Harper and Gerrits review recent information on uncoupling proteins (UCPs), which are mitochondrial transporters present in the mitochondrial inner membrane. The first to be identified, UCP2, is expressed in brown adipose tissue and is unequivocally linked to thermogenesis. Over the past seven years, at least four novel UCPs have been discovered with different tissue distributions and functions. UCP2 is expressed in several tissues, including the stomach, lung, spleen, pancreatic islet b-cells, neurons and various tumour cells. It appears to play an important role in protection from reactive oxygen species and acts as an anti-death protein in tumour cells and neurons. Indeed, protection against reactive oxygen species might also be a function of UCP3, which has a more restricted tissue expression when compared with that of UCP2. UCP3 could have an important role in muscle fatty acid oxidation and in protecting mitochondria from damage induced by fatty acid anions. Much work is needed but the intriguing observation that patients with type 2 diabetes have reduced muscle UCP3 protein levels might link UCP3 to protection from muscle lipid peroxidation and lipotoxicity, and may implicate deficiencies in UCP3 in the aetiology of type 2 diabetes. Little is known about UCP4, expressed exclusively in the brain, or UCP5, which is also abundantly expressed in the brain but at lower levels in other tissues.
Of increasing interest to those working in the fields of diabetes and obesity is the enzyme 11b-hydroxysteroid dehydrogenase-1 (11b-HSD1) which catalyses the regeneration of cortisol from cortisone. The review by Seckl focuses on this enzyme and highlights the consequences of its deficiency. Knockout mice (11b-HSD1 / ) are resistant to stress- or high-fat-induced hyperglycaemia; have reduced serum triglycerides, raised high-density lipoprotein cholesterol and lowered hepatic fibrinogen synthesis; and show reduced expression of ‘insulin resistance cytokines’ (e.g. resistin and tumour necrosis factora) in adipose tissue. Moreover, when the 11b-HSD1 / phenotype is superimposed on an obesity-prone background, the mice gain less weight on a high-fat diet despite showing relative hyperphagia. These observations indicate that 11b-HSD1 is an important therapeutic target for the ‘metabolic syndrome’; indeed, the first inhibitors of this enzyme were found to augment hepatic insulin action and to lower blood glucose in normal and www.sciencedirect.com
Pawlikowski and Mełen´-Mucha have reviewed the rapidly developing field of therapy using somatostatin analogues. Somatostatin, originally discovered as a hypothalamic hormone that inhibited growth hormone (GH) secretion, is now known to inhibit the secretion of many other hormones, decrease gastrointestinal motility and prevent the proliferation of normal and neoplastic cells. The long-acting analogues octreotide and lanreotide show selectivity for the sst2 receptor, with lower affinity for sst3 and sst5 subtypes, and are widely used to treat acromegaly, neuroendocrine tumours and many other conditions, including the control of bleeding of esophageal varices, diarrhoea due to AIDS or chemotherapy, breast cancer, Zollinger-Ellison syndrome and postgastrectomy dumping syndrome. As pharmacologists. we are usually interested in agonists that are highly selective for a single receptor subtype. However, tumours can lose expression of sst2, have mutated sst2 receptors that stimulate rather than inhibit proliferation, or express other receptor subtypes. Therefore, an agent such as SOM230 with high affinity for sst1, sst2, sst3 and sst5 might have Current Opinion in Pharmacology 2004, 4:580–582
582 Endocrine and metabolic diseases
greater therapeutic potential. Chimeric molecules such as BIM-23A387, which selectively binds to sst2 and dopamine D2 receptors, could have great potential in treating acromegaly, prolactinomas and non-functioning pituitary adenomas. There is also considerable interest in coupling somatostatin analogues to cytotoxic drugs or radioisotopes to selectively target tumours expressing high levels of somatostatin receptors. The next two reviews in the section focus on anabolic agents. The first, by Bahrke and Yesalis, discusses anabolic steroids and focuses particularly on androstenedione and dehydroepiandrosterone. Although these two agents are widely used by athletes, there is very little evidence for their effectiveness in increasing strength. The review by Vanhorebeek and Van den Berghe provides a beautiful illustration of the importance of understanding the fundamental pathophysiology of a disorder before designing a rational treatment. Prolonged critical illness results in a hypercatabolic state and a non-specific wasting syndrome with severe muscle weakness, intestinal atrophy, delayed tissue healing and immune dysfunction. Pulsatile GH secretion, which would be anabolic, is suppressed, with a resulting reduction in levels of circulating insulin-like growth factor-I and insulin-like growth factor binding protein. This appears to be a result of hypothalamic deficiency, as normal responsiveness to GH secretagogues is maintained. Other hypothalamic functions, including secretion of TSH-releasing hormone (TRH), are also depressed, leading to impaired thyroid function. However, the restoration of thyroid function requires administration of both TRH and GH secretagogues.
Current Opinion in Pharmacology 2004, 4:580–582
High dose GH administration was predicted to provide a valuable therapy for the wasting syndrome of prolonged critical illness on the basis that GH-deficiency of acute critical illness persists into the chronic phase. A large multi-centre trial showed that this regimen actually increased morbidity and mortality. The authors conclude that now is the time to initiate large-scale clinical trials to examine the effects of hypothalamic secretagogues, such as combinations of GH secretagogues and TRH. The final review by Goulding provides new insights into the molecular actions of glucocorticoids. It addresses the identification of the mechanisms through which glucocorticoids suppress inflammation in an attempt to dissociate these from the actions of glucocorticoids on other metabolic pathways. Recent research has revealed an increasing complexity of the effect of glucocorticoids in relation both to their genomic effects and to their much more rapid non-genomic actions, which also impact upon the inflammatory and immune responses. The review concludes with a temporal spatial model of glucocorticoid action and highlights novel approaches to glucocorticoid pharmacology using gene array technology and complex cluster analysis. In conclusion, we thank the authors for a series of fascinating reviews. These have provided new insights and pointed the way to important therapeutic advances; for example, in the treatment of obesity and the metabolic syndrome, in the treatment of acromegaly and neuroendocrine tumours and in the prevention of the catabolism associated with prolonged critical illness.
www.sciencedirect.com