EDITORIAL URRENT C OPINION
Editorial: diabetes and the endocrine pancreas I David M. Harlan
When I began my medical education over 35 years ago, I recall being awed by all that was known about anatomy, physiology, and microbiology in health, and disease. I was eager to learn as much as I could so that I could accurately diagnose disease, and administer curative therapies, or to at least help patients by minimizing their pain and suffering. Like many, I discounted the older professors who told us that the amount we knew was dwarfed by our ignorance, and the need for research to advance medicine. This month’s Current Opinion in Endocrinology, Diabetes, and Obesity, covers such an ignorance-to-knowledge spectrum and highlights several research and therapeutic advances. The review by Drs Singer, Arnes, and Sussel (pp. 77–85) entitled, ‘Noncoding RNAs in b Cell Biology’, discusses the functional effects of RNA species not even known to exist before the mid1990s. That is, although the roles played by mRNA, ribosomal RNA, and tRNA have been known since the 1960s, more recent research has identified many other noncoding RNAs that play important roles in gene regulation, immune responses, and cellular biology. In particular, the review by Singer et al. (pp. 77–85) identifies recent research uncovering important functions served by ‘long noncoding RNAs’, and ‘micro-RNAs’ in pancreatic b cell biology, function, and gene regulation. A greater understanding of the noncoding RNA species expression and function holds great promise as a source of whole new classes of therapeutic agents, or for use as biomarkers to track disease progression. In 2011, Dr in’t Veld (pp. 86–90) published an article entitled, ‘Insulitis in human T1D: The quest for an elusive lesion’ (Islets, Vols. 3–4, pages 131–138) that, in an Emperor Wears No Clothes-like fashion, at least questioned a central tenet of modern human T1D pathogenesis. That is, although considerable evidence supports the T-cell-mediated autoimmune killing of pancreatic b cells as a driving cause of the progressively declining insulin production characteristic of T1D, his article pointed out that very few human pancreata had ever been studied to evaluate the strength of the association with its expected histopathological hallmark, that is, islet infiltrating T lymphocytes (‘insulitis’). It had
generally been assumed that the pancreatic islet T-cell infiltration observed in the autoimmune nonobese diabetic mouse would closely parallel observations in human T1D patient pancreatic specimens. In this journal, Dr in’t Veld now points out in his manuscript, ‘Rodent versus human insulitis, why the huge disconnect?’ that the presumed close correlation between human and mouse pancreatic immunohistology during the autoimmune diabetes pathogenic process is not supported by the data. His review points out the importance of questioning all assumptions in medicine, and may explain why various therapeutic agents with remarkable efficacy in the nonobese diabetic mouse model have yielded far less success in humans. This issue includes two manuscripts devoted to therapies for the obesity epidemic sweeping the world. Drs Mordes, Liu, and Xu (pp. 91–97) have written a nice review of the various medical therapies for obesity, including medications currently approved in the USA, medicines once approved for weight loss but then withdrawn from the market because of safety concerns, and last Chinese herbal medicines that, although not approved in the USA, are widely used in Asia where both diabetes and obesity have reached epidemic proportions as dire as those faced in Western countries. In a concise fashion, the authors have discussed what is known about each agent’s mechanism of action, efficacy, and safety. Among the authors’ most important conclusions are that: first, medical therapies for obesity are not as effective as surgical approaches, second, many agents appear to be effective over relatively short periods (up to 1 year), but have not supported continued weight loss beyond 1 year, third, all medical therapies must sit upon a bedrock of a well supervised diet and exercise regimen, fourth, the medical-therapy-for-obesity field is more University of Massachusetts Medical School, Worcester, Massachusetts, USA Correspondence to David M. Harlan, University of Massachusetts, 55 Lake Avenue North, Worcester, MA 01655, USA. E-mail: David.Harlan @umassmemorial.org Curr Opin Endocrinol Diabetes Obes 2015, 22:75–76 DOI:10.1097/MED.0000000000000145
1752-296X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-endocrinology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Diabetes and the endocrine pancreas I
cluttered than most with medications once thought to be well tolerated and effective only to be later withdrawn because of safety concerns, fifth, as with all medicines, a careful weighing of risks and benefits is paramount, and sixth, studies evaluating the Chinese herbal medicines do not (in general) achieve the rigor demanded of medicines use in the USA but the Chinese herbal medicines have been used abroad for years and display efficacy comparable to some earlier weight loss drugs used in the USA. The other approach to patients with obesityassociated serious morbidity is, of course, surgical. Indeed, bariatric surgery has become one of the most widely performed procedures in modern medicine. Dr Malkani (pp. 98–105) has done a very nice job reviewing the medical literature pertaining to the various surgical options. In a concise fashion, he has compared each procedures’ efficacy relative to other surgical approaches, as well as to currently available medical approaches. He has also reviewed what is known about each procedures’ mechanisms of action. He makes several other relevant points that all are also infrequently made in other reviews, for example, that true randomized controlled studies are practically difficult if not impossible in the obese population, that the procedures’ long-term safety and efficacy data are rather limited, and that diabetes ‘remission’ is temporary for many who undergo the surgery. The last diabetes-focused submission for this edition, written by Dr Russell (pp. 106–111), describes international efforts by several groups to develop a practical ‘artificial pancreas’. For those not familiar with the term, an artificial pancreas is any electronic system designed to continuously monitor a patient’s blood glucose concentration
76
www.co-endocrinology.com
and that then feeds that data into a self-contained and patient-carried computer algorithm to control subcutaneous hormonal therapy to regulate the individual’s glycemia. Clearly, the ultimate goal for such systems is to facilitate care, and minimize both the acute and chronic complications of the disease. Dr Russell and his colleagues are major contributors to that effort, and with his nice review (pp. 106–111), he has provided an overview of the field’s most recent progress, and current limitations. He compares outcomes from studies evaluating sensor augmented pumps that simply suppress insulin infusion when the blood glucose falls too low, with groups developing an artificial pancreas, and in particular, the two ‘flavors’ of artificial pancreas, that is, those designed to infuse insulin alone, compared with those that can infuse either (as appropriate) insulin or glucagon. He highlights potential risks and benefits associated with each approach and the critical need to compare each strategy in well designed studies. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest I am a colleague of both Drs Malkani and Mordes within the Department of Medicine at the University of Massachusetts Medical School, and I have served as the University of Massachusetts Medical School Principal Investigator for a study designed to test the efficacy of an artificial pancreas system. Dr Russell is that multicenter study’s Principal Investigator.
Volume 22 Number 2 April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Editorial: diabetes and the endocrine pancreas I David M. Harlan
When I began my medical education over 35 years ago, I recall being awed by all that was known about anatomy, physiology, and microbiology in health, and disease. I was eager to learn as much as I could so that I could accurately diagnose disease, and administer curative therapies, or to at least help patients by minimizing their pain and suffering. Like many, I discounted the older professors who told us that the amount we knew was dwarfed by our ignorance, and the need for research to advance medicine. This month’s Current Opinion in Endocrinology, Diabetes, and Obesity, covers such an ignorance-to-knowledge spectrum and highlights several research and therapeutic advances. The review by Drs Singer, Arnes, and Sussel (pp. 77–85) entitled, ‘Noncoding RNAs in b Cell Biology’, discusses the functional effects of RNA species not even known to exist before the mid1990s. That is, although the roles played by mRNA, ribosomal RNA, and tRNA have been known since the 1960s, more recent research has identified many other noncoding RNAs that play important roles in gene regulation, immune responses, and cellular biology. In particular, the review by Singer et al. (pp. 77–85) identifies recent research uncovering important functions served by ‘long noncoding RNAs’, and ‘micro-RNAs’ in pancreatic b cell biology, function, and gene regulation. A greater understanding of the noncoding RNA species expression and function holds great promise as a source of whole new classes of therapeutic agents, or for use as biomarkers to track disease progression. In 2011, Dr in’t Veld (pp. 86–90) published an article entitled, ‘Insulitis in human T1D: The quest for an elusive lesion’ (Islets, Vols. 3–4, pages 131–138) that, in an Emperor Wears No Clothes-like fashion, at least questioned a central tenet of modern human T1D pathogenesis. That is, although considerable evidence supports the T-cell-mediated autoimmune killing of pancreatic b cells as a driving cause of the progressively declining insulin production characteristic of T1D, his article pointed out that very few human pancreata had ever been studied to evaluate the strength of the association with its expected histopathological hallmark, that is, islet infiltrating T lymphocytes (‘insulitis’). It had
generally been assumed that the pancreatic islet T-cell infiltration observed in the autoimmune nonobese diabetic mouse would closely parallel observations in human T1D patient pancreatic specimens. In this journal, Dr in’t Veld now points out in his manuscript, ‘Rodent versus human insulitis, why the huge disconnect?’ that the presumed close correlation between human and mouse pancreatic immunohistology during the autoimmune diabetes pathogenic process is not supported by the data. His review points out the importance of questioning all assumptions in medicine, and may explain why various therapeutic agents with remarkable efficacy in the nonobese diabetic mouse model have yielded far less success in humans. This issue includes two manuscripts devoted to therapies for the obesity epidemic sweeping the world. Drs Mordes, Liu, and Xu (pp. 91–97) have written a nice review of the various medical therapies for obesity, including medications currently approved in the USA, medicines once approved for weight loss but then withdrawn from the market because of safety concerns, and last Chinese herbal medicines that, although not approved in the USA, are widely used in Asia where both diabetes and obesity have reached epidemic proportions as dire as those faced in Western countries. In a concise fashion, the authors have discussed what is known about each agent’s mechanism of action, efficacy, and safety. Among the authors’ most important conclusions are that: first, medical therapies for obesity are not as effective as surgical approaches, second, many agents appear to be effective over relatively short periods (up to 1 year), but have not supported continued weight loss beyond 1 year, third, all medical therapies must sit upon a bedrock of a well supervised diet and exercise regimen, fourth, the medical-therapy-for-obesity field is more University of Massachusetts Medical School, Worcester, Massachusetts, USA Correspondence to David M. Harlan, University of Massachusetts, 55 Lake Avenue North, Worcester, MA 01655, USA. E-mail: David.Harlan @umassmemorial.org Curr Opin Endocrinol Diabetes Obes 2015, 22:75–76 DOI:10.1097/MED.0000000000000145
1752-296X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-endocrinology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Diabetes and the endocrine pancreas I
cluttered than most with medications once thought to be well tolerated and effective only to be later withdrawn because of safety concerns, fifth, as with all medicines, a careful weighing of risks and benefits is paramount, and sixth, studies evaluating the Chinese herbal medicines do not (in general) achieve the rigor demanded of medicines use in the USA but the Chinese herbal medicines have been used abroad for years and display efficacy comparable to some earlier weight loss drugs used in the USA. The other approach to patients with obesityassociated serious morbidity is, of course, surgical. Indeed, bariatric surgery has become one of the most widely performed procedures in modern medicine. Dr Malkani (pp. 98–105) has done a very nice job reviewing the medical literature pertaining to the various surgical options. In a concise fashion, he has compared each procedures’ efficacy relative to other surgical approaches, as well as to currently available medical approaches. He has also reviewed what is known about each procedures’ mechanisms of action. He makes several other relevant points that all are also infrequently made in other reviews, for example, that true randomized controlled studies are practically difficult if not impossible in the obese population, that the procedures’ long-term safety and efficacy data are rather limited, and that diabetes ‘remission’ is temporary for many who undergo the surgery. The last diabetes-focused submission for this edition, written by Dr Russell (pp. 106–111), describes international efforts by several groups to develop a practical ‘artificial pancreas’. For those not familiar with the term, an artificial pancreas is any electronic system designed to continuously monitor a patient’s blood glucose concentration
76
www.co-endocrinology.com
and that then feeds that data into a self-contained and patient-carried computer algorithm to control subcutaneous hormonal therapy to regulate the individual’s glycemia. Clearly, the ultimate goal for such systems is to facilitate care, and minimize both the acute and chronic complications of the disease. Dr Russell and his colleagues are major contributors to that effort, and with his nice review (pp. 106–111), he has provided an overview of the field’s most recent progress, and current limitations. He compares outcomes from studies evaluating sensor augmented pumps that simply suppress insulin infusion when the blood glucose falls too low, with groups developing an artificial pancreas, and in particular, the two ‘flavors’ of artificial pancreas, that is, those designed to infuse insulin alone, compared with those that can infuse either (as appropriate) insulin or glucagon. He highlights potential risks and benefits associated with each approach and the critical need to compare each strategy in well designed studies. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest I am a colleague of both Drs Malkani and Mordes within the Department of Medicine at the University of Massachusetts Medical School, and I have served as the University of Massachusetts Medical School Principal Investigator for a study designed to test the efficacy of an artificial pancreas system. Dr Russell is that multicenter study’s Principal Investigator.
Volume 22 Number 2 April 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
