Diabetes Mellitus: Associated Conditions
Foreword
Derek LeRoith, MD, PhD Consulting Editor
In this second issue on diabetic complications and associated conditions, Drs Liao and Poretsky have assembled articles that further describe the problems that physicians and their patients face. As with the first issue, the articles cover both basic mechanisms and clinical approaches, making these issues very topical and of value to endocrinologists and health care professionals. Metabolic syndrome remains a description of a number of risk factors that independently increase the risk of cardiovascular complications in both obese individuals and those with type 2 diabetes. The definition includes waist circumference as a measure of visceral adiposity, hypertension, hypertriglyceridemia with low HDL, and glucose intolerance. The underlying cause remains the overweight-associated insulin resistance and hyperinsulinemia. As Drs Samson and Garber discuss, there is some debate as to the utility of the syndrome because the group of risk factors does not influence the outcomes more than the sum of the individual risk factors and the appropriate management is to address each risk factor individually. Drs Szuszkiewicz-Garcia and Davidson describe the increased cardiovascular complications of diabetes, interestingly more in women than in men. The cardiometabolic risk factors are well known and need to be controlled fairly aggressively. Although the evidence for tight glucose control has not been demonstrated to reduce the impact on macrovascular complications, health care professionals and patients should be aware that prevention of microvascular complications is still dependent on glucose control. Drs Kovacic, Castellano, Farkouh, and Fuster discuss the epidemic of type 2 diabetes and one of its most important complications, namely, cardiovascular disease. As they discuss, prevention is critical and the judicious use of medications for the cardiometabolic risk factors needs emphasizing both to health-care professionals and to patients. Recent outcome trials have demonstrated that bypass surgery surpasses angioplasties and stents of various kinds in diabetic patients and this needs to be seriously considered when advising patients on therapy following diagnostic catheterization. In the subsequent article, Drs Hoffman and Tranbaugh develop the theme further and describe the evidence that diabetic patients often have more extensive coronary
Endocrinol Metab Clin N Am 43 (2014) xiii–xvi http://dx.doi.org/10.1016/j.ecl.2013.10.004 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
xiv
Foreword
disease. Furthermore, percutaneous coronary intervention is inferior to coronary artery bypass and the technique of using the radial artery instead of saphenous vein for the bypass is superior. They also conclude that medical therapy after bypass is critical for secondary prevention. Glucocorticoids have long been known to affect the metabolic status of patients. Whether due to pituitary or adrenal tumors, chronic administration for immune disorders, or even stress with overactivity of the hypothalamic-pituitary-adrenal axis, these effects are seen. The effects include central obesity and excessive hepatic lipogenesis that are mediated, in part, by 11b-hydroxysteroid dehydrogenase 1. Drs Geer, Islam, and Buettner go on to discuss the effects of glucocorticoids on adipocyte lipolysis and how overall chronic glucocorticoid excess causes increased insulin resistance and worsening of the metabolic status, including type 2 diabetes. Hypertension is commonly seen in obese individuals, those with metabolic syndrome, and most diabetic patients, especially those with type 2 diabetes, although eventually those with type 1 diabetes as well. Traditionally, the cause of hypertension has been considered to be secondary to the insulin resistance and hyperinsulinemia. Concomitant secondary effects are the oxidative stress, activation of the renin-angiotensin system, impaired insulin-mediated vasodilatation, augmented sympathetic nervous system activity, and excessive sodium reabsorption in the kidney. Drs Lastra, Syed, Kurukulasuriya, Manrique, and Sowers also stress that antihypertensive therapy in diabetic patients should include blockers of the renin-angiotensin axis. Drs Nandi, Jian, Chen, Patel, and Poretsky discuss the polycystic ovarian syndrome (PCOS), one of the most common causes of infertility in women. There is strong evidence of the presence and role of insulin resistance in the cause of PCOS. The evidence is from both laboratory and animal studies, as well as from human studies that include the existence of hyperandrogenism. Because insulin resistance and hyperinsulinemia are the underlying pathophysiological mechanisms in obesity, metabolic syndrome, and type 2 diabetes, it is not surprising that PCOS is common in these conditions. Furthermore, therapies like metformin and thiazolidinediones that reduce insulin resistance have been successful in treating PCOS. Because the incidence of peripheral vascular disease in patients with diabetes is four-fold greater than in the general population, it presents many problems to both patients and health care providers. Clearly the cause is related to the general atherosclerotic process that is accelerated in diabetic individuals, especially those that are poorly controlled in regard to hypertension, hyperlipidemia, and hyperglycemia. Drs Mascarenhas, Albayati, Shearman, and Jude discuss how, in addition to general physical examination, the use of ankle brachial pressure index has become an excellent screening tool. They also stress, of course, that prevention is critical because the poor outcomes, including amputation in diabetic patients, can be devastating. In the article by Drs Zelenko and Gallagher there is a description of the impact of obesity and diabetes on cancer risk and cancer-related mortality. Many different common cancers are involved and, as described, the mechanisms probably involve many of the factors that present in these syndromes, namely, insulin resistance, hyperinsulinemia, inflammatory cytokines, hyperglycemia, insulin-like growth factors, and leptin, to name a few important examples. The connection between obesity, metabolic syndrome, and type 2 diabetes is exemplified by the response to bariatric surgery, where the risk of cancer-related mortality is reduced. In their article, the authors cover the epidemiology and the potential mechanisms involved in the association between these metabolic syndromes and cancer risk.
Foreword
Obesity (and therefore type 2 diabetes) has always been known to be associated with obstructive sleep apnea. What Drs Morgenstein, Wang, Beatty, Batemarco, Sica, and Greenberg discuss is the opposite sequence of events, namely, that sleep apnea may actually be causative in insulin resistance, obesity, and diabetes. Sleep apnea causes hypoxia that in turn induces an inflammatory process with resultant insulin resistance. Further studies have shown that lack of sleep is associated with overeating and obesity. Most interestingly, type 2 diabetic individuals who are not overweight have an increased incidence of sleep apnea, suggesting a central effect of the diabetic abnormality; as yet, the cause is unknown. Over the past decade there have been multiple reports of the value of measuring serum vitamin D levels and supplementation of vitamin D for numerous conditions other than for bone health. There have even been reports of its value in type 1 and type 2 diabetes. As Drs Mitri and Pittas discuss in their article, most of the evidence on the effect of vitamin D on b-cell function, insulin action, and immunological function arises from laboratory and animal studies. Unfortunately clinical trials have shown mixed results and have been generally disappointing. Of interest is the recent announcement by the NIH that a controlled clinical trial is to be funded. Given the very few side effects seen with vitamin D, it would be very advantageous if a clinical successful trial could be seen. A largely less well-recognized complication of diabetes is osteoporosis in patients with type 1 and type 2 diabetes. Although these types of diabetes have different origins and pathophysiology, there are often similarities in the effects on bone. One of the more perplexing effects of diabetes on bone has been the increase in bone fragility that often results in nonclassic fractures of peripheral bones. Although further research is warranted and on-going, Drs Kurra, Fink, and Siris discuss the importance of evaluating all patients with diabetes for osteoporosis and that standard therapies for osteoporosis are equally effective in patients with diabetes as they are in nondiabetic individuals. Finally, the use of medications, such as thiazolidinediones that may increase the bone fragility and/or osteoporosis in type 2 diabetes, needs to be carefully evaluated. It is now well-recognized that in diabetic patients the incidence of cognitive dysfunction and even neurodegenerative diseases such as Alzheimers is increased. The causes for this association are discussed in the article by Dr de la Monte. Evidence suggests that genetics may play a role as well as central nervous system insulin and insulin-like growth factor-1 resistance as well as insulin deficiency. Another suggestion is that the diabetes including the abnormalities in glycemic control may be exacerbating the underlying cognitive dysfunction that has a separate cause. This would suggest that tight glycemic control and delivering insulin locally, for example, by nasal insulin administration, should be capable of reducing the cognitive decline seen in diabetic patients and others with Alzheimers. Health care professionals have been aware for a long time that in dealing with patients with diabetes, both type 1 and type 2, anxiety and depression are common and often complicate many aspects of the therapeutic armamentarium, leading to poor compliance. Drs Bystritsky, Danial, and Kronemyer remind us that there is a further component that should be considered and that is the effects of antianxiety and antidepressant medications on metabolic syndrome. For example, antipsychotics are well known to cause increased weight and frank obesity in some patients. Furthermore, anxiety and changes in the hormonal axes can enhance the clinical presentations of type 2 diabetes, if not actually precipitating the appearance of the disorder.
xv
xvi
Foreword
As the reader will find, the articles in this issue are written by experts and should be extremely important for understanding of the pathophysiology and management of diabetic patients with the various complications. I personally would like to thank both the issue editors and the authors for an amazing compilation of articles. Derek LeRoith, MD, PhD Division of Endocrinology, Metabolism, and Bone Diseases Department of Medicine Mount Sinai School of Medicine One Gustave L. Levy Place Box 1055, Altran 4-36 New York, NY 10029, USA E-mail address: [email protected]
Foreword
Derek LeRoith, MD, PhD Consulting Editor
In this second issue on diabetic complications and associated conditions, Drs Liao and Poretsky have assembled articles that further describe the problems that physicians and their patients face. As with the first issue, the articles cover both basic mechanisms and clinical approaches, making these issues very topical and of value to endocrinologists and health care professionals. Metabolic syndrome remains a description of a number of risk factors that independently increase the risk of cardiovascular complications in both obese individuals and those with type 2 diabetes. The definition includes waist circumference as a measure of visceral adiposity, hypertension, hypertriglyceridemia with low HDL, and glucose intolerance. The underlying cause remains the overweight-associated insulin resistance and hyperinsulinemia. As Drs Samson and Garber discuss, there is some debate as to the utility of the syndrome because the group of risk factors does not influence the outcomes more than the sum of the individual risk factors and the appropriate management is to address each risk factor individually. Drs Szuszkiewicz-Garcia and Davidson describe the increased cardiovascular complications of diabetes, interestingly more in women than in men. The cardiometabolic risk factors are well known and need to be controlled fairly aggressively. Although the evidence for tight glucose control has not been demonstrated to reduce the impact on macrovascular complications, health care professionals and patients should be aware that prevention of microvascular complications is still dependent on glucose control. Drs Kovacic, Castellano, Farkouh, and Fuster discuss the epidemic of type 2 diabetes and one of its most important complications, namely, cardiovascular disease. As they discuss, prevention is critical and the judicious use of medications for the cardiometabolic risk factors needs emphasizing both to health-care professionals and to patients. Recent outcome trials have demonstrated that bypass surgery surpasses angioplasties and stents of various kinds in diabetic patients and this needs to be seriously considered when advising patients on therapy following diagnostic catheterization. In the subsequent article, Drs Hoffman and Tranbaugh develop the theme further and describe the evidence that diabetic patients often have more extensive coronary
Endocrinol Metab Clin N Am 43 (2014) xiii–xvi http://dx.doi.org/10.1016/j.ecl.2013.10.004 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
xiv
Foreword
disease. Furthermore, percutaneous coronary intervention is inferior to coronary artery bypass and the technique of using the radial artery instead of saphenous vein for the bypass is superior. They also conclude that medical therapy after bypass is critical for secondary prevention. Glucocorticoids have long been known to affect the metabolic status of patients. Whether due to pituitary or adrenal tumors, chronic administration for immune disorders, or even stress with overactivity of the hypothalamic-pituitary-adrenal axis, these effects are seen. The effects include central obesity and excessive hepatic lipogenesis that are mediated, in part, by 11b-hydroxysteroid dehydrogenase 1. Drs Geer, Islam, and Buettner go on to discuss the effects of glucocorticoids on adipocyte lipolysis and how overall chronic glucocorticoid excess causes increased insulin resistance and worsening of the metabolic status, including type 2 diabetes. Hypertension is commonly seen in obese individuals, those with metabolic syndrome, and most diabetic patients, especially those with type 2 diabetes, although eventually those with type 1 diabetes as well. Traditionally, the cause of hypertension has been considered to be secondary to the insulin resistance and hyperinsulinemia. Concomitant secondary effects are the oxidative stress, activation of the renin-angiotensin system, impaired insulin-mediated vasodilatation, augmented sympathetic nervous system activity, and excessive sodium reabsorption in the kidney. Drs Lastra, Syed, Kurukulasuriya, Manrique, and Sowers also stress that antihypertensive therapy in diabetic patients should include blockers of the renin-angiotensin axis. Drs Nandi, Jian, Chen, Patel, and Poretsky discuss the polycystic ovarian syndrome (PCOS), one of the most common causes of infertility in women. There is strong evidence of the presence and role of insulin resistance in the cause of PCOS. The evidence is from both laboratory and animal studies, as well as from human studies that include the existence of hyperandrogenism. Because insulin resistance and hyperinsulinemia are the underlying pathophysiological mechanisms in obesity, metabolic syndrome, and type 2 diabetes, it is not surprising that PCOS is common in these conditions. Furthermore, therapies like metformin and thiazolidinediones that reduce insulin resistance have been successful in treating PCOS. Because the incidence of peripheral vascular disease in patients with diabetes is four-fold greater than in the general population, it presents many problems to both patients and health care providers. Clearly the cause is related to the general atherosclerotic process that is accelerated in diabetic individuals, especially those that are poorly controlled in regard to hypertension, hyperlipidemia, and hyperglycemia. Drs Mascarenhas, Albayati, Shearman, and Jude discuss how, in addition to general physical examination, the use of ankle brachial pressure index has become an excellent screening tool. They also stress, of course, that prevention is critical because the poor outcomes, including amputation in diabetic patients, can be devastating. In the article by Drs Zelenko and Gallagher there is a description of the impact of obesity and diabetes on cancer risk and cancer-related mortality. Many different common cancers are involved and, as described, the mechanisms probably involve many of the factors that present in these syndromes, namely, insulin resistance, hyperinsulinemia, inflammatory cytokines, hyperglycemia, insulin-like growth factors, and leptin, to name a few important examples. The connection between obesity, metabolic syndrome, and type 2 diabetes is exemplified by the response to bariatric surgery, where the risk of cancer-related mortality is reduced. In their article, the authors cover the epidemiology and the potential mechanisms involved in the association between these metabolic syndromes and cancer risk.
Foreword
Obesity (and therefore type 2 diabetes) has always been known to be associated with obstructive sleep apnea. What Drs Morgenstein, Wang, Beatty, Batemarco, Sica, and Greenberg discuss is the opposite sequence of events, namely, that sleep apnea may actually be causative in insulin resistance, obesity, and diabetes. Sleep apnea causes hypoxia that in turn induces an inflammatory process with resultant insulin resistance. Further studies have shown that lack of sleep is associated with overeating and obesity. Most interestingly, type 2 diabetic individuals who are not overweight have an increased incidence of sleep apnea, suggesting a central effect of the diabetic abnormality; as yet, the cause is unknown. Over the past decade there have been multiple reports of the value of measuring serum vitamin D levels and supplementation of vitamin D for numerous conditions other than for bone health. There have even been reports of its value in type 1 and type 2 diabetes. As Drs Mitri and Pittas discuss in their article, most of the evidence on the effect of vitamin D on b-cell function, insulin action, and immunological function arises from laboratory and animal studies. Unfortunately clinical trials have shown mixed results and have been generally disappointing. Of interest is the recent announcement by the NIH that a controlled clinical trial is to be funded. Given the very few side effects seen with vitamin D, it would be very advantageous if a clinical successful trial could be seen. A largely less well-recognized complication of diabetes is osteoporosis in patients with type 1 and type 2 diabetes. Although these types of diabetes have different origins and pathophysiology, there are often similarities in the effects on bone. One of the more perplexing effects of diabetes on bone has been the increase in bone fragility that often results in nonclassic fractures of peripheral bones. Although further research is warranted and on-going, Drs Kurra, Fink, and Siris discuss the importance of evaluating all patients with diabetes for osteoporosis and that standard therapies for osteoporosis are equally effective in patients with diabetes as they are in nondiabetic individuals. Finally, the use of medications, such as thiazolidinediones that may increase the bone fragility and/or osteoporosis in type 2 diabetes, needs to be carefully evaluated. It is now well-recognized that in diabetic patients the incidence of cognitive dysfunction and even neurodegenerative diseases such as Alzheimers is increased. The causes for this association are discussed in the article by Dr de la Monte. Evidence suggests that genetics may play a role as well as central nervous system insulin and insulin-like growth factor-1 resistance as well as insulin deficiency. Another suggestion is that the diabetes including the abnormalities in glycemic control may be exacerbating the underlying cognitive dysfunction that has a separate cause. This would suggest that tight glycemic control and delivering insulin locally, for example, by nasal insulin administration, should be capable of reducing the cognitive decline seen in diabetic patients and others with Alzheimers. Health care professionals have been aware for a long time that in dealing with patients with diabetes, both type 1 and type 2, anxiety and depression are common and often complicate many aspects of the therapeutic armamentarium, leading to poor compliance. Drs Bystritsky, Danial, and Kronemyer remind us that there is a further component that should be considered and that is the effects of antianxiety and antidepressant medications on metabolic syndrome. For example, antipsychotics are well known to cause increased weight and frank obesity in some patients. Furthermore, anxiety and changes in the hormonal axes can enhance the clinical presentations of type 2 diabetes, if not actually precipitating the appearance of the disorder.
xv
xvi
Foreword
As the reader will find, the articles in this issue are written by experts and should be extremely important for understanding of the pathophysiology and management of diabetic patients with the various complications. I personally would like to thank both the issue editors and the authors for an amazing compilation of articles. Derek LeRoith, MD, PhD Division of Endocrinology, Metabolism, and Bone Diseases Department of Medicine Mount Sinai School of Medicine One Gustave L. Levy Place Box 1055, Altran 4-36 New York, NY 10029, USA E-mail address: [email protected]
