Review
New insights into cystic fibrosis-related diabetes in children Katie L Ode, Antoinette Moran Lancet Diabetes Endocrinol 2013; 1: 52–58 Published Online May 23, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70015-9 Department of Pediatrics, University of Iowa Children’s Hospital, University of Iowa, Iowa City, IA, USA (K L Ode MD); and Department of Pediatrics, Amplatz Children’s Hospital, University of Minnesota, Minneapolis, MN, USA (Prof A Moran MD) Correspondence to: Dr Katie L Ode, Department of Pediatrics, Division of Endocrinology and Diabetes, 200 Hawkins Dr, 2861 JPP, Iowa City, IA 52242-1083, USA [email protected]
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Cystic fibrosis-related diabetes (CFRD) is the most common complication of cystic fibrosis. It is associated with significantly increased morbidity and mortality in adults and children. Adolescents with cystic fibrosis have a much higher prevalence of diabetes than any other similar age population. Glucose abnormalities that precede diabetes are even more common, especially in children younger than 10 years. The pathophysiology of glucose metabolic abnormalities is poorly understood, but insulin insufficiency is clearly the main component. Findings from animal studies have provided insight into the pathophysiology of CFRD, and imply that carbohydrate metabolic abnormalities might begin at much younger ages than was previously thought in patients with cystic fibrosis, and might be related to the basic cystic fibrosis chloride channel defect. In this Review we explore present knowledge of CFRD in children and adolescents, and new data that indicate that the pathophysiology of CFRD begins in very young patients.
Introduction Cystic fibrosis is the most common fatal recessive genetic disorder in white populations. The disorder is caused by mutations leading to abnormalities in the cystic fibrosis transmembrane conductance regulator (CFTR)—a chloride channel involved in electrolyte and water movement across cell membranes. The most common mutation of CFTR is ΔF508, in which a phenylalanine is lost at position 508.1 CFTR dysfunction results in multisystem disease, the most important aspect of which is obstructive and inflammatory lung disease caused by thick secretions. The average lifespan of people with cystic fibrosis has increased greatly because of improved treatments for lung disease; thus, other complications of cystic fibrosis have become much more important. Cystic fibrosis-related diabetes (CFRD) is the most common secondary complication of cystic fibrosis, and in some paediatric diabetes practices patients with CFRD are the second largest group of patients after children with type 1 diabetes mellitus.2 CFRD is a unique form of diabetes that does not have the same pathophysiology or clinical picture as either type 1 or type 2 diabetes, although it has features in common with both. Although lung disease is not a major component of type 1 or type 2 diabetes pathophysiology, CFRD increases the risk of pulmonary death in patients with cystic fibrosis.3 CFRD has been associated with rapid decline in lung function and reduced nutritional status, both of which increase morbidity and mortality.4 Furthermore, clinical decline seems to happen years before patients develop frank diabetes, when they have abnormal glucose tolerance.4 Authors of several reviews of CFRD have investigated the disease primarily from the perspective of the adult patient, or by combining paediatric and adult patients.2,5–10 Stalvey11 discussed the basic science of CFRD, and the Health Technology Assessment from the National Health Service in Great Britain contains a thorough review of screening for CFRD.12 In this Review we focus on what is and is not known about glucose metabolism abnormalities in children and adolescents with cystic fibrosis, with particular attention to questions that have
arisen from new animal models of infant and paediatric glucose metabolism, and what they might imply about the pathophysiology of CFRD.
Pathophysiology Inadequate insulin secretion is the main pathological feature of CFRD. Patients with cystic fibrosis, even those with normal glucose tolerance, tend to have decreasing insulin secretion over time.13,14 Patients with cystic fibrosis who are 8 years and older have delayed and eventually diminished insulin secretion in response to oral and intravenous stimuli, and increased glucose concentrations compared with controls.15 Insulin sensitivity is generally normal or only slightly decreased, except in the settings of acute illness or glucocorticoid treatment when insulin resistance can be severe.13,14,16,17 The basis of our understanding of the pathophysiology of CFRD and related glucose abnormalities in cystic fibrosis has evolved since diabetes was first described in patients with cystic fibrosis in the 1950s.18 Initially, the disorder was thought to be due to collateral damage to the endocrine pancreas after scarring and fibrosis of the exocrine pancreas. Concentrations of islet hormones other than insulin, such as glucagon, are also abnormal in adults with CFRD, which supports the theory that total islets are destroyed by fibrosis.19 However, although all patients with cystic fibrosis seem to have substantial β-cell loss by this mechanism, it cannot be the sole cause of CFRD since results of histopathology studies have shown that patients with cystic fibrosis with CFRD do not necessarily have more pancreatic fibrosis at autopsy than do patients with cycstic fibrosis without CFRD.19 Blackman and colleagues20,21 have shown that susceptibility genes for type 2 diabetes are more common in patients with CFRD compared with patients with cystic fibrosis without diabetes, which suggests that CFRD is associated with similar intrinsic β-cell defects as are associated with type 2 diabetes. Furthermore, evidence suggests that the CFTR defect itself might be involved in altered insulin secretion. CFTR is expressed in α-cells and β-cells in the rat pancreas, although its role in these cells is unknown.22 www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
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Non-CF-1 Non-CF-2 Non-CF-3
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Figure 1: Impaired glycaemic regulation in 1–3-month-old ferrets Blood glucose measured on non-fasted, randomly fed CFTR-null and wild-type ferret sibling pairs during the first 3 months of life. Blood draws were taken simultaneously from each animal in the pair. Three independent cystic fibrosis and non-cystic fibrosis sibling pairs are shown. Non-CF=non-cystic fibrosis. CF=cystic fibrosis. Adapted from Olivier and colleagues,25 by permission of the American Society for Clinical Investigation.
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New insights into cystic fibrosis-related diabetes in children Katie L Ode, Antoinette Moran Lancet Diabetes Endocrinol 2013; 1: 52–58 Published Online May 23, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70015-9 Department of Pediatrics, University of Iowa Children’s Hospital, University of Iowa, Iowa City, IA, USA (K L Ode MD); and Department of Pediatrics, Amplatz Children’s Hospital, University of Minnesota, Minneapolis, MN, USA (Prof A Moran MD) Correspondence to: Dr Katie L Ode, Department of Pediatrics, Division of Endocrinology and Diabetes, 200 Hawkins Dr, 2861 JPP, Iowa City, IA 52242-1083, USA [email protected]
52
Cystic fibrosis-related diabetes (CFRD) is the most common complication of cystic fibrosis. It is associated with significantly increased morbidity and mortality in adults and children. Adolescents with cystic fibrosis have a much higher prevalence of diabetes than any other similar age population. Glucose abnormalities that precede diabetes are even more common, especially in children younger than 10 years. The pathophysiology of glucose metabolic abnormalities is poorly understood, but insulin insufficiency is clearly the main component. Findings from animal studies have provided insight into the pathophysiology of CFRD, and imply that carbohydrate metabolic abnormalities might begin at much younger ages than was previously thought in patients with cystic fibrosis, and might be related to the basic cystic fibrosis chloride channel defect. In this Review we explore present knowledge of CFRD in children and adolescents, and new data that indicate that the pathophysiology of CFRD begins in very young patients.
Introduction Cystic fibrosis is the most common fatal recessive genetic disorder in white populations. The disorder is caused by mutations leading to abnormalities in the cystic fibrosis transmembrane conductance regulator (CFTR)—a chloride channel involved in electrolyte and water movement across cell membranes. The most common mutation of CFTR is ΔF508, in which a phenylalanine is lost at position 508.1 CFTR dysfunction results in multisystem disease, the most important aspect of which is obstructive and inflammatory lung disease caused by thick secretions. The average lifespan of people with cystic fibrosis has increased greatly because of improved treatments for lung disease; thus, other complications of cystic fibrosis have become much more important. Cystic fibrosis-related diabetes (CFRD) is the most common secondary complication of cystic fibrosis, and in some paediatric diabetes practices patients with CFRD are the second largest group of patients after children with type 1 diabetes mellitus.2 CFRD is a unique form of diabetes that does not have the same pathophysiology or clinical picture as either type 1 or type 2 diabetes, although it has features in common with both. Although lung disease is not a major component of type 1 or type 2 diabetes pathophysiology, CFRD increases the risk of pulmonary death in patients with cystic fibrosis.3 CFRD has been associated with rapid decline in lung function and reduced nutritional status, both of which increase morbidity and mortality.4 Furthermore, clinical decline seems to happen years before patients develop frank diabetes, when they have abnormal glucose tolerance.4 Authors of several reviews of CFRD have investigated the disease primarily from the perspective of the adult patient, or by combining paediatric and adult patients.2,5–10 Stalvey11 discussed the basic science of CFRD, and the Health Technology Assessment from the National Health Service in Great Britain contains a thorough review of screening for CFRD.12 In this Review we focus on what is and is not known about glucose metabolism abnormalities in children and adolescents with cystic fibrosis, with particular attention to questions that have
arisen from new animal models of infant and paediatric glucose metabolism, and what they might imply about the pathophysiology of CFRD.
Pathophysiology Inadequate insulin secretion is the main pathological feature of CFRD. Patients with cystic fibrosis, even those with normal glucose tolerance, tend to have decreasing insulin secretion over time.13,14 Patients with cystic fibrosis who are 8 years and older have delayed and eventually diminished insulin secretion in response to oral and intravenous stimuli, and increased glucose concentrations compared with controls.15 Insulin sensitivity is generally normal or only slightly decreased, except in the settings of acute illness or glucocorticoid treatment when insulin resistance can be severe.13,14,16,17 The basis of our understanding of the pathophysiology of CFRD and related glucose abnormalities in cystic fibrosis has evolved since diabetes was first described in patients with cystic fibrosis in the 1950s.18 Initially, the disorder was thought to be due to collateral damage to the endocrine pancreas after scarring and fibrosis of the exocrine pancreas. Concentrations of islet hormones other than insulin, such as glucagon, are also abnormal in adults with CFRD, which supports the theory that total islets are destroyed by fibrosis.19 However, although all patients with cystic fibrosis seem to have substantial β-cell loss by this mechanism, it cannot be the sole cause of CFRD since results of histopathology studies have shown that patients with cystic fibrosis with CFRD do not necessarily have more pancreatic fibrosis at autopsy than do patients with cycstic fibrosis without CFRD.19 Blackman and colleagues20,21 have shown that susceptibility genes for type 2 diabetes are more common in patients with CFRD compared with patients with cystic fibrosis without diabetes, which suggests that CFRD is associated with similar intrinsic β-cell defects as are associated with type 2 diabetes. Furthermore, evidence suggests that the CFTR defect itself might be involved in altered insulin secretion. CFTR is expressed in α-cells and β-cells in the rat pancreas, although its role in these cells is unknown.22 www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
Review
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Non-CF-1 Non-CF-2 Non-CF-3
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Blood glucose (mmol/L)
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70
80
90
Age (days)
Figure 1: Impaired glycaemic regulation in 1–3-month-old ferrets Blood glucose measured on non-fasted, randomly fed CFTR-null and wild-type ferret sibling pairs during the first 3 months of life. Blood draws were taken simultaneously from each animal in the pair. Three independent cystic fibrosis and non-cystic fibrosis sibling pairs are shown. Non-CF=non-cystic fibrosis. CF=cystic fibrosis. Adapted from Olivier and colleagues,25 by permission of the American Society for Clinical Investigation.
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