Comment
this group subsequently developed increased fasting glucose concentrations. Færch and colleagues recommend that strategies to prevent loss of β-cell function might be beneficial for people with fasting hyperglycaemia, but do not suggest what these strategies might be. They report a subgroup analysis from the Diabetes Prevention Program,8 which suggested that metformin seemed to be more effective at preventing diabetes in people with high fasting glucose concentrations (6·2–6·9 mmol/L) at baseline than in those with low fasting concentrations (5·3–6·1 mmol/L) in a population that also had 2 h glucose concentrations in the range of 7·8–11·0 mmol/L. Færch and coworkers appropriately conclude that further research is needed to establish whether the different subgroups of type 2 diabetes (as defined by glucose or HbA1c criteria) respond differently to lifestyle interventions or drugs, and whether complications differ between subgroups. A better understanding of the pathogenesis of type 2 diabetes in an individual will probably lead to improved targeting of available effective interventions for hyperglycaemia.
Sarah H Wild*, Christopher D Byrne Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK (SHW); Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK (CDB); and Southampton National Institute for Health Research Biomedical Research Centre, Southampton, UK (CDB) [email protected] We declare that we have no conflicts of interest. 1
2 3
4
5
6
7 8
WHO, International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. Geneva: World Health Organization, 2006. WHO. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Geneva: World Health Organization, 2011. Færch K, Witte DR, Tabák AG, et al. Trajectories of cardiometabolic risk factors before diagnosis of three subtypes of type 2 diabetes: a post-hoc analysis of the longitudinal Whitehall II cohort study. Lancet Diabetes Endocrinol 2013; published online Feb 21. http://dx.doi.org/10.1016/S2213-8587(13)70008-1. Arterburn DE, Bogart A, Sherwood NE, et al. A multisite study of long-term remission and relapse of type 2 diabetes mellitus following gastric bypass. Obes Surg 2013; 23: 93–102. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011, 54: 2506–14. Morris AP, Voight BF, Teslovich TM, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012; 44: 981–90. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131–57. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403.
Making sense of chromogranin A in heart disease Chromogranin A is an acidic protein present in secretory granules of neuroendocrine cells. In plasma, chromogranin A is an important marker of neuroendocrine tumours. Chromogranin A measurement has gained interest in cardiovascular disease, because increased plasma concentrations are associated with risk of clinical deterioration and death in patients with acute coronary syndromes or chronic heart failure. Cardiac chromogranin A is stored in atrial granules with cardiac natriuretic peptides—the principal cardiac hormones associated with systemic homoeostasis of water and blood pressure. Expression of cardiac chromogranin A is decreased in patients treated with mechanical assist device therapy, which parallels findings on B-type natriuretic peptide mRNA expression and concomitant plasma concentrations.1 Support for a cardiovascular role for chromogranin A comes from mice deficient in chromogranin A gene expression, because they display a hypertensive phenotype that can be fully reversed by infusion with the chromogranin A fragment catestatin.2 One proposed www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
explanation for this is that mice deficient in chromogranin A have increased catecholamine release, which is a known mechanism in essential hypertension. The first observation of chromogranin A in myocardial infarction was reported by Omland and colleagues in 2003.3 Plasma concentrations of chromogranin A were measured in 119 patients 3 days after onset of symptoms. Increased plasma chromogranin A concentrations were associated with an increased risk of death, but the association disappeared when the results were adjusted for patient age. In a later study from the same researchers,4 plasma chromogranin A concentrations were found to be predictive of patient outcomes following myocardial infarction after multivariable analyses that included patient age, diabetes, and sex. The largest study so far on chromogranin A in acute coronary syndromes included 1268 patients with a follow-up of 7·5 years.5 Basal chromogranin A concentrations in plasma were strongly associated with long-term mortality, admissions to hospital for heart failure, and recurrent myocardial infarction, with hazard
Published Online June 13, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70035-4
7
Comment
19
457
19
94
19 19
97
457 131
58
272 194 215
319
375
446
370 390
Aminoacid position
Figure: Chromogranin A (19—457) and its processing products Fragments 19–94 and 19–131 (vasostatin 1 and 2), 272–319 (pancreastatin), and 370–390 (catestatin) are proposed to have independent inhibitory hormonal activity similar to statins. Signal peptide (fragment 1–18) not shown.
ratios between 1·27 (95% CI 1·10–1·47) and 1·57 (95% CI 1·44–1·70). The association was maintained even after the results were adjusted for conventional risk markers. Chronic heart failure is characterised by pronounced activation of the neuroendocrine system and adrenal noradrenaline release; chromogranin A could be a useful clinical marker in this syndrome.6 So far, the largest study of plasma chromogranin A measurement in chronic heart failure is the GISSI-Heart Failure trial.7 The study included 1233 patients with stable heart failure and followed them up for 4 years. In univariable analysis, increased chromogranin A plasma concentrations were associated with all-cause mortality, with hazard ratios between 1·58 (95% CI 1·17–2·11) and 2·35 (95% CI 1·78–3·10). However, after adjustment for known risk factors of mortality the association was lost. Thus, this clinically well characterised study concluded that chromogranin A measurement does not seem to be useful in the assessment of mortality risk in stable chronic heart failure beyond what physical examination, routine biochemical analyses, and cardiac natriuretic peptide measurement already offer. Since this study, two small investigations have been reported on chromogranin A as a biomarker in heart failure.8,9 Both suggest that chromogranin A measurement adds independent prognostic information beyond B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement. Measurement of plasma chromogranin A is a complex matter. Chromogranin A is a protein that contains many dibasic aminoacid motifs prone to endoproteolytical cleavage. The cellular processing of chromogranin A encompasses a plethora of fragments from the primary precursor, some of which are proposed to have independent hormonal activity (figure). However, no specific receptor-mediated mechanisms have been identified for the fragments. The primary structure of 8
the peptide fragments also challenges the idea that they act as soluble hormones in plasma. One way around the troublesome processing of chromogranin A could be to use a processing-independent assay for measurement. By production of a uniform peptide fragment for standard measurement by epitope-specific radioimmunoassay (or other types of immunoassays), the assay can be correctly calibrated and can measure the total sum of chromogranin A translational products irrespective of its variable and poorly characterised cellular processing.10 A processing-independent assay has the general advantage of storage stability of plasma samples, since they need treatment with trypsin or another suitable endoprotease to release the measured ligand. For now, we conclude that the present studies should be interpreted with caution, because plasma chromogranin A is not a uniform analyte, and the assays used so far measure different—and often unknown—epitopes within the primary protein structure. Jens P Goetze*, Urban Alehagen, Allan Flyvbjerg, Jens F Rehfeld Department of Clinical Biochemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark (JPG, JFR); Division of Cardiovascular Medicine, Linköping University, Sweden (UA); Medical Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark (AF); and Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark (AF) [email protected] We declare that we have no conflicts of interest. JPG is supported by a non-commercial research grant from Rigshospitalets Forskningsråd. 1
2
3
4
5
6 7
8
9 10
Wohlschlaeger J, von Winterfeld M, Milting H, et al. Decreased myocardial chromogranin A expression and colocalization with brain natriuretic peptide during reverse cardiac remodeling after ventricular unloading. J Heart Lung Transplant 2008; 27: 442–49. Mahapatra NR, O’Connor DT, Vaingankar SM, et al. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest 2005; 115: 1942–52. Omland T, Dickstein K, Syversen U. Association between plasma chromogranin A concentration and long-term mortality after myocardial infarction. Am J Med 2003; 114: 25–30. Estensen ME, Hognestad A, Syversen U, et al. Prognostic value of plasma chromogranin A levels in patients with complicated myocardial infarction. Am Heart J 2006; 152: 927 e1–6. Jansson AM, Røsjø H, Omland T, et al. Prognostic value of circulating chromogranin A levels in acute coronary syndromes. Eur Heart J 2009; 30: 25–32. Braunwald E. Biomarkers in heart failure. N Engl J Med 2008; 358: 2148–59. Røsjø H, Masson S, Latini R, for the GISSI-HF Investigators. Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial. Eur J Heart Fail 2010; 12: 549–56. Dieplinger B, Gegenhuber A, Kaar G, Poelz W, Haltmayer M, Mueller T. Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department. Clin Biochem 2010; 43: 714–19. Zhu D, Wang F, Yu H, Mi L, Gao W. Catestatin is useful in detecting patients with stage B heart failure. Biomarkers 2011; 16: 691–97. Goetze JP, Hunter I, Lippert SK, Bardram L, Rehfeld JF. Processing-independent analysis of peptide hormones and prohormones in plasma. Front Biosci 2012; 17: 1804–15.
www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
this group subsequently developed increased fasting glucose concentrations. Færch and colleagues recommend that strategies to prevent loss of β-cell function might be beneficial for people with fasting hyperglycaemia, but do not suggest what these strategies might be. They report a subgroup analysis from the Diabetes Prevention Program,8 which suggested that metformin seemed to be more effective at preventing diabetes in people with high fasting glucose concentrations (6·2–6·9 mmol/L) at baseline than in those with low fasting concentrations (5·3–6·1 mmol/L) in a population that also had 2 h glucose concentrations in the range of 7·8–11·0 mmol/L. Færch and coworkers appropriately conclude that further research is needed to establish whether the different subgroups of type 2 diabetes (as defined by glucose or HbA1c criteria) respond differently to lifestyle interventions or drugs, and whether complications differ between subgroups. A better understanding of the pathogenesis of type 2 diabetes in an individual will probably lead to improved targeting of available effective interventions for hyperglycaemia.
Sarah H Wild*, Christopher D Byrne Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK (SHW); Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK (CDB); and Southampton National Institute for Health Research Biomedical Research Centre, Southampton, UK (CDB) [email protected] We declare that we have no conflicts of interest. 1
2 3
4
5
6
7 8
WHO, International Diabetes Federation. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. Geneva: World Health Organization, 2006. WHO. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Geneva: World Health Organization, 2011. Færch K, Witte DR, Tabák AG, et al. Trajectories of cardiometabolic risk factors before diagnosis of three subtypes of type 2 diabetes: a post-hoc analysis of the longitudinal Whitehall II cohort study. Lancet Diabetes Endocrinol 2013; published online Feb 21. http://dx.doi.org/10.1016/S2213-8587(13)70008-1. Arterburn DE, Bogart A, Sherwood NE, et al. A multisite study of long-term remission and relapse of type 2 diabetes mellitus following gastric bypass. Obes Surg 2013; 23: 93–102. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011, 54: 2506–14. Morris AP, Voight BF, Teslovich TM, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012; 44: 981–90. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132: 2131–57. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403.
Making sense of chromogranin A in heart disease Chromogranin A is an acidic protein present in secretory granules of neuroendocrine cells. In plasma, chromogranin A is an important marker of neuroendocrine tumours. Chromogranin A measurement has gained interest in cardiovascular disease, because increased plasma concentrations are associated with risk of clinical deterioration and death in patients with acute coronary syndromes or chronic heart failure. Cardiac chromogranin A is stored in atrial granules with cardiac natriuretic peptides—the principal cardiac hormones associated with systemic homoeostasis of water and blood pressure. Expression of cardiac chromogranin A is decreased in patients treated with mechanical assist device therapy, which parallels findings on B-type natriuretic peptide mRNA expression and concomitant plasma concentrations.1 Support for a cardiovascular role for chromogranin A comes from mice deficient in chromogranin A gene expression, because they display a hypertensive phenotype that can be fully reversed by infusion with the chromogranin A fragment catestatin.2 One proposed www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
explanation for this is that mice deficient in chromogranin A have increased catecholamine release, which is a known mechanism in essential hypertension. The first observation of chromogranin A in myocardial infarction was reported by Omland and colleagues in 2003.3 Plasma concentrations of chromogranin A were measured in 119 patients 3 days after onset of symptoms. Increased plasma chromogranin A concentrations were associated with an increased risk of death, but the association disappeared when the results were adjusted for patient age. In a later study from the same researchers,4 plasma chromogranin A concentrations were found to be predictive of patient outcomes following myocardial infarction after multivariable analyses that included patient age, diabetes, and sex. The largest study so far on chromogranin A in acute coronary syndromes included 1268 patients with a follow-up of 7·5 years.5 Basal chromogranin A concentrations in plasma were strongly associated with long-term mortality, admissions to hospital for heart failure, and recurrent myocardial infarction, with hazard
Published Online June 13, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70035-4
7
Comment
19
457
19
94
19 19
97
457 131
58
272 194 215
319
375
446
370 390
Aminoacid position
Figure: Chromogranin A (19—457) and its processing products Fragments 19–94 and 19–131 (vasostatin 1 and 2), 272–319 (pancreastatin), and 370–390 (catestatin) are proposed to have independent inhibitory hormonal activity similar to statins. Signal peptide (fragment 1–18) not shown.
ratios between 1·27 (95% CI 1·10–1·47) and 1·57 (95% CI 1·44–1·70). The association was maintained even after the results were adjusted for conventional risk markers. Chronic heart failure is characterised by pronounced activation of the neuroendocrine system and adrenal noradrenaline release; chromogranin A could be a useful clinical marker in this syndrome.6 So far, the largest study of plasma chromogranin A measurement in chronic heart failure is the GISSI-Heart Failure trial.7 The study included 1233 patients with stable heart failure and followed them up for 4 years. In univariable analysis, increased chromogranin A plasma concentrations were associated with all-cause mortality, with hazard ratios between 1·58 (95% CI 1·17–2·11) and 2·35 (95% CI 1·78–3·10). However, after adjustment for known risk factors of mortality the association was lost. Thus, this clinically well characterised study concluded that chromogranin A measurement does not seem to be useful in the assessment of mortality risk in stable chronic heart failure beyond what physical examination, routine biochemical analyses, and cardiac natriuretic peptide measurement already offer. Since this study, two small investigations have been reported on chromogranin A as a biomarker in heart failure.8,9 Both suggest that chromogranin A measurement adds independent prognostic information beyond B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide measurement. Measurement of plasma chromogranin A is a complex matter. Chromogranin A is a protein that contains many dibasic aminoacid motifs prone to endoproteolytical cleavage. The cellular processing of chromogranin A encompasses a plethora of fragments from the primary precursor, some of which are proposed to have independent hormonal activity (figure). However, no specific receptor-mediated mechanisms have been identified for the fragments. The primary structure of 8
the peptide fragments also challenges the idea that they act as soluble hormones in plasma. One way around the troublesome processing of chromogranin A could be to use a processing-independent assay for measurement. By production of a uniform peptide fragment for standard measurement by epitope-specific radioimmunoassay (or other types of immunoassays), the assay can be correctly calibrated and can measure the total sum of chromogranin A translational products irrespective of its variable and poorly characterised cellular processing.10 A processing-independent assay has the general advantage of storage stability of plasma samples, since they need treatment with trypsin or another suitable endoprotease to release the measured ligand. For now, we conclude that the present studies should be interpreted with caution, because plasma chromogranin A is not a uniform analyte, and the assays used so far measure different—and often unknown—epitopes within the primary protein structure. Jens P Goetze*, Urban Alehagen, Allan Flyvbjerg, Jens F Rehfeld Department of Clinical Biochemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark (JPG, JFR); Division of Cardiovascular Medicine, Linköping University, Sweden (UA); Medical Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark (AF); and Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark (AF) [email protected] We declare that we have no conflicts of interest. JPG is supported by a non-commercial research grant from Rigshospitalets Forskningsråd. 1
2
3
4
5
6 7
8
9 10
Wohlschlaeger J, von Winterfeld M, Milting H, et al. Decreased myocardial chromogranin A expression and colocalization with brain natriuretic peptide during reverse cardiac remodeling after ventricular unloading. J Heart Lung Transplant 2008; 27: 442–49. Mahapatra NR, O’Connor DT, Vaingankar SM, et al. Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest 2005; 115: 1942–52. Omland T, Dickstein K, Syversen U. Association between plasma chromogranin A concentration and long-term mortality after myocardial infarction. Am J Med 2003; 114: 25–30. Estensen ME, Hognestad A, Syversen U, et al. Prognostic value of plasma chromogranin A levels in patients with complicated myocardial infarction. Am Heart J 2006; 152: 927 e1–6. Jansson AM, Røsjø H, Omland T, et al. Prognostic value of circulating chromogranin A levels in acute coronary syndromes. Eur Heart J 2009; 30: 25–32. Braunwald E. Biomarkers in heart failure. N Engl J Med 2008; 358: 2148–59. Røsjø H, Masson S, Latini R, for the GISSI-HF Investigators. Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial. Eur J Heart Fail 2010; 12: 549–56. Dieplinger B, Gegenhuber A, Kaar G, Poelz W, Haltmayer M, Mueller T. Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department. Clin Biochem 2010; 43: 714–19. Zhu D, Wang F, Yu H, Mi L, Gao W. Catestatin is useful in detecting patients with stage B heart failure. Biomarkers 2011; 16: 691–97. Goetze JP, Hunter I, Lippert SK, Bardram L, Rehfeld JF. Processing-independent analysis of peptide hormones and prohormones in plasma. Front Biosci 2012; 17: 1804–15.
www.thelancet.com/diabetes-endocrinology Vol 1 September 2013
