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Published in: Diabetologia 8/2012

Open Access 01-08-2012 | Article

Disease-specific mortality among stage I–III colorectal cancer patients with diabetes: a large population-based analysis

Authors: L. V. van de Poll-Franse, H. R. Haak, J. W. W. Coebergh, M. L. G. Janssen-Heijnen, V. E. P. P. Lemmens

Published in: Diabetologia | Issue 8/2012

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Abstract

Aims/hypothesis

The aim of our study was to investigate overall and disease-specific mortality of colorectal cancer patients with diabetes.

Methods

In this population-based study, we included all colorectal cancer patients, newly diagnosed with stage I–III cancer, between 1997 and 2007 in the registration area of the Eindhoven Cancer Registry. Stage of cancer, cancer treatment and comorbidities were actively collected by reviewing hospital medical records. Data on patients with and without diabetes were linked to Statistics Netherlands to assess vitality, date of death and underlying cause of death. Follow-up of all patients was completed until 1 January 2009.

Results

We included 6,974 patients with colon cancer and 3,888 patients with rectal cancer, of whom 820 (12%) and 404 (10%), respectively, had diabetes at the time of cancer diagnosis. During follow-up, death occurred in 611 (50%) of 1,224 cancer patients with diabetes and 3,817 (40%) of 9,638 cancer patients without diabetes. Multivariate Cox regression analyses, adjusted for age, sex, socioeconomic status, stage, lymph nodes examined, adjuvant therapy and year of diagnosis, showed that overall mortality was significantly higher for colon (HR 1.12, 95% CI 1.01, 1.25) and rectal (HR 1.21, 95% CI 1.03, 1.41) cancer patients with diabetes than for those without. Disease-specific mortality was only significantly increased for rectal cancer patients (HR 1.30, 95% CI 1.06, 1.60).

Conclusions/interpretation

Diabetes at the time of rectal cancer diagnosis was independently associated with an increased risk of colorectal cancer mortality compared with no diabetes, suggesting a specific interaction between diabetes and rectal cancer. Future in-depth studies including detailed diabetes- and cancer-related variables should elucidate pathways.
Literature
1.
go back to reference Janssen-Heijnen ML, Houterman S, Lemmens VE, Louwman MW, Maas HA, Coebergh JW (2005) Prognostic impact of increasing age and co-morbidity in cancer patients: a population-based approach. Crit Rev Oncol Hematol 55:231–240PubMedCrossRef Janssen-Heijnen ML, Houterman S, Lemmens VE, Louwman MW, Maas HA, Coebergh JW (2005) Prognostic impact of increasing age and co-morbidity in cancer patients: a population-based approach. Crit Rev Oncol Hematol 55:231–240PubMedCrossRef
2.
go back to reference Evans JM, Barnett KN, Ogston SA, Morris AD (2007) Increasing prevalence of type 2 diabetes in a Scottish population: effect of increasing incidence or decreasing mortality? Diabetologia 50:729–732PubMedCrossRef Evans JM, Barnett KN, Ogston SA, Morris AD (2007) Increasing prevalence of type 2 diabetes in a Scottish population: effect of increasing incidence or decreasing mortality? Diabetologia 50:729–732PubMedCrossRef
3.
go back to reference Stovring H, Andersen M, Beck-Nielsen H, Green A, Vach W (2003) Rising prevalence of diabetes: evidence from a Danish pharmaco-epidemiological database. Lancet 362:537–538PubMedCrossRef Stovring H, Andersen M, Beck-Nielsen H, Green A, Vach W (2003) Rising prevalence of diabetes: evidence from a Danish pharmaco-epidemiological database. Lancet 362:537–538PubMedCrossRef
4.
go back to reference National Institutes of Health (2008) National Institute of Diabetes and Digestive and Kidney Diseases National Diabetes Statistics, 2007 fact sheet. US Department of Health and Human Services, Bethesda, MD National Institutes of Health (2008) National Institute of Diabetes and Digestive and Kidney Diseases National Diabetes Statistics, 2007 fact sheet. US Department of Health and Human Services, Bethesda, MD
5.
go back to reference van de Poll-Franse LV, Houterman S, Janssen-Heijnen ML, Dercksen MW, Coebergh JW, Haak HR (2007) Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis. Int J Cancer 120:1986–1992PubMedCrossRef van de Poll-Franse LV, Houterman S, Janssen-Heijnen ML, Dercksen MW, Coebergh JW, Haak HR (2007) Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis. Int J Cancer 120:1986–1992PubMedCrossRef
6.
go back to reference Cancer in the Netherlands (2004) Trends, prognoses and implications for healthcare. Signalling Committee Cancer of the Dutch Cancer Society, Amsterdam. ISBN 90-71229-13-0 Cancer in the Netherlands (2004) Trends, prognoses and implications for healthcare. Signalling Committee Cancer of the Dutch Cancer Society, Amsterdam. ISBN 90-71229-13-0
7.
go back to reference Barone BB, Yeh HC, Snyder CF et al (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300:2754–2764PubMedCrossRef Barone BB, Yeh HC, Snyder CF et al (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300:2754–2764PubMedCrossRef
8.
go back to reference Stein KB, Snyder CF, Barone BB et al (2010) Colorectal cancer outcomes, recurrence, and complications in persons with and without diabetes mellitus: a systematic review and meta-analysis. Dig Dis Sci 55:1839–1851PubMedCrossRef Stein KB, Snyder CF, Barone BB et al (2010) Colorectal cancer outcomes, recurrence, and complications in persons with and without diabetes mellitus: a systematic review and meta-analysis. Dig Dis Sci 55:1839–1851PubMedCrossRef
9.
go back to reference Giovannucci E, Harlan DM, Archer MC et al (2010) Diabetes and cancer: a consensus report. Diabetes Care 33:1674–1685PubMedCrossRef Giovannucci E, Harlan DM, Archer MC et al (2010) Diabetes and cancer: a consensus report. Diabetes Care 33:1674–1685PubMedCrossRef
10.
go back to reference Renehan A, Smith U, Kirkman MS (2010) Linking diabetes and cancer: a consensus on complexity. Lancet 375:2201–2202PubMedCrossRef Renehan A, Smith U, Kirkman MS (2010) Linking diabetes and cancer: a consensus on complexity. Lancet 375:2201–2202PubMedCrossRef
11.
go back to reference Siddiqui AA, Spechler SJ, Huerta S, Dredar S, Little BB, Cryer B (2008) Elevated HbA1c is an independent predictor of aggressive clinical behavior in patients with colorectal cancer: a case–control study. Dig Dis Sci 53:2486–2494PubMedCrossRef Siddiqui AA, Spechler SJ, Huerta S, Dredar S, Little BB, Cryer B (2008) Elevated HbA1c is an independent predictor of aggressive clinical behavior in patients with colorectal cancer: a case–control study. Dig Dis Sci 53:2486–2494PubMedCrossRef
12.
go back to reference Hammarsten J, Hogstedt B (2005) Hyperinsulinaemia: a prospective risk factor for lethal clinical prostate cancer. Eur J Cancer 41:2887–2895PubMedCrossRef Hammarsten J, Hogstedt B (2005) Hyperinsulinaemia: a prospective risk factor for lethal clinical prostate cancer. Eur J Cancer 41:2887–2895PubMedCrossRef
13.
go back to reference Folsom AR, Anderson KE, Sweeney C, Jacobs DR Jr (2004) Diabetes as a risk factor for death following endometrial cancer. Gynecol Oncol 94:740–745PubMedCrossRef Folsom AR, Anderson KE, Sweeney C, Jacobs DR Jr (2004) Diabetes as a risk factor for death following endometrial cancer. Gynecol Oncol 94:740–745PubMedCrossRef
14.
go back to reference Dehal AN, Newton CC, Jacobs EJ, Patel AV, Gapstur SM, Campbell PT (2010) Impact of diabetes mellitus and insulin use on survival after colorectal cancer diagnosis: the Cancer Prevention Study-II Nutrition Cohort. J Clin Oncol 30:53–59CrossRef Dehal AN, Newton CC, Jacobs EJ, Patel AV, Gapstur SM, Campbell PT (2010) Impact of diabetes mellitus and insulin use on survival after colorectal cancer diagnosis: the Cancer Prevention Study-II Nutrition Cohort. J Clin Oncol 30:53–59CrossRef
15.
go back to reference Chia VM, Newcomb PA, Trentham-Dietz A, Hampton JM (2007) Obesity, diabetes, and other factors in relation to survival after endometrial cancer diagnosis. Int J Gynecol Cancer 17:441–446PubMedCrossRef Chia VM, Newcomb PA, Trentham-Dietz A, Hampton JM (2007) Obesity, diabetes, and other factors in relation to survival after endometrial cancer diagnosis. Int J Gynecol Cancer 17:441–446PubMedCrossRef
16.
go back to reference Polednak AP (2006) Comorbid diabetes mellitus and risk of death after diagnosis of colorectal cancer: a population-based study. Cancer Detect Prev 30:466–472PubMedCrossRef Polednak AP (2006) Comorbid diabetes mellitus and risk of death after diagnosis of colorectal cancer: a population-based study. Cancer Detect Prev 30:466–472PubMedCrossRef
17.
go back to reference Will JC, Galuska DA, Vinicor F, Calle EE (1998) Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol 147:816–825PubMedCrossRef Will JC, Galuska DA, Vinicor F, Calle EE (1998) Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol 147:816–825PubMedCrossRef
18.
go back to reference Jullumstro E, Kollind M, Lydersen S, Edna TH (2009) Diabetes mellitus and outcomes of colorectal cancer. Acta Oncol 48:361–367PubMedCrossRef Jullumstro E, Kollind M, Lydersen S, Edna TH (2009) Diabetes mellitus and outcomes of colorectal cancer. Acta Oncol 48:361–367PubMedCrossRef
19.
go back to reference Giovannucci E, Harlan DM, Archer MC et al (2010) Diabetes and cancer: a consensus report. CA Cancer J Clin 60:207–221PubMedCrossRef Giovannucci E, Harlan DM, Archer MC et al (2010) Diabetes and cancer: a consensus report. CA Cancer J Clin 60:207–221PubMedCrossRef
20.
go back to reference Schouten LJ, Hoppener P, van den Brandt PA, Knottnerus JA, Jager JJ (1993) Completeness of cancer registration in Limburg, the Netherlands. Int J Epidemiol 22:369–376PubMedCrossRef Schouten LJ, Hoppener P, van den Brandt PA, Knottnerus JA, Jager JJ (1993) Completeness of cancer registration in Limburg, the Netherlands. Int J Epidemiol 22:369–376PubMedCrossRef
21.
go back to reference Kieszak SM, Flanders WD, Kosinski AS, Shipp CC, Karp H (1999) A comparison of the Charlson comorbidity index derived from medical record data and administrative billing data. J Clin Epidemiol 52:137–142PubMedCrossRef Kieszak SM, Flanders WD, Kosinski AS, Shipp CC, Karp H (1999) A comparison of the Charlson comorbidity index derived from medical record data and administrative billing data. J Clin Epidemiol 52:137–142PubMedCrossRef
22.
go back to reference Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383PubMedCrossRef Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383PubMedCrossRef
23.
go back to reference van Duijn C, Keij I (2002) Sociaal–economische status indicator op postcode niveau. Maandstatistiek van de Bevolking 50:32–35 van Duijn C, Keij I (2002) Sociaal–economische status indicator op postcode niveau. Maandstatistiek van de Bevolking 50:32–35
24.
go back to reference Babyak MA (2004) What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med 66:411–421PubMedCrossRef Babyak MA (2004) What you see may not be what you get: a brief, nontechnical introduction to overfitting in regression-type models. Psychosom Med 66:411–421PubMedCrossRef
25.
go back to reference Lemmens VE, van Halteren AH, Janssen-Heijnen ML, Vreugdenhil G, Repelaer van Driel OJ, Coebergh JW (2005) Adjuvant treatment for elderly patients with stage III colon cancer in the southern Netherlands is affected by socioeconomic status, gender, and comorbidity. Ann Oncol 16:767–772PubMedCrossRef Lemmens VE, van Halteren AH, Janssen-Heijnen ML, Vreugdenhil G, Repelaer van Driel OJ, Coebergh JW (2005) Adjuvant treatment for elderly patients with stage III colon cancer in the southern Netherlands is affected by socioeconomic status, gender, and comorbidity. Ann Oncol 16:767–772PubMedCrossRef
26.
go back to reference Lee L, Cheung WY, Atkinson E, Krzyzanowska MK (2011) Impact of comorbidity on chemotherapy use and outcomes in solid tumors: a systematic review. J Clin Oncol 29:106–117PubMedCrossRef Lee L, Cheung WY, Atkinson E, Krzyzanowska MK (2011) Impact of comorbidity on chemotherapy use and outcomes in solid tumors: a systematic review. J Clin Oncol 29:106–117PubMedCrossRef
27.
go back to reference De Marco MF, Janssen-Heijnen ML, van der Heijden LH, Coebergh JW (2000) Comorbidity and colorectal cancer according to subsite and stage: a population-based study. Eur J Cancer 36:95–99PubMedCrossRef De Marco MF, Janssen-Heijnen ML, van der Heijden LH, Coebergh JW (2000) Comorbidity and colorectal cancer according to subsite and stage: a population-based study. Eur J Cancer 36:95–99PubMedCrossRef
28.
go back to reference Lemmens VE, Janssen-Heijnen ML, Houterman S et al (2007) Which comorbid conditions predict complications after surgery for colorectal cancer? World J Surg 31:192–199PubMedCrossRef Lemmens VE, Janssen-Heijnen ML, Houterman S et al (2007) Which comorbid conditions predict complications after surgery for colorectal cancer? World J Surg 31:192–199PubMedCrossRef
29.
go back to reference Caudle AS, Kim HJ, Tepper JE et al (2008) Diabetes mellitus affects response to neoadjuvant chemoradiotherapy in the management of rectal cancer. Ann Surg Oncol 15:1931–1936PubMedCrossRef Caudle AS, Kim HJ, Tepper JE et al (2008) Diabetes mellitus affects response to neoadjuvant chemoradiotherapy in the management of rectal cancer. Ann Surg Oncol 15:1931–1936PubMedCrossRef
30.
go back to reference Meyerhardt JA, Catalano PJ, Haller DG et al (2003) Impact of diabetes mellitus on outcomes in patients with colon cancer. J Clin Oncol 21:433–440PubMedCrossRef Meyerhardt JA, Catalano PJ, Haller DG et al (2003) Impact of diabetes mellitus on outcomes in patients with colon cancer. J Clin Oncol 21:433–440PubMedCrossRef
31.
go back to reference Richardson LC, Pollack LA (2005) Therapy insight: influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat Clin Pract Oncol 2:48–53PubMedCrossRef Richardson LC, Pollack LA (2005) Therapy insight: influence of type 2 diabetes on the development, treatment and outcomes of cancer. Nat Clin Pract Oncol 2:48–53PubMedCrossRef
32.
go back to reference Goodwin PJ, Ennis M, Pritchard KI et al (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20:42–51PubMedCrossRef Goodwin PJ, Ennis M, Pritchard KI et al (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20:42–51PubMedCrossRef
33.
go back to reference Wolpin BM, Meyerhardt JA, Chan AT et al (2009) Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J Clin Oncol 27:176–185PubMedCrossRef Wolpin BM, Meyerhardt JA, Chan AT et al (2009) Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J Clin Oncol 27:176–185PubMedCrossRef
34.
go back to reference Hemkens LG, Grouven U, Bender R et al (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52:1732–1744PubMedCrossRef Hemkens LG, Grouven U, Bender R et al (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52:1732–1744PubMedCrossRef
35.
go back to reference Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777PubMedCrossRef Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777PubMedCrossRef
36.
go back to reference Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625PubMedCrossRef Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625PubMedCrossRef
37.
go back to reference Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ (2010) Metformin associated with lower cancer mortality in type 2 diabetes (ZODIAC-16). Diabetes Care 33:322–6PubMedCrossRef Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ (2010) Metformin associated with lower cancer mortality in type 2 diabetes (ZODIAC-16). Diabetes Care 33:322–6PubMedCrossRef
38.
go back to reference Meyerhardt JA, Heseltine D, Niedzwiecki D et al (2006) Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Clin Oncol 24:3535–3541PubMedCrossRef Meyerhardt JA, Heseltine D, Niedzwiecki D et al (2006) Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Clin Oncol 24:3535–3541PubMedCrossRef
39.
go back to reference Meyerhardt JA, Giovannucci EL, Holmes MD et al (2006) Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24:3527–3534PubMedCrossRef Meyerhardt JA, Giovannucci EL, Holmes MD et al (2006) Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24:3527–3534PubMedCrossRef
40.
go back to reference Meyerhardt JA, Catalano PJ, Haller DG et al (2003) Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 98:484–495PubMedCrossRef Meyerhardt JA, Catalano PJ, Haller DG et al (2003) Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 98:484–495PubMedCrossRef
41.
go back to reference Meyerhardt JA, Tepper JE, Niedzwiecki D et al (2004) Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from Intergroup Trial 0114. J Clin Oncol 22:648–657PubMedCrossRef Meyerhardt JA, Tepper JE, Niedzwiecki D et al (2004) Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from Intergroup Trial 0114. J Clin Oncol 22:648–657PubMedCrossRef
42.
go back to reference Dignam JJ, Polite BN, Yothers G et al (2006) Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst 98:1647–1654PubMedCrossRef Dignam JJ, Polite BN, Yothers G et al (2006) Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst 98:1647–1654PubMedCrossRef
43.
go back to reference Haydon AM, Macinnis RJ, English DR, Giles GG (2006) Effect of physical activity and body size on survival after diagnosis with colorectal cancer. Gut 55:62–67PubMedCrossRef Haydon AM, Macinnis RJ, English DR, Giles GG (2006) Effect of physical activity and body size on survival after diagnosis with colorectal cancer. Gut 55:62–67PubMedCrossRef
44.
go back to reference Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579–591PubMedCrossRef Calle EE, Kaaks R (2004) Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4:579–591PubMedCrossRef
45.
go back to reference Sandhu MS, Dunger DB, Giovannucci EL (2002) Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst 94:972–980PubMedCrossRef Sandhu MS, Dunger DB, Giovannucci EL (2002) Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst 94:972–980PubMedCrossRef
46.
go back to reference Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16:1103–1123PubMedCrossRef Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16:1103–1123PubMedCrossRef
47.
go back to reference Yin D, Morris CR, Bates JH, German RR (2011) Effect of misclassified underlying cause of death on survival estimates of colon and rectal cancer. J Natl Cancer Inst 103:1130–1133PubMedCrossRef Yin D, Morris CR, Bates JH, German RR (2011) Effect of misclassified underlying cause of death on survival estimates of colon and rectal cancer. J Natl Cancer Inst 103:1130–1133PubMedCrossRef
48.
go back to reference Wolbers M, Koller MT, Witteman JC, Steyerberg EW (2009) Prognostic models with competing risks: methods and application to coronary risk prediction. Epidemiology 20:555–561PubMedCrossRef Wolbers M, Koller MT, Witteman JC, Steyerberg EW (2009) Prognostic models with competing risks: methods and application to coronary risk prediction. Epidemiology 20:555–561PubMedCrossRef
49.
go back to reference Carstensen B, Kristensen JK, Ottosen P, Borch-Johnsen K (2008) The Danish National Diabetes Register: trends in incidence, prevalence and mortality. Diabetologia 51:2187–2196PubMedCrossRef Carstensen B, Kristensen JK, Ottosen P, Borch-Johnsen K (2008) The Danish National Diabetes Register: trends in incidence, prevalence and mortality. Diabetologia 51:2187–2196PubMedCrossRef
50.
go back to reference Hansen MB, Jensen ML, Carstensen B (2012) Causes of death among diabetic patients in Denmark. Diabetologia 55:294–302PubMedCrossRef Hansen MB, Jensen ML, Carstensen B (2012) Causes of death among diabetic patients in Denmark. Diabetologia 55:294–302PubMedCrossRef
Metadata
Title
Disease-specific mortality among stage I–III colorectal cancer patients with diabetes: a large population-based analysis
Authors
L. V. van de Poll-Franse
H. R. Haak
J. W. W. Coebergh
M. L. G. Janssen-Heijnen
V. E. P. P. Lemmens
Publication date
01-08-2012
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 8/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-012-2555-8

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