Elevated markers of DNA damage and senescence are associated with the progression of albuminuria and restrictive lung disease in patients with type 2 diabetesResearch in context
Kumar Varun,
Kender Zoltan,
Sulaj Alba,
Blume Manuel,
Kliemank Elisabeth,
Tsilingiris Dimitrios,
Groener Jan B,
Brune Maik,
Shahzad Khurrum,
Isermann Berend,
Herzig Stephen,
Fleming Thomas,
Szendroedi Julia,
Nawroth Peter,
Kopf Stefan
Affiliations
Kumar Varun
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; European Molecular Biology Laboratory, Advanced Light Microscopy Facility, Heidelberg, Germany
Kender Zoltan
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Sulaj Alba
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Blume Manuel
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany
Kliemank Elisabeth
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Tsilingiris Dimitrios
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Groener Jan B
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Medicover Neuroendokrinologie, Munich, Germany
Brune Maik
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany
Shahzad Khurrum
Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital of Leipzig, Germany
Isermann Berend
Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital of Leipzig, Germany
Herzig Stephen
German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Helmholtz Diabetes Center, Institute for Diabetes and Cancer, Helmholtz Center Munich, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany
Fleming Thomas
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Szendroedi Julia
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
Nawroth Peter
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Internal Medicine I, Heidelberg University Hospital, Heidelberg, Germany
Kopf Stefan
Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Heidelberg, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany; Corresponding author. Department of Endocrinology, Diabetology and Clinical Chemistry (Internal Medicine I), University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Summary: Background: This study was conducted to investigate the cascade involving DNA damage, senescence, and senescence-associated secretory phenotype (SASP) in experimental diabetes and in a four-year follow-up study in patients with pre-diabetes and type 2 diabetes. Methods: Kidney, lung, and liver were studied in 4 months diabetic db/db mice and age-matched controls for the presence of DNA damage and fibrosis. DNA damage (comet-tail-length and ɤH2Ax-positivity in white blood cells), urinary p21-excretion, and plasma IL-6 and TGF-β1 were determined from 115 healthy participants, 34 patients with pre-diabetes and 221 with type 2 diabetes. Urinary albumin-creatinine-ratio, lung function, and transient elastography of the liver were performed in a prospective follow-up study over 4 years. Findings: db/db mice showed an increased nuclear ɤH2AX signal in all tissues as compared to the background control. Markers for DNA damage, senescence, and SASP were increased in patients with diabetes. The presence of nephropathy, restrictive lung disease (RLD), and increased liver stiffness was in a cross-sectional design associated with increased markers for DNA damage, senescence, and SASP. The progression of nephropathy over 4 years was predicted by increased DNA damage, senescence, and SASP, while the progression of RLD was associated with increased DNA damage and IL-6 only. The progression of liver stiffness was not associated with any of these parameters. HbA1c was not predictive for progression. Interpretation: In db/db mice, the cascade of DNA damage is associated with diabetes-related complications. In patients with diabetes, the progression of complications in the kidney and lung is predicted by markers reflecting DNA damage, and senescence-triggered organ fibrosis. Funding: This work was supported by the German Research Foundation (DFG) in the CRC 1118 and CRC 1158, by the GRK DIAMICOM, by the German Center for Diabetes Research (DZD e.V.), and by the Ministry of Science, Research and the Arts, Baden-Württemberg (Kompetenznetzwerk Präventivmedizin).
