ORIGINAL ARTICLE Fasting and postprandial liver glycogen content in patients with type 1 diabetes mellitus after successful pancreas–kidney transplantation with systemic venous insulin delivery M. Stadler* , † , ††, M. Kr  s  s ak‡, D. Jankovic‡, C. G€ obl‡, Y. Winhofer‡, G. Pacini§, M. Bischof‡, M. Haidingerk, M. Saemannk, F. M€ uhlbacher**, M. Korbonits††, S. M. Baumgartner-Parzer‡, A. Luger‡, R. Prager* , †, C.-H. Anderwald‡ , § , ¶ and M. Krebs‡ *3rd Medical Department of Metabolic Diseases and Nephrology, Hietzing Hospital, †Karl Landsteiner Institute of Metabolic Diseases and Nephrology, ‡Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria, §Metabolic Unit, Institute of Biomedical Engineering, National Research Council (ISIB-CNR), Padova, Italy, ¶Medical Direction, Specialized Hospital Complex Agathenhof, Micheldorf, kDivision of Nephrology, Department of Internal Medicine III, Medical University Vienna, **Department of Surgery, Medical University Vienna, Vienna, Austria and ††Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK Abstract Background In patients with type 1 diabetes mellitus (T1DM), insulin is usually replaced systemically (subcutaneously) and not via the physiological portal route. According to previous studies, the liver’s capacity to store glycogen is reduced in T1DM patients, but it remains unclear whether this is due to hyperglycaemia, or whether the route of insulin supply could contribute to this phe- nomenon. T1DM patients after successful pancreas–kidney trans- plantation with systemic venous drainage (T1DM-PKT) represent a suitable human model to further investigate this question, because they are normoglycaemic, but their liver receives insulin from the pancreas transplant via the systemic route. Materials and methods In nine T1DM-PKT, nine controls without diabetes (CON) and seven patients with T1DM (T1DM), liver glycogen content was measured at fasting and after two standardized meals employing 13 C-nuclear-magnetic- resonance-spectroscopy. Circulating glucose and glucoregulatory hormones were measured repeatedly throughout the study day. Results The mean and fasting concentrations of peripheral plasma glucose, insulin, glucagon and C-peptide were comparable between T1DM-PKT and CON, whereas T1DM were hyperglycaemic and hyperinsulinaemic (P < 005 vs T1DM-PKT and CON). Total liver glycogen content at fasting and after breakfast did not differ in the three groups. After lunch, T1DM-PKT and T1DM had a 14% and 21% lower total liver glycogen content than CON (P < 002). Conclusion In spite of normalized glycaemic control, postpran- dial liver glycogen content was reduced in T1DM-PKT with sys- temic venous drainage. Thus, not even optimized systemic insulin substitution is able to resolve the defect in postprandial liver glycogen storage seen in T1DM patients. (Received 17 September 2012; returned for revision 4 December 2012; finally revised 17 December 2012; accepted 7 January 2013) Introduction Insulin replacement in type 1 diabetes mellitus (T1DM) is usu- ally via the systemic (subcutaneous), rather than the physiologi- cal portal route. So far it remains unclear, whether this systemic route of insulin administration might contribute to the meta- bolic defects observed in these patients, including impaired post- prandial hepatic glycogen storage. 1 The deficiency in glycogen synthesis has possible clinical implications: The majority of glu- cose taken up after a meal is stored as glycogen in both skeletal muscle and liver. 2,3 Thus, any impairment in insulin-stimulated hepatic glycogen synthesis would leave more glucose in the cir- culation, which would contribute to postprandial hyperglyca- emia. Furthermore, lower hepatic glycogen stores could limit the ability of patients with T1DM to adequately respond to hypo- glycaemia, as the mobilization of hepatic glycogen plays a crucial role in counter regulatory response to hypoglycaemia. 4,5 In patients with T1DM with terminal kidney disease, successful combined pancreas and kidney transplantation (PKT) results in normalization of glycaemic control. 6 However, in T1DM-PKT with systemic venous drainage of the pancreas, pancreatic hor- mones are released directly into the systemic circulation. In Correspondence: Christian-Heinz Anderwald, Associate Professor of Internal Medicine, Division of Endocrinology and Metabolism, Depart- ment of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43 1 40400 7249; Fax: +43 1 40400 7790; Email: christian-heinz.anderwald@meduniwien.ac.at © 2013 John Wiley & Sons Ltd 1 Clinical Endocrinology (2013) doi: 10.1111/cen.12146