Magnitude and mechanisms of glucose counterregulation following islet transplantation in patients with type 1 diabetes suffering from severe hypoglycaemic episodes
- 426 Downloads
Pancreatic islet transplantation stabilises glycaemic control in type 1 diabetes mellitus patients with neuroglycopoenia, despite them not achieving insulin independence because of limited graft function. However, the extent and underlying metabolic pathways of restored glucose counterregulation are unknown. We therefore compared systemic glucose turnover, including lactate gluconeogenesis (GN) and muscle glucose uptake, in individuals with type 1 diabetes who were transplant recipients with partial graft function (T1DM/ITx+), matched non-transplanted individuals with type 1 diabetes (T1DM/ITx−) and matched healthy non-diabetic individuals.
Participants (n = 12 in each group) underwent a euglycaemic and a hypoglycaemic (2.5–2.8 mmol/l) hyperinsulinaemic clamp (0.8 mU kg−1 min−1) in a randomised crossover fashion. Systemic and skeletal muscle glucose and lactate kinetics were assessed using a combination of isotopic and forearm balance techniques.
Whole-body glucose counterregulation, the difference in glucose infusion rates required to maintain the glycaemic goal between the hypoglycaemic and euglycaemic clamps, was improved in T1DM/ITx+ (7.8 ± 1.3 μmol kg−1 min−1) compared with T1DM/ITx− (0.3 ± 0.9 μmol kg−1 min−1), but was ∼45% lower than in controls (14.1 ± 2.1 μmol kg−1 min−1). Increased endogenous glucose production (EGP) and decreased systemic glucose disposal accounted for 49% and 39% of glucose counterregulation in T1DM/ITx+, respectively, compared with 60% and 36% in controls. Lactate GN increased in T1DM/ITx+ (2.7 ± 0.4 μmol kg−1 min−1) and controls (1.7 ± 0.5 μmol kg−1 min−1), such that it accounted for 70% and 20% of the increased EGP, respectively. Skeletal muscle accounted for similar proportions of the decrease in systemic glucose disposal in controls (49%) and T1DM/ITx+ (41%).
Partial islet graft function improves hypoglycaemia counterregulation by increasing EGP, largely via lactate GN and decreasing systemic glucose disposal. This may explain the reduction in severe hypoglycaemic events in T1DM/ITx+ individuals.
Trial registration: ClinicalTrials.gov NCT01668485
KeywordsHypoglycaemia counterregulation Pancreatic islet transplantation Type 1 diabetes mellitus
Endogenous glucose production
Forearm blood flow
Rate of appearance/release
Rate of disappearance/disposal
Individuals with type 1 diabetes who were transplant recipients with partial graft function
Matched non-transplanted individuals with type 1 diabetes
We thank the staff of the Clinical Research Unit for their technical assistance, especially P. Saar, B. Fischer and M. Eckhard, and the participants for their contribution to this study. We also thank S. Mehta and S. Welle from the Clinical Research Center of the University of Rochester Medical Center for analysing plasma 2H and 13C enrichments.
This work was supported (MDB and RGB) by the immune modulation and tolerance induction to human islets study (1999–2004), NIH-NIDDK R01-DK56962-01 and the international multicentre clinical islet transplantation trial using new immunosuppressive protocol without the use of corticosteroids (2001–2009), Immune Tolerance Network (NIDDK, NIAID, JDRFI) NO1-AI-15416. TL was funded by Schwerpunktprogramm der Justus Liebig Universität Mensch-Ernährung-Umwelt.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
All authors were involved in the development of the manuscript. TL and CM contributed to the concept and design of the study, acquisition of data, analysis and calculation of data. MDB and RGB contributed to the acquisition and interpretation of data. MA performed statistical analysis, interpreted data and wrote the manuscript. CM, MDB, RGB and TL wrote and revised the manuscript critically for important intellectual content. All authors approved the final version of the manuscript for submission.
- 15.Wolfe R (1992) Radioactive and stable isotope tracers in biomedicine: Principles and practice of kinetic analysis. Wiley-Liss, New YorkGoogle Scholar