title: Magnitude and mechanisms of glucose counterregulation following islet transplantation in patients with type 1 diabetes suffering from severe hypoglycaemic episodes.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01668485.
authors.affiliation: Clinical Research Unit, Medical Clinic and Policlinic III, Justus Liebig University, Klinikstrasse 33, 35392, Giessen, Germany.
authors.forename: Meidjie
authors.initials: M
authors.lastname: Ang
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
authors.forename: Mathias D
authors.initials: MD
authors.lastname: Brendel
authors.forename: Reinhard G
authors.initials: RG
authors.lastname: Bretzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Linn
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000601:surgery; D005260:Female; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism* / Q000601:surgery; D016381:Islets of Langerhans Transplantation; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D005947:Glucose; D006442:Glycated Hemoglobin; D019344:Lactic Acid; C517652:hemoglobin A1c protein, human