GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes

Thea A.S. Halden, Erlend J. Egeland, Anders Åsberg, Anders Hartmann, Karsten Midtvedt, Hassan Z. Khiabani, Jens J. Holst, Filip K. Knop, Mads Hornum, Bo Feldt-Rasmussen, Trond Jenssen
2016 Diabetes Care  
OBJECTIVE Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon-like peptide 1 (GLP-1) during fasting and hyperglycemic conditions, respectively. RESEARCH DESIGN AND METHODS Renal transplant recipients with (n = 12) and without (n = 12) PTDM underwent two separate
more » ... nt two separate experimental days with 3-h intravenous infusions of GLP-1 (0.8 pmol/kg/min) and saline, respectively. After 1 h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp. RESULTS Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups. In PTDM patients, glucose-induced glucagon suppression was significantly less pronounced (maximal suppression from baseline: 43 6 12 vs. 65 6 12%, P < 0.001), while firstand second-phase insulin secretion were significantly lower. The PTDM group also exhibited a significantly lower insulin response to arginine (P = 0.01) but similar glucagon and proinsulin responses compared with control subjects. In the preclamp phase, GLP-1 lowered fasting plasma glucose to the same extent in both groups but reduced glucagon only in PTDM patients. During hyperglycemic clamp, GLP-1 reduced glucagon concentrations and increased firstand second-phase insulin secretion in both groups. CONCLUSIONS PTDM is characterized by reduced glucose-induced insulin secretion and attenuated glucagon suppression during a hyperglycemic clamp. Similar to the case in type 2 diabetes, GLP-1 infusion seems to improve (insulin) or even normalize (glucagon) these pathophysiological defects. In renal transplant recipients, cardiovascular disease persists as the leading cause of premature death (1). Development of posttransplantation diabetes (PTDM) is associated with further increased cardiovascular risk and mortality (2-4). PTDM is primarily believed to be a variant of type 2 diabetes possibly induced by immunosuppressive therapy (5) and/or viral infections (e.g., cytomegalovirus and hepatitis C) that reduce both insulin secretion and insulin sensitivity (6). Importantly, the risk of PTDM can be significantly reduced by proper dosing of the immunosuppressive
doi:10.2337/dc15-2383 pmid:26908914 fatcat:nj7v3rmzareoldeo5m2xkeh4li