Mechanisms of Glucose Counterregulation in Pancreatic Islet Transplantation

Pancreatic islet transplantation improves glucose counterregulation and stabilizes glycemic control in patients with type 1 diabetes mellitus prone to severe hypoglycemia even if insulin independence is not achieved. However, the extent and underlying metabolic pathways of this improvement are unknown. Investigators therefore compare systemic glucose turnover including lactate gluconeogenesis and muscle glucose utilization, between insulin-requiring islet transplant recipients, matched type 1 diabetic subjects who did not receive islet transplantation, and matched healthy non-diabetic subjects.

Subjects (n=12 each group) undergo a hypoglycemic and a euglycemic hyperinsulinemic clamp in a randomized fashion. Systemic and skeletal muscle glucose and lactate kinetics are assessed using a combination of isotopic and forearm balance techniques.

Each study participant will be subjected to a continuous infusion of insulin at a rate of 0.8 mU·kg-1·min-1 to induce hypoglycemia (blood glucose 2.8-3 mmol/l) for 30 minutes. At least two weeks later an identical insulin infusion will be administered and euglycemia (blood glucose 5 mmol/l) will be targeted. The order of these interventions will be subject to randomization.

Whole body glucose counterregulation is the difference in glucose infusion rates required to maintain the glycemic goal between the hypoglycemic and euglycemic clamp. Clamps were performed at two time points at least two weeks apart. Participants will be followed for the duration of 6-8 weeks to perform the hypoglycemic and euglycemic clamp tests.

Systemic glucose release is the amount of glucose released primarily from the liver into the blood compartment during a given time. The unit of measure is μmol/kg/min. Participants will be followed for the duration of 6-8 weeks to perform the hypoglycemic and euglycemic clamp tests that will yield this parameter.

Participants will be followed for the duration of 6-8 weeks to perform the euglycemic and hypoglycemic clamp tests. The unit of measure of this parameters is μmol/kg/min.

This parameter is determined by labelled lactate infused into the proband. The rate of the de novo synthesis of glucose (gluconeogenesis) is determined by the degree of incorporation of the lactate label into glucose molecules. The unit of measure of this parameter is μmol/kg/min.

T1DM/ITX+ Inclusion Criteria: Type 1 Diabetes Pancreatic islet transplantation Exclusion Criteria: Type 2 Diabetes

Ang M, Meyer C, Brendel MD, Bretzel RG, Linn T. Magnitude and mechanisms of glucose counterregulation following islet transplantation in patients with type 1 diabetes suffering from severe hypoglycaemic episodes. Diabetologia. 2014 Mar;57(3):623-32. doi: 10.1007/s00125-013-3120-9. Epub 2013 Dec 5.