Mechanisms of Glucose Counterregulation in Pancreatic Islet Transplantation

Metabolic Studies in Type 1 Diabetic Patients After Allogenic Intraportal 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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Procedure: Hypoglycemic and euglycemic glucose clamp

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Hessia
    • Giessen, Hessia, Germany, 35392
      • Justus Liebig University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

T1DM/ITX+

Inclusion Criteria:

• Type 1 Diabetes
• Pancreatic islet transplantation

Exclusion Criteria:

• Type 2 Diabetes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Islet transplant recipients; Hypoglycemic and euglycemic glucose clamp	Procedure: Hypoglycemic and euglycemic glucose clamp; 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.
Placebo Comparator: Type 1 diabetic subjects; Hypoglycemic and euglycemic glucose clamp.	Procedure: Hypoglycemic and euglycemic glucose clamp; 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.
Active Comparator: Non-diabetic subjects; Hypoglycemic and euglycemic glucose clamp	Procedure: Hypoglycemic and euglycemic glucose clamp; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole body glucose counterregulation	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.	6-8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic glucose release	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.	6-8 weeks
Skeletal muscle glucose disposal	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.	6-8 weeks
Gluconeogenesis from lactate	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.	6-8 weeks

Collaborators and Investigators

• Sponsor: University of Giessen
• Investigators: Principal Investigator: Thomas Linn, MD, Justus Liebig University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2001
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2011

Study Registration Dates

• First Submitted: August 13, 2012
• First Submitted That Met QC Criteria: August 15, 2012
• First Posted (Estimate): August 20, 2012

Study Record Updates

• Last Update Posted (Estimate): August 21, 2012
• Last Update Submitted That Met QC Criteria: August 17, 2012
• Last Verified: August 1, 2012

More Information

Terms related to this study

• Keywords: Type 1 diabetes mellitus; pancreatic islet transplantation; hypoglycemia counterregulation,
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Hypoglycemic Agents
• Other Study ID Numbers: T1DM/ITX