GLP-1 Effects on Insulin and Glucagon in PTDM

GLP-1 Restores Altered Insulin and Glucagon Secretion in Post-transplantation Diabetes Mellitus

Post-transplantation diabetes mellitus (PTDM) develops in 10-15 % of all renal transplant recipients within 10 weeks after transplantation, and has been associated with increased risk of cardiovascular disease and impaired patient survival. PTDM is primarily believed to be a variant of type 2 diabetes mellitus (T2DM), but the pathophysiology underlying the impaired glucose metabolism in renal transplant recipients with PTDM is unclear and some aspects are still poorly investigated. Hyperglycemic clamp investigations with concomitant infusion of glucagon-like peptide-1 (GLP-1) are warranted for a thorough characterization of the α-cell and β-cell function.

The primary objective of the present study is to investigate whether hyperglucagonemia is present in renal transplant recipients with PTDM. Furthermore, the investigators aim to examine the insulinotropic and glucagon suppressive effects of GLP-1 (compared to placebo) in PTDM patients during fasting glycemia and during hyperglycemic conditions (hyperglycemic clamp), respectively.

Study Overview

• Status: Completed
• Conditions: Post-transplant Diabetes Mellitus
• Intervention / Treatment: Dietary supplement: Glucagon-like peptide-1 (GLP-1); Other: Hyperglycemic clamp; Other: Isotonic saline

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, N-0424
    • Oslo University Hospital, Rikshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Renal transplant recipients more than 1 year post transplant with stable renal function (less than 20% deviation in serum creatinine within the last 2 months) and stable prednisolone dose (maximum 5 mg/day) the last three months before inclusion
• Diagnose of PTDM on standard clinical follow-up performed 8 weeks and 1 year post transplant at OUS-Rikshospitalet (fasting plasma glucose ≥ 7.0 mmol/l and/or 2-hour plasma glucose ≥ 11.1 mmol/l following an oral glucose tolerance test) OR
• Non-diabetic renal transplant recipients with a normal glucose tolerance test (control group)
• > 18 years of age
• BMI 18.5-29.9 kg/m2
• Signed informed consent

Exclusion Criteria:

• Severe liver disease
• Pancreatitis (chronic or acute), previous bowel resection, inflammatory bowel disease, malignancy (previous or actual)
• Estimated GFR < 25 ml/min/1.73 m2
• Pregnant or nursing mothers

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Glucagon-like peptide-1 (GLP-1); Twelve eligible renal transplant recipients with PTDM and twelve age, gender, BMI and renal function-matched non-diabetic renal transplant recipients will be randomized to continuous unblinded intravenous infusion of GLP-1 with an infusion rate of 0.8 pmol/kg/min or isotonic saline (placebo) on two experimental days performed 2-4 weeks apart. The GLP-1 infusion will consist of 42.5 nmol/mL GLP-1 (7-36) amide, 12.5 mL 5% human albumin and isotonic saline added to a total volume of 50 mL. After 60 min, a 2 hour hyperglycemic clamp will be initiated, where plasma glucose will be elevated by 5 mmol/L from each individual fasting plasma glucose in both groups. This will be done to measure concentrations of glucagon and insulin in hyperglycemic conditions.	Dietary supplement: Glucagon-like peptide-1 (GLP-1); Other: Hyperglycemic clamp
Placebo Comparator: Isotonic saline; The included patients will receive concomitant intravenous infusion of isotonic saline on one of the two experimental days	Other: Hyperglycemic clamp; Other: Isotonic saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of glucagon during fasting glycemia and during hyperglycemic conditions measured in picomoles per liter	The primary objective of the present study is to measure fasting plasma glucagon concentration and the suppression of glucagon during hyperglycemia (hyperglycemic clamp) measured in picomoles per liter with and without concomitant iv infusion of glucagon-like peptide-1 (GLP-1) in renal transplant recipients with and without PTDM	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose-potentiated arginine test	Investigate the functional reserve capacity in glucagon and insulin release (measurement of functional α-cell and β-cell mass) by a glucose-potentiated arginine test; since arginine is a glucose-independent stimulator of the release of both hormones.	4 weeks
Insulin sensitivity index	Estimate insulin sensitivity index (ISI) by recording the glucose infusion rate during the hyperglycemic clamp, corrected for the prevailing plasma insulin concentrations.	4 weeks

Collaborators and Investigators

• Sponsor: Oslo University Hospital

Publications and helpful links

General Publications

• Halden TA, Egeland EJ, Asberg A, Hartmann A, Midtvedt K, Khiabani HZ, Holst JJ, Knop FK, Hornum M, Feldt-Rasmussen B, Jenssen T. GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes. Diabetes Care. 2016 Apr;39(4):617-24. doi: 10.2337/dc15-2383. Epub 2016 Feb 23.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: August 17, 2015
• First Submitted That Met QC Criteria: October 29, 2015
• First Posted (Estimate): October 30, 2015

Study Record Updates

• Last Update Posted (Estimate): March 31, 2016
• Last Update Submitted That Met QC Criteria: March 30, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Glucagon; Glucagon-Like Peptide 1
• Other Study ID Numbers: 2014/666