GLP-1 Effects on Insulin and Glucagon in PTDM

Not Applicable

Completed

• Conditions: Post-transplant Diabetes Mellitus
• Interventions: Dietary Supplement: Glucagon-like peptide-1 (GLP-1); Other: Isotonic saline; Other: Hyperglycemic clamp

• Registration Number: NCT02591849
• Lead Sponsor: Oslo University Hospital

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2014-10
• Primary Completion: 2015-03
• Study Completion: 2015-03
• Study First Submitted: 2015-08-17
• Study First Submitted QC: 2015-10-29
• Study First Posted: 2015-10-30
• Status Verified: 2016-03
• Last Update Submitted: 2016-03-30
• Last Update Posted: 2016-03-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Isotonic saline	Hyperglycemic clamp	The included patients will receive concomitant intravenous infusion of isotonic saline on one of the two experimental days
Glucagon-like peptide-1 (GLP-1)	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.
Glucagon-like peptide-1 (GLP-1)	Hyperglycemic clamp	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.
Isotonic saline	Isotonic saline	The included patients will receive concomitant intravenous infusion of isotonic saline on one of the two experimental days

Primary Outcome Measures

Name	Time	Method
Concentration of glucagon during fasting glycemia and during hyperglycemic conditions measured in picomoles per liter	4 weeks	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

Secondary Outcome Measures

Name	Time	Method
Glucose-potentiated arginine test	4 weeks	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.
Insulin sensitivity index	4 weeks	Estimate insulin sensitivity index (ISI) by recording the glucose infusion rate during the hyperglycemic clamp, corrected for the prevailing plasma insulin concentrations.

Trial Locations

Locations (1)

Oslo University Hospital, Rikshospitalet; 🇳🇴 Oslo, Norway