GLP-1 Effects on Insulin and Glucagon in PTDM

Study Overview
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Brief Summary
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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.

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

Conditions
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Post-transplant Diabetes Mellitus

Intervention / Treatment
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* Dietary Supplement: Glucagon-like peptide-1 (GLP-1)
* Other: Isotonic saline
* Other: Hyperglycemic clamp


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glucagon-like peptide-1 (GLP-1)<br>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)<br> <br> Other: Hyperglycemic clamp<br> <br> |
| Placebo Comparator: Isotonic saline<br>The included patients will receive concomitant intravenous infusion of isotonic saline on one of the two experimental days | Other: Isotonic saline<br> <br> Other: Hyperglycemic clamp<br> <br> |

What is the study measuring?
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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 |