Lixisenatide-The Effects on Glucose and Lipid Metabolism in Type 2 Diabetes
brief summary
Glucagon-like-peptide-1 (GLP-1) analogues are a new treatment for type 2 diabetes, which have recently been shown to have beneficial effects on weight, glycaemic control and postprandial triglyceride concentrations. Postprandial hypertriglyceridaemia, which is associated with an increased risk of cardiovascular disease, is a feature of type 2 diabetes. Hypertriglyceridaemia is due to excess triglyceride-rich lipoproteins (TRL) which consist of very low-density lipoproteins, (VLDL) synthesised by the liver which contain the higher molecular weight form of apolipoproteinB (apoB), apoB-100, and chylomicrons which are synthesised in the intestine in response to an intake of dietary fat and contain the lower molecular weight form of apoB, apoB-48. A recent study has shown that GLP-1 receptor signalling is required for the control of postprandial lipoprotein synthesis and secretion in hamsters and mice. GLP-1 was shown to reduce apoB-48 TRL production while a GLP-1 receptor antagonist increased apoB-48 TRL production. This study will investigate the effect of the GLP-1 analogue lixisenatide compared with placebo, in a double blind crossover study, on postprandial triglyceride metabolism in 12 patients with type 2 diabetes. Chylomicron and VLDL production and clearance rates will be measured in a repeated meal study by labelling apoB-100 and apoB-48 and by labelling triglycerides using stable isotope methodology. Glucose flux in response to a mixed fluid meal will also be investigated using stable isotope methodology. Gastric emptying and post heparin LPL activity will be measured. The hypothesis is that i\] lixisenatide will lower postprandial glycaemia due to a decrease in endogenous glucose output and an increase in glucose clearance by peripheral tissues as a result of an improvement in insulin sensitivity.
detailed description
GLP-1 analogues are a new treatment for type 2 diabetes, which have recently been shown to have beneficial effects on weight, glycaemic control and postprandial triglyceride concentrations. Postprandial hypertriglyceridaemia, which is associated with an increased risk of cardiovascular disease, is a feature of type 2 diabetes. Hypertriglyceridaemia is due to excess triglyceride-rich lipoproteins (TRL) which consist of very low-density lipoproteins, (VLDL) synthesised by the liver which contain the higher molecular weight form of apolipoproteinB (apoB), apoB-100, and chylomicrons which are synthesised in the intestine in response to an intake of dietary fat and contain the lower molecular weight form of apoB, apoB-48. A recent study has shown that GLP-1 receptor signalling is required for the control of postprandial lipoprotein synthesis and secretion in hamsters and mice. GLP-1 was shown to reduce apoB-48 TRL production while a GLP-1 receptor antagonist increased apoB-48 TRL production.
This study will investigate the effect of the GLP-1 analogue lixisenatide compared with placebo, in a double blind crossover study, on postprandial triglyceride metabolism in 12 patients with type 2 diabetes. Chylomicron and VLDL production and clearance rates will be measured in a repeated meal study (Visits 4 and 8) by labelling apoB-100 and apoB-48 with 1-13C leucine (infusion for 8 hours) and by labelling triglycerides with \[1,1,2,3,3-2H5 \]glycerol (as a bolus injection) and 13C triolein. Blood samples will be taken for 4 hours prior to during the 8 hr isotopic infusion to measure the enrichment of apoB-100 and apoB-48 with 1-13C leucine by gas chromatography mass spectrometry.
At Visits 3 and 7, glucose flux in response to a mixed fluid meal containing U-13C glucose will be investigated. Endogenous glucose production will also be measured by infusing \[6,6-2H2\] glucose for 6hours.
Gastric emptying will be measured by acetaminophen (1000 mg) absorption. Patients will also receive heparin (50U/kg) at the end of the study after 15 minutes a blood sample will be taken to determine post heparin lipoprotein lipase (LPL) activity.
During the study the patients will be asked to monitor their blood glucose for three days with continuous glucose monitoring and to fill in a 7 day food diary.
The hypothesis is that i\] lixisenatide will lower postprandial glycaemia due to a decrease in endogenous glucose output and an increase in glucose clearance by peripheral tissues as a result of an improvement in insulin sensitivity.
official title
The Effect of Lixisenatide on Postprandial Lipid and Glucose Metabolism in Patients with Type 2 Diabetes