Acute Effect of Intensive Insulin Infusion on Intestinal Triglyceride-rich-lipoprotein-apoB48 Metabolism in Type 2 Diabetic Patients

February 24, 2014 updated by: Assistance Publique Hopitaux De Marseille

Atherosclerotic cardiovascular disease (ASCD) is the first cause of morbidity and mortality at type 2 diabetes. The typical dyslipidemia that is associated with insulin resistance, which includes a postprandial elevation of triglyceride-rich lipoproteins (TRLs) with excess of intestinal triglyceride-rich-lipoprotein-apoB48 (TRL-apoB48), is felt to play an important role in the accelerated ASCD.

The investigators' objectives in this study are to determine whether an acute elevation of plasma insulin, secondarily to plasma insulin infusion, modulates the production and the clearance rates of intestinal TRL-apoB48 in type 2 diabetic patients in the fed state and to determine if this is a direct effect of insulin or an indirect effect due to the decrease of plasma FFA or the decrease of plasma glucose.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Background: Atherosclerotic cardiovascular disease (ASCD) is the first cause of morbidity and mortality at type 2 diabetes. The typical dyslipidemia that is associated with insulin resistance, which includes a postprandial elevation of triglyceride-rich lipoproteins (TRLs) with excess of intestinal triglyceride-rich-lipoprotein-apoB48 (TRL-apoB48), is felt to play an important role in the accelerated ASCD. Recently, intestinal TRL-apoB48 overproduction appeared as a newly recognized component of insulin resistance. Despite ample evidence supporting the delayed clearance of intestinal TRL-apoB48, there is only a limited amount of information in the literature regarding the factors modulating the production of intestinal TRL-apoB48 in the setting of insulin resistance and type 2 diabetes mellitus. Several arguments suggest that the intestine is not a "passive" organ with respect to lipoprotein production, but an organ metabolically active, receiving information from intestinal lumen and blood and able to modulate its syntheses and its lipid secretions according to the substrata, to the insulin or to other substances. There are functional relationships between the intestine and the liver. For example, it has been recently shown that acute elevation of plasma free fatty acids (FFA) in humans stimulates intestinal TRL-apoB48 and hepatic TRL-apoB100 production.

Aims: Our objectives in this study are to determine whether an acute elevation of plasma insulin, secondarily to plasma insulin infusion, modulates the production and the clearance rates of intestinal TRL-apoB48 in type 2 diabetic patients in the fed state and to determine if this is a direct effect of insuline or an indirect effect due to the decrease of plasma FFA or the decrease of plasma glucose.

Patients and methods: This study will be performed in 30 men with type 2 diabetes in a 2-step protocol. We use a stable isotope method (D3-L-leucine) to study the kinetic of the intestinal TRL-apoB48 and hepatic TRL-apoB100 (production and clearance rates).

In the first step of the protocol, all the patients will have a kinetic study of the TRL-apoB48 in conditions of a saline infusion to measure the "basal" production and clearance rates of the TRL-apoB48. In the second step, type 2 diabetic patients will be divided in 3 different paired groups: one performing an euglycaemic hyperinsulinic clamp to maintain plasma glucose around 1g/l ; one performing an euglycaemic hyperinsulinic clamp to maintain plasma glucose around 1g/l, but being infused with Endolipide 20 % (12,5 ml/h) and heparin (250 U/h) to prevent the suppressive effect of insulin on plasma FFA ; one performing a hyperglycaemic hyperinsulinic clamp to maintain plasma glucose around 2 g/l to prevent the decreasing effect of insulin on plasma glucose.

The research ethics board of the Université de la Méditerranée (Comité de protection des personnes-Sud méditerranée I) and the Afssaps (Agence française de sécurité sanitaire des produits de santé) approved the study and all subjects gave written informed consent prior to their participation.

General objective: Given the potential atherogenicity of the intestinal TRL-apoB48 particles, understanding the factors and the biochemical mechanisms of their accumulation in the plasma in the insulin resistant states may lead to specific therapeutic modalities that reduce their plasma concentration and protect against the highly prevalent atherosclerosis that is associated with insulin resistance and type 2 diabetes.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Marseille, France
        • Assistance Publique-Hôpitaux de Marseille

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • type 2 diabetic patients according to the criteria of the American Diabetes Association
  • body mass index between 25 and 40 kg/m2
  • Subject the therapeutic care of which bases only on the oral anti-diabetics excepted of glitazones and inhibitors of alpha-glucosidases
  • Subject without cardiovascular event in the previous 6 months or perturbing disease the lipid balance assessment (dysthyroidism, pituitary disease, adrenal disease)
  • No anemia, no coagulation disturb, creatinine clearance > 60 ml/min, fasting triglycerides < 4g/l

Exclusion Criteria:

  • Hypersensitivity to egg
  • Subject with severe disease associated with diabete

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: euglycaemic hyperinsulinic clamp
In the first step of the protocol, all the patients will have a kinetic study of the TRL-apoB48 in conditions of a saline infusion to measure the "basal" production and clearance rates of the TRL-apoB48. In the second step,the patients of this arm will perform an euglycaemic hyperinsulinic clamp to maintain plasma glucose around 1g/l.
Dietary supplement: saline infusion
In the first step of the protocol, all the patients will have a kinetic study of the TRL-apoB48 in conditions of a saline infusion to measure the "basal" production and clearance rates of the TRL-apoB48
Other: euglycaemic hyperinsulinic clamp
an euglycaemic hyperinsulinic clamp to maintain plasma glucose around 1g/l
Active Comparator: euglycaemic hyperinsulinic clamp with Endolipide and heparin
In the first step of the protocol, all the patients will have a kinetic study of the TRL-apoB48 in conditions of a saline infusion to measure the "basal" production and clearance rates of the TRL-apoB48. In the second step,the patients of this arm will perform an euglycaemic hyperinsulinic clamp to maintain plasma glucose around 1g/l but will be also infused with Endolipide 20 % (12,5 ml/h) and heparin (250 U/h) to prevent the suppressive effect of insulin on plasma free fatty acids.
Dietary supplement: saline infusion
In the first step of the protocol, all the patients will have a kinetic study of the TRL-apoB48 in conditions of a saline infusion to measure the "basal" production and clearance rates of the TRL-apoB48
Other: euglycaemic hyperinsulinic clamp
an euglycaemic hyperinsulinic clamp to maintain plasma glucose around 1g/l
Dietary supplement: infusion of Endolipide and heparin
an infusion with Endolipide 20 % (12,5 ml/h) and heparin (250 U/h) to prevent the suppressive effect of insulin on plasma free fatty acids
Active Comparator: hyperglycaemic hyperinsulinic clamp
In the first step of the protocol, all the patients will have a kinetic study of the TRL-apoB48 in conditions of a saline infusion to measure the "basal" production and clearance rates of the TRL-apoB48. In the second step,the patients of this arm will perform a hyperglycaemic hyperinsulinic clamp to maintain plasma glucose around 2 g/l to prevent the decreasing effect of insulin on plasma glucose.
Dietary supplement: saline infusion
In the first step of the protocol, all the patients will have a kinetic study of the TRL-apoB48 in conditions of a saline infusion to measure the "basal" production and clearance rates of the TRL-apoB48
Other: hyperglycaemic hyperinsulinic clamp
a hyperglycaemic hyperinsulinic clamp to maintain plasma glucose around 2 g/l to prevent the decreasing effect of insulin on plasma glucose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To determine whether an acute elevation of plasma insulin, secondarily to plasma insulin infusion, modulates the production and the clearance rates of intestinal TRL-apoB48 in type 2 diabetic patients in the fed state
Time Frame: 3 years
3 years

Secondary Outcome Measures

Outcome Measure
Time Frame
To determine if this is a direct effect of insulin or an indirect effect due to the decrease of plasma FFA or the decrease of plasma glucose.
Time Frame: 3 years
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique Hopitaux De Marseille

Investigators

  • Principal Investigator: Rene Valero, Assistance Publique Hopitaux de Marseille

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2008

Primary Completion (Actual)

July 1, 2011

Study Completion (Actual)

July 1, 2011

Study Registration Dates

First Submitted

July 30, 2009

First Submitted That Met QC Criteria

July 30, 2009

First Posted (Estimate)

July 31, 2009

Study Record Updates

Last Update Posted (Estimate)

February 25, 2014

Last Update Submitted That Met QC Criteria

February 24, 2014

Last Verified

February 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2007/17
  • 2007-002791-33

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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