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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Assistance Publique Hopitaux De Marseille
ClinicalTrials.gov Identifier:
NCT00950209
First received: July 30, 2009
Last updated: February 24, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention
Type 2 Diabetes
Dietary Supplement: saline infusion
Other: euglycaemic hyperinsulinic clamp
Dietary Supplement: infusion of Endolipide and heparin
Other: hyperglycaemic hyperinsulinic clamp

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Acute Effect of Intensive Insulin Infusion on Intestinal Triglyceride-rich-lipoprotein-apoB48 Metabolism in Type 2 Diabetic Patients

Resource links provided by NLM:


Further study details as provided by Assistance Publique Hopitaux De Marseille:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 20
Study Start Date: April 2008
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

Ages Eligible for Study:   30 Years to 70 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00950209

Locations
France
Assistance Publique-Hopitaux de Marseille
Marseille, France
Sponsors and Collaborators
Assistance Publique Hopitaux De Marseille
Investigators
Principal Investigator: Rene Valero Assistance Publique Hopitaux De Marseille
  More Information

No publications provided by Assistance Publique Hopitaux De Marseille

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Assistance Publique Hopitaux De Marseille
ClinicalTrials.gov Identifier: NCT00950209     History of Changes
Other Study ID Numbers: 2007/17, 2007-002791-33
Study First Received: July 30, 2009
Last Updated: February 24, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Assistance Publique Hopitaux De Marseille:
type 2 diabetic patients in the fed state

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Calcium heparin
Heparin
Insulin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on April 17, 2014