Acute Effect of Intensive Insulin Infusion on Intestinal Triglyceride-rich-lipoprotein-apoB48 Metabolism in Type 2 Diabetic Patients
Condition: Type 2 Diabetes
Study type: Interventional

Summary: 
      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.
    

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.
    

Intervention name(s): saline infusion; euglycaemic hyperinsulinic clamp; infusion of Endolipide and heparin; hyperglycaemic hyperinsulinic clamp
Intervention type(s): Dietary Supplement; Other; Dietary Supplement; Other
Intervention description(s): 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; an euglycaemic hyperinsulinic clamp to maintain plasma glucose around 1g/l; 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; a hyperglycaemic hyperinsulinic clamp to maintain plasma glucose around 2 g/l to prevent the decreasing effect of insulin on plasma glucose.
Intervention MeSH terms: Heparin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: type 2 diabetic patients in the fed state