Beta Cell Relieving and Cardiovascular Protective Effects of LANTUS Treatment in Type 2 Diabetes Patients
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Observational

Summary: 
      The purpose of this phase IV clinical trial is to investigate the effect of Insulin glargine
      + metformin treatment vs. sulfonylurea + metformin treatment vs. DPP-4 + metformin treatment
      vs. healthy volunteers on ß-cell function after the uptake of a standardized meal.
    

Detailed description: 
      Type 2 diabetes mellitus is a progressive disease characterised by a steady loss of beta cell
      function and an increase in the proinsulin/insulin ratio. During the recent years intact
      proinsulin has been the topic of interest in numerous preclinical and clinical studies in
      patients with type 2 diabetes mellitus. Intact proinsulin was confirmed as a marker of
      functional beta cell failure and as a predictor of increased beta cell loss due to apoptosis
      and/or diminished neogenesis.

      A number of population based studies showed that intact proinsulin is a strong predictor of
      coronary heart disease in diabetic, and in non-diabetic patients. In a clinical trial
      investigating human proinsulin as a therapeutic approach for the treatment of diabetes
      mellitus an eight fold increase in CVD was found during treatment with human proinsulin
      compared to human regular insulin, indicating a thrombo-embolic potential of intact
      proinsulin. In a recent investigation an association could be confirmed between increased
      proinsulin plasma concentrations and the severity of angiographical characterised CHD.

      Even the exact mechanism how proinsulin is involved in the pathogenesis of atherosclerosis is
      not completely recognized, it was already shown that PAI-1 activity increases after
      proinsulin administration in vitro, and there is increasing evidence that the atherogenic
      effects of proinsulin might be linked to increasing plasminogen activator inhibitor-1 (PAI-1)
      levels with subsequent inhibition of fibrinolysis and an augmented thrombogenic potency.

      Treatment with sulfonylurea increases intact proinsulin secretion, and in a couple of
      studies, sulfonylurea treatment was found to be associated with an increased cardiovascular
      risk. In contrast, several studies have shown that after the introduction of insulin
      treatment in type 2 diabetic patients intact proinsulin levels and plasma PAI 1 levels
      decline, indicating not only beta cell protection, but also antiatherogenic properties of
      insulin. In a recent study, we have shown that treatment with basal insulin in combination
      with metformin effectively reduces intact proinsulin levels, and that insulin glargine is
      superior to NPH insulin in controlling postprandial release of intact proinsulin over an
      entire day.

      Recently a new therapeutic concept using DPP IV inhibitors in combination with metformin has
      been introduced in the treatment of type 2 diabetic patients. There is some evidence that, in
      the beta cell, DPP IV Inhibitors might improve the conversion of intact Proinsulin into
      Insulin and C-peptide and thereby reduce circulating intact proinsulin levels. Since the
      number of type 2 diabetic patients treated with DPP-IV inhibitors is steadily increasing,
      there is a need to generate more data on the postprandial release of intact proinsulin in
      patients treated with DPP-IV inhibitors compared to Insulin or sulfonylurea treatment.

      The rationale of the study is to investigate the effect of glargine and metformin treatment
      compared to sulfonylurea and metformin treatment and compared to DPP-4 inhibitor and
      metformin treatment on postprandial intact proinsulin release and postprandial PAI-1 levels.
      Accompanying a comparison of postprandial intact proinsulin release and the time course of
      postprandial PAI-levels in between all three antidiabetic treatment groups and a non-diabetic
      control group will be performed as well.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        -  Group 1 (n=20): Healthy subjects

          -  Group 2 (n=20): T2DM patients treated with continuous SU + MET therapy as individually
             prescriped by the primary care physicians

          -  Group 3 (n=20): T2DM patients treated with continuous LANTUS + MET therapy as
             individually prescriped by the primary care physicians

          -  Group 4 (n=20): T2DM patients treated with continuous DPP-4 + MET therapy as
             individually prescriped by the primary care physicians
      
Keywords: Diabetes Mellitus Type 2; insulin glargine; Metformin