Study of Sulphonylurea Synergy With Incretins
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological
      study in the form of two matched isoglycaemic clamps. A matched clamp consists of an of oral
      glucose tolerance test followed by an isoglycaemic intravenous glucose infusion (IGII). The
      study will investigate whether there is synergy between a physiological sulphonylurea (SU)
      stimulus and the incretin effect, causing augmentation of insulin secretion in patients with
      type 2 diabetes mellitus (T2DM). The study will take place at The Clinical Research Centre at
      Ninewells Hospital in Dundee over five visits. It will evaluate 20 patients with T2DM on no
      diabetes therapy, or metformin monotherapy.

      All participants will undergo two matched clamps. The first matched clamp will be with no
      intervention. The second intervention matched clamp, low-dose liquid gliclazide will be
      administered 1-hour prior to each test. The sulphonylurea, Gliclazide, in this this instance
      will be used as a physiological stimulus and will only be given on two occasions as part of
      the second matched clamp. The first eight participants will participate in the dose-ranging
      phase. They will receive either 10mg or 20mg gliclazide as a stimulus to augment the incretin
      effect. A further twelve participants will then be recruited to complete the study utilising
      the dose which caused the greatest increment in insulin secretion. LOGIC will also evaluate
      the cohort for effect of KCNJ11 genotype on physiological response.
    

Detailed description: 
      The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological
      study in the form of two matched isoglycaemic clamps. A matched clamp consists of an of oral
      glucose bolus test followed by an isoglycaemic intravenous glucose infusion (IGII) the next
      day. The study will investigate whether there is synergy between a physiological
      sulphonylurea (SU) stimulus and the incretin effect, causing augmentation of insulin
      secretion in patients with type 2 diabetes mellitus (T2DM).

      The study will take place at The Clinical Research Centre at Ninewells Hospital in Dundee
      over five visits. It will evaluate 20 patients with T2DM on no diabetes therapy, or metformin
      monotherapy.

      The first visit is a screening visit to ensure the participant meets inclusion and exclusion
      criteria, and, if so, to obtain written informed consent for study. Visits 2-5 will all occur
      following an overnight 10-hour fast at home. The second and third visits will make up the
      first matched clamp. In visit 2, the participant will undergo a 75-gram oral glucose bolus
      with frequent blood sampling to assess the glucose variance, insulin secretion and incretin
      hormone response from an oral glucose stimulus. Blood glucose level (BGL) will be sampled
      every 5 minutes along with hormone biochemical analysis at regular defined time points. The
      third visit consists of an IGII to replicate the glucose curve from the OGTT to allow
      measurement of incretin effect. BGL will again be sampled every 5 minutes with regular
      biochemical analysis of hormones.

      The investigators aim to establish whether a low-dose of sulphonylurea will have a
      synergistic role on insulin secretion with endogenously secreted GLP-1 and GIP, therefore
      visits four and five will complete the same matched clamp, however, low-dose liquid
      gliclazide will be administered 1-hour prior to each test. The sulphonylurea, Gliclazide, in
      this this instance will be used as a physiological stimulus and will only be given on two
      occasions as part of the second matched clamp. The first eight participants will receive
      either 10mg or 20mg gliclazide as a stimulus to augment the incretin effect. A further twelve
      patients will then be recruited to complete the study utilising the dose which caused the
      greatest increment in insulin secretion.

      The comparison of these tests will investigate the hypothesis that there is a synergistic
      effect between low-dose sulphonylurea and augmentation of the incretin effect on the beta
      cell. LOGIC will also evaluate the cohort for effect of KCNJ11 genotype on physiological
      response. Participants will be consented for genotyping as part of this study.
    

Intervention name(s): Gliclazide
Intervention type(s): Drug
Intervention description(s): Low dose liquid gliclazide will be used with the second matched clamp (OGTT/IGII) in visits 4 & 5.
Other intervention name(s): Diamicron; Zicron
Intervention MeSH terms: Gliclazide
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Proof-of-Concept Physiological Study
Masking: None (Open Label)
Primary purpose: Basic Science