The SUGAR-MGH investigators are studying the influence of inherited gene variants on the response to two commonly prescribed type 2 diabetes medications, metformin and glipizide. They hypothesize that variants in genes that are associated with type 2 diabetes or related traits may impact the effect of anti-diabetic medications. In addition, physiological responses to an insulin secretagogue or an insulin sensitizer may shed light on the mechanism of action of reported genetic associations.

NCT01762046

Conditions

1. Diabetes Mellitus, Type 2

Interventions

1. Drug: Glipizide
2. Drug: Metformin
3. Other: Oral Glucose Tolerance Test

MeSH:Diabetes Mellitus Diabetes Mellitus, Type 2

HPO:Diabetes mellitus Type II diabetes mellitus

In particular, sulfonylureas may have differential effects on individuals depending on the allelic variant they carry at KCNJ11 E23K; conversely, because TCF7L2 is postulated to influence insulin secretion by regulating the action of glucagon-like peptide 1 (GLP-1), and sulfonylureas act at a different step in the insulin secretion pathway, the effect of sulfonylureas on insulin secretion could be independent of genetic variation at TCF7L2. --- E23K ---

Gliclazide has greater glucose lowering efficacy than glibenclamide among type 2 diabetes mellitus patients with minor haplotype (K23/A1369) at the KCNJ11/ABCC gene locations.

NCT02201602

Conditions

1. Diabetes

Interventions

1. Drug: Gliclazide
2. Drug: Glibenclamide

Interestingly, the KCNJ11 E23K (rs5219) variant was shown to confer susceptibility to T2DM and the ABCC8 S1369A (rs757110) variant was found to be in complete linkage disequilibrium with it i.e. inherited together as a genetic block (haplotype). --- E23K ---

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.

NCT03705195

Conditions

1. Type 2 Diabetes Mellitus

Interventions

1. Drug: Gliclazide

MeSH:Diabetes Mellitus, Type 2

HPO:Type II diabetes mellitus

Insulin secretory response analysed by KCNJ11 Genotype (E23K, E23E, K23K). --- E23K ---

insulin secretory response for E23K, E23E, K23K variants.. Inclusion Criteria: - Age 40 - 80, - Age of Diabetes Diagnoses ≥ 35 - T2DM on no treatment or metformin monotherapy - White British - HbA1c ≤ 8% (64mmol/mol) - eGFR ≥ 50ml/min-1 - ALT ≤ 2.5 x ULN - Able to consent Exclusion Criteria: - Type 1 Diabetes Mellitus - HbA1c > 8.0% (> 64mmol/mol) - eGFR <50ml/min-1 - ALT >2.5 x ULN - Anaemia (Haemoglobin <12.0 g/dL for women, <13.0 g/dL for men) - Pregnancy, lactation or a female planning to conceive within the study period - Established pancreatic disease - Participating in clinical phase of another interventional trial/study or have done so within the last 30 days - Any other significant medical reason for exclusion as determined by the investigator Inclusion Criteria: - Age 40 - 80, - Age of Diabetes Diagnoses ≥ 35 - T2DM on no treatment or metformin monotherapy - White British - HbA1c ≤ 8% (64mmol/mol) - eGFR ≥ 50ml/min-1 - ALT ≤ 2.5 x ULN - Able to consent Exclusion Criteria: - Type 1 Diabetes Mellitus - HbA1c > 8.0% (> 64mmol/mol) - eGFR <50ml/min-1 - ALT >2.5 x ULN - Anaemia (Haemoglobin <12.0 g/dL for women, <13.0 g/dL for men) - Pregnancy, lactation or a female planning to conceive within the study period - Established pancreatic disease - Participating in clinical phase of another interventional trial/study or have done so within the last 30 days - Any other significant medical reason for exclusion as determined by the investigator Type 2 Diabetes Mellitus Diabetes Mellitus, Type 2 The Study of Sulphonylurea Synergy with Incretins (LOGIC) is a Proof-of-Concept Physiological study in the form of two matched isoglycaemic clamps. --- E23K ---

The Study of Sulphonylurea Synergy with DPP4 Inhibitors (SSS Study) will establish whether a very low dose of sulphonylurea will have a synergistic role on augmentation of insulin secretion when given in combination with a DPP4 inhibitor as a primary outcome. The study will recruit 30 patients with type 2 diabetes mellitus controlled with no treatment or metformin monotherapy with an HbA1c <64mmol/mol (<8%). In this unblinded, randomised physiological study, participants will receive four 14-day intervention blocks: low dose sulphonylurea alone, DPP4 inhibitor alone, low dose sulphonylurea + DPP4 inhibitor or no treatment change. The primary outcome will be assessed through evaulation of insulin secretion and sensitivity at mixed meal test at the end of each treatment block. Glycaemic variability on continuous glucose monitoring for each intervention block will be evaluated as a secondary outcome. In addition, the primary outcome will be evaulated for KCNJ11 genotype as an additional secondary outcome.

NCT04192292

Conditions

1. Type 2 Diabetes

Interventions

1. Drug: Sulfonylurea
2. Drug: DPP4 Inhibitor

insulin secretory response for E23K, E23E, K23K variants.. Variation in blood glucose during intervention blocks analysed by continuous glucose monitoring. --- E23K ---