SNPMiner Trials (Home Page)
Report for Mutation E23K
Developed by Shray Alag, 2020.
SNP Clinical Trial Gene
There are 4 clinical trials
Clinical Trials
1 Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans
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 Diabetes Mellitus, Type 2 Drug: Glipizide Drug: Metformin 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 ---
Primary Outcomes
Description: Investigators will measure insulin and glucose levels for 240 minutes after Glipizide administration on Visit 1, and compare them by genotype at selected loci.
Measure: Glipizide response Time: Between 0-240 minutes, Visit 1Description: Investigators will measure the change in glycemic measures between Visit 1 and Visit 2 as an index of Metformin response, and compare them by genotype at selected loci.
Measure: Metformin response Time: 7 daysSecondary Outcomes
Description: Investigators will measure GLP-1 and GIP during the 120 minutes of Visit 2, and compare them by genotype at selected loci.
Measure: Incretin levels Time: 120 minutes, Visit 2Description: Investigators will measure proinsulin and glucagon levels at regular intervals during Visits 1 and 2, and compare them by genotype at selected loci.
Measure: Proinsulin, glucagon Time: 7 daysDescription: Investigators will perform metabolomic profiling of plasma samples at regular intervals in Visits 1 and 2, by using initially a targeted approach on an existing platform that measures ~400 metabolites (both polar and non-polar); they will compare their relative concentrations by genotype at selected loci before and after the interventions.
Measure: Metabolomics Time: 7 daysDescription: Investigators will measure 25-hydroxy vitamin D levels at baseline, and examine its effects on glycemic measures during Visits 1 and 2.
Measure: Vitamin D Time: Baseline2 Sulphonylurea Receptor Mutation and Responsiveness to Gliclazide - a Pilot Proof of Concept, Randomised Cross-over Study
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 Diabetes Drug: Gliclazide 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 ---
Primary Outcomes
Measure: Mean blood glucose level Time: 6 daysSecondary Outcomes
Description: Glycemic variability will be assessed using the EasyGV software (http://www.phc.ox.ac.uk/research/diabetes/software/easygv/) which is capable of calculating 10 different measures of glycemic variability from continuous glucose monitoring data, such as Standard Deviation (SD) and M-value, mean amplitude of glycemic excursions (MAGE).
Measure: Glycemic variability Time: 6 days3 Study of Sulphonylurea Synergy With Incretins
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 Type 2 Diabetes Mellitus 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 ---
Primary Outcomes
Description: Comparison of two matched clamps (oral glucose tolerance test + isoglycaemic intravenous glucose infusion). Matched clamp 1 - control. Matched clamp 2 - low dose gliclazide. Levels of insulin/c-peptide, incretin hormones and plasma glucose will be compared in the presence and absence of low dose gliclazide
Measure: Difference in insulin secretion and incretin effect between two matched clamps (presence and absence of low dose gliclazide) Time: Through four study visits completed over 4 weeksSecondary Outcomes
Description: Difference in insulin secretory response to low dose gliclazide calculated by insulin/cpeptide levels in matched clamp(gliclazide). Differences will then be compared by participants genotype e.g. insulin secretory response for E23K, E23E, K23K variants.
Measure: Insulin secretory response analysed by KCNJ11 Genotype (E23K, E23E, K23K) Time: Through four study visits completed over 4 weeks4 Study of Sulphonylurea Synergy With DPP4 Inhibitors
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 Type 2 Diabetes Drug: Sulfonylurea Drug: DPP4 Inhibitor
insulin secretory response for E23K, E23E, K23K variants.. Variation in blood glucose during intervention blocks analysed by continuous glucose monitoring. --- E23K ---
Primary Outcomes
Description: Comparison of four mixed meal tests performed at the end of each intervention block. Meal tests will evaluate 1) No intervention 2) Low dose sulphonylurea alone 3) DPP4 inhibitor alone 4) Low dose sulphonylurea + DPP4 inhibitor. Measures of the incretin effect will be compared between the different blocks.
Measure: Difference in incretin effect between mixed meal tests Time: Through four mixed meal tests which take place at the end of each 14 day intervention block. The four intervention blocks will be completed during an 8 week clinical phase of study.Secondary Outcomes
Description: Difference in insulin secretory response to low dose gliclazide calculated by insulin/cpeptide levels in each meal test visit. Differences will then be compared by participants genotype e.g. insulin secretory response for E23K, E23E, K23K variants.
Measure: Insulin secretory response analysed by KCNJ11 genotype Time: Through 4 meal test visits completed over an 8 week clinical phase of study. Outcome will also be evaluated through variability of glucose levels observed on continuous glucose monitoring worn for duration of 8 week clinical phase.Description: Comparison time-in-range of blood sugars as low, target and high on continuous glucose monitoring between each intervention block
Measure: Variation in blood glucose during intervention blocks analysed by continuous glucose monitoring Time: Meansurements taken via continuous glucose monitoring sensors worn by participants for duration of 8 week clinical phase