Sulphonylurea Receptor Mutation and Responsiveness to Gliclazide - a Pilot Proof of Concept, Randomised Cross-over Study

Khoo Teck Puat Hospital

Status and phase

Completed

Phase 4

Conditions

Diabetes

Treatments

Drug: Glibenclamide

Drug: Gliclazide

Study type

Interventional

Funder types

Other

Identifiers

NCT02201602

Gliclazide

Details and patient eligibility

About

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.

Full description

Sulphonylurea (SU) is a glucose-lowering agent used widely to treat type 2 diabetes mellitus (T2DM). SU promotes insulin secretion from the pancreatic islet beta cell via binding and inhibition of the ATP-sensitive potassium (KATP) channel. The KATP channel is made up of two subcomponents, an inner Kir6.2 K+ channel (coded by the KCNJ11 gene) and an outer SU receptor 1 (SUR1) (coded by the ABCC8 gene). Although all SUs are mechanistically similar in terms of increasing insulin secretion, they bind to distinct regions of Kir 6.2 and SUR1 to exert their function. Different types of SU (e.g. tolbutamide, glibenclamide, glipizide, glimepiride and gliclazide) can therefore be grouped by their binding sites (A/B/A+B site) on the KATP channel [3]. 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). A recent in vitro molecular study suggested that the minor haplotype (K23/A1369) of KATP channel is sensitive to inhibition by gliclazide (binds to A-site) but not glibenclamide (binds to A+B site), and that the increased responsiveness to gliclazide was largely due to the A1369 allele. Understanding how the response to these two SUs may vary with the presence of the minor haplotype (K23/A1369) would therefore be beneficial for customization of patient treatment to achieve better clinical outcomes.

Enrollment

8 patients

Sex

All

Ages

21 to 65 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Type 2 diabetes
Age 21-65
HbA1c >8.0% on two consecutive visits

Exclusion criteria

Currently taking insulin at a regime more complex than basal insulin
Not willing to perform self-blood glucose monitoring (SBGM)
Renal impairment i.e. eGFR<50mls/min
Pregnancy or unwilling to practice adequate contraception
Taking other medications that may affect blood glucose e.g. systemic glucocorticoids.