Genetic Variation in CLTCL1 and Whole-body Glucose Control

The Role of Genetic Variation in CLTCL1 and Other Related Genes in Relation to Whole-body Glucose Control: A Pilot Study

Maintaining stable blood glucose concentrations after eating has important implications for health. Individuals who are better able to maintain stable blood glucose concentrations after consuming carbohydrate have a lower risk of mortality from cardiovascular disease. Muscle is the primary tissue for glucose disposal following a meal, and responsiveness of this tissue to insulin is dictated by GLUT4 translocation to the muscle cell membrane. Clathrin heavy chain isoform 22 (CHC22) is a protein that plays a key role in intracellular GLUT4 action, and it may play an important role in whole-body glucose control. Genetic variation in the gene which codes for CHC22 may be able to explain differences in glucose control at the whole-body level.

Study Overview

• Status: Completed
• Conditions: Glucose Control
• Intervention / Treatment: Diagnostic test: Oral glucose tolerance test

Detailed Description

The ability to maintain relatively stable blood glucose concentrations after eating has important implications for health. Individuals who are better able to maintain stable blood glucose concentrations after consuming carbohydrate have a lower risk of mortality and morbidity from cardiovascular disease. Muscle is the primary tissue for glucose disposal after a meal and the ability to tolerate a glucose load is largely dependent on the ability of muscle to respond to insulin by translocating the glucose transporter, GLUT4, to the muscle cell membrane, facilitating glucose import into muscle from the circulation. Therefore, by understanding the mechanisms that explain why some people are better able to maintain glucose control can give insight into how to target physiological pathways (such as muscle glucose uptake) to reduce disease risk and improve health.

Clathrins are cytoplasmic proteins that play essential roles in cell membrane trafficking pathways. Pilot data indicate that the clathrin heavy chain isoform 22 (CHC22) plays a key role in intracellular targeting of GLUT4 and may therefore play an important role in whole-body glucose control. Cell-based studies suggest that genetic variation in the CLTCL1 gene (which encodes for CHC22) at SNP rs1061325, influences GLUT4 retention. It is currently unknown whether genetic variation in CHC22 has consequences for whole-body glucose control in humans.

• Study Type: Interventional
• Enrollment (Actual): 82
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Bath, United Kingdom, BA2 7AY
    • Department for Health, University of Bath

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body mass index between 18.5-29.9 kg/m^2
• Aged 18-65 years
• Able and willing to provide informed consent and safely comply with study procedures

Exclusion Criteria:

• Any reported condition or behaviour deemed either to pose undue personal risk to the participant or introduce bias
• Any diagnosed metabolic disease (e.g. type 1 or type 2 diabetes)
• Any reported use of substances which may pose undue personal risk to the participants or introduce bias into the experiment
• Lifestyle not conforming to standard sleep-wake cycle (e.g. shift worker)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trial; Participants will undergo one trial visit where they will ingest an oral glucose load diluted in solution (oral glucose tolerance test) and blood samples will be measured over the following 2-hours. The buffy coat layer from the baseline sample will be obtained to extract DNA.	Diagnostic test: Oral glucose tolerance test; Participants will ingest 75 g anhydrous glucose dissolved in water and the blood responses will be measured over the following 2-hours using a venous cannula.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma glucose incremental area under the curve (CHC22 genotype)	Plasma glucose samples will be obtained throughout the 2-hour postprandial period and the incremental area under the curve will be calculated, this will be grouped by CHC22 genotype.	2 hours
Peak plasma glucose (CHC22 genotype)	Plasma glucose samples will be obtained throughout the 2-hour postprandial period and the peak glucose concentration will be measured, this will be grouped by CHC22 genotype.	2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting plasma glucose concentrations (CHC22 genotype)	Plasma glucose will be measured at baseline and will be grouped by CHC22 genotype.	2 hours
Plasma glucose incremental area under the curve (other genotypes)	Plasma glucose samples will be obtained throughout the 2-hour postprandial period and the incremental area under the curve will be calculated, this will be grouped by genotyping other genes related to glucose control or sweet taste sensitivity.	2 hours
Fasting plasma glucose concentrations (other genotypes)	Plasma glucose will be measured at baseline and will be grouped by genotypes related to glucose control and sweet taste sensitivity.	2 hours
Matsuda insulin sensitivity index	Matsuda insulin sensitivity index will be calculated using blood samples collected in the 2-hour postprandial period.	2 hours
Homeostasis model of insulin resistance	Homeostasis model of insulin resistance will be calculated using blood samples collected in the 2-hour postprandial period.	2 hours

Collaborators and Investigators

• Sponsor: Javier Gonzalez
• Collaborators: University College, London

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2018
• Primary Completion (Actual): February 1, 2022
• Study Completion (Actual): March 1, 2022

Study Registration Dates

• First Submitted: June 24, 2019
• First Submitted That Met QC Criteria: June 24, 2019
• First Posted (Actual): June 26, 2019

Study Record Updates

• Last Update Posted (Actual): May 4, 2022
• Last Update Submitted That Met QC Criteria: May 2, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Glucose; Genetic variation; CHC22; CLTCL1
• Other Study ID Numbers: EP 17/18 252

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No