Hannah J Burden1,2, Shannon Adams3, Braydon Kulatea3, Morag Wright-McNaughton4, Danielle Sword4, Jennifer J Ormsbee5, Conor Watene-O'Sullivan2,6,7, Tony R Merriman2,8,9, Jennifer L Knopp5, J Geoffrey Chase5, Jeremy D Krebs2,4, Rosemary M Hall2,4, Lindsay D Plank10, Rinki Murphy2,11, Peter R Shepherd1,2, Troy L Merry12,13. 1. Department of Molecular Medicine and Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand. 2. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand. 3. Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland, New Zealand. 4. Department of Medicine, University of Otago Wellington, Wellington, New Zealand. 5. Centre for Bioengineering, Department of Mechanical Bioengineering, University of Canterbury, Christchurch, New Zealand. 6. Moko Foundation, Kaitaia, New Zealand. 7. Waharoa Ki Te Toi Research Centre, Kaitaia, New Zealand. 8. Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand. 9. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA. 10. Department of Surgery, School of Medicine, The University of Auckland, Auckland, New Zealand. 11. Department of Medicine, School of Medicine, The University of Auckland, Auckland, New Zealand. 12. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand. t.merry@auckland.ac.nz. 13. Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland, New Zealand. t.merry@auckland.ac.nz.
Abstract
AIMS/HYPOTHESIS: The minor A allele of rs373863828 (CREBRF p.Arg457Gln) is associated with increased BMI, but reduced risk of type 2 and gestational diabetes in Polynesian (Pacific peoples and Aotearoa New Zealand Māori) populations. This study investigates the effect of the A allele on insulin release and sensitivity in overweight/obese men without diabetes. METHODS: A mixed meal tolerance test was completed by 172 men (56 with the A allele) of Māori or Pacific ancestry, and 44 (24 with the A allele) had a frequently sampled IVGTT and hyperinsulinaemic-euglycaemic clamp. Mixed linear models with covariates age, ancestry and BMI were used to analyse the association between the A allele of rs373863828 and markers of insulin release and blood glucose regulation. RESULTS: The A allele of rs373863828 is associated with a greater increase in plasma insulin 30 min following a meal challenge without affecting the elevation in plasma glucose or incretins glucagon-like polypeptide-1 or gastric inhibitory polypeptide. Consistent with this point, following an i.v. infusion of a glucose bolus, participants with an A allele had higher early (p < 0.05 at 2 and 4 min) plasma insulin and C-peptide concentrations for a similar elevation in blood glucose as those homozygous for the major (G) allele. Despite increased plasma insulin, rs373863828 genotype was not associated with a significant difference (p > 0.05) in insulin sensitivity index or glucose disposal during hyperinsulinaemic-euglycaemic clamp. CONCLUSIONS/ INTERPRETATION: rs373863828-A allele associates with increased glucose-stimulated insulin release without affecting insulin sensitivity, suggesting that CREBRF p.Arg457Gln may increase insulin release to reduce the risk of type 2 diabetes.
AIMS/HYPOTHESIS: The minor A allele of rs373863828 (CREBRF p.Arg457Gln) is associated with increased BMI, but reduced risk of type 2 and gestational diabetes in Polynesian (Pacific peoples and Aotearoa New Zealand Māori) populations. This study investigates the effect of the A allele on insulin release and sensitivity in overweight/obese men without diabetes. METHODS: A mixed meal tolerance test was completed by 172 men (56 with the A allele) of Māori or Pacific ancestry, and 44 (24 with the A allele) had a frequently sampled IVGTT and hyperinsulinaemic-euglycaemic clamp. Mixed linear models with covariates age, ancestry and BMI were used to analyse the association between the A allele of rs373863828 and markers of insulin release and blood glucose regulation. RESULTS: The A allele of rs373863828 is associated with a greater increase in plasma insulin 30 min following a meal challenge without affecting the elevation in plasma glucose or incretins glucagon-like polypeptide-1 or gastric inhibitory polypeptide. Consistent with this point, following an i.v. infusion of a glucose bolus, participants with an A allele had higher early (p < 0.05 at 2 and 4 min) plasma insulin and C-peptide concentrations for a similar elevation in blood glucose as those homozygous for the major (G) allele. Despite increased plasma insulin, rs373863828 genotype was not associated with a significant difference (p > 0.05) in insulin sensitivity index or glucose disposal during hyperinsulinaemic-euglycaemic clamp. CONCLUSIONS/ INTERPRETATION: rs373863828-A allele associates with increased glucose-stimulated insulin release without affecting insulin sensitivity, suggesting that CREBRF p.Arg457Gln may increase insulin release to reduce the risk of type 2 diabetes.
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