The minor allele of the CREBRF rs373863828 p.R457Q coding variant is associated with reduced levels of myostatin in males: Implications for body composition.

OBJECTIVE: The minor allele (A) of the rs373863828 variant (p.Arg457Gln) in CREBRF is restricted to indigenous peoples of the Pacific islands (including New Zealand Maori and peoples of Polynesia), with a frequency of up to 25% in these populations. This allele associates with a large increase in body mass index (BMI) but with significantly lower risk of type-2 diabetes (T2D). It remains unclear whether the increased BMI is driven by increased adiposity or by increased lean mass. METHODS: We undertook body composition analysis using DXA in 189 young men of Maori and Pacific descent living in Aotearoa New Zealand. Further investigation was carried out in two orthologous Arg458Gln knockin mouse models on FVB/NJ and C57BL/6j backgrounds. RESULTS: The rs373863828 A allele was associated with lower fat mass when adjusted for BMI (p < 0.05) and was associated with significantly lower circulating levels of the muscle inhibitory hormone myostatin (p < 0.05). Supporting the human data, significant reductions in adipose tissue mass were observed in the knockin mice. This was more significant in older mice in both backgrounds and appeared to be the result of reduced age-associated increases in fat mass. The older male knockin mice on C57BL/6j background also had increased grip strength (p < 0.01) and lower levels of myostatin (p < 0.05). CONCLUSION: Overall, these results prove that the rs373863828 A-allele is associated with a reduction of myostatin levels which likely contribute to an age-dependent lowering of fat mass, at least in males.

Variability in Estimated Modelled Insulin Secretion.

BACKGROUND: The ability to measure insulin secretion from pancreatic beta cells and monitor glucose-insulin physiology is vital to current health needs. C-peptide has been used successfully as a surrogate for plasma insulin concentration. Quantifying the expected variability of modelled insulin secretion will improve confidence in model estimates. METHODS: Forty-three healthy adult males of Maori or Pacific peoples ancestry living in New Zealand participated in an frequently sampled, intravenous glucose tolerance test (FS-IVGTT) with an average age of 29 years and a BMI of 33 kg/m2. A 2-compartment model framework and standardized kinetic parameters were used to estimate endogenous pancreatic insulin secretion from plasma C-peptide measurements. Monte Carlo analysis (N = 10 000) was then used to independently vary parameters within ±2 standard deviations of the mean of each variable and the 5th and 95th percentiles determined the bounds of the expected range of insulin secretion. Cumulative distribution functions (CDFs) were calculated for each subject for area under the curve (AUC) total, AUC Phase 1, and AUC Phase 2. Normalizing each AUC by the participant's median value over all N = 10 000 iterations quantifies the expected model-based variability in AUC. RESULTS: Larger variation is found in subjects with a BMI > 30 kg/m2, where the interquartile range is 34.3% compared to subjects with a BMI ≤ 30 kg/m2 where the interquartile range is 24.7%. CONCLUSIONS: Use of C-peptide measurements using a 2-compartment model and standardized kinetic parameters, one can expect ~±15% variation in modelled insulin secretion estimates. The variation should be considered when applying this insulin secretion estimation method to clinical diagnostic thresholds and interpretation of model-based analyses such as insulin sensitivity.

The Impact of Exogenous Insulin Input on Calculating Hepatic Clearance Parameters.

OBJECTIVE: Model-based metabolic tests require accurate identification of subject-specific parameters from measured assays. Insulin assays are used to identify insulin kinetics parameters, such as general and first-pass hepatic clearances. This study assesses the impact of intravenous insulin boluses on parameter identification precision. METHOD: Insulin and C-peptide data from two intravenous glucose tolerance test (IVGTT) trials of healthy adults (N = 10 × 2; denoted A and B), with (A) and without (B) insulin modification, were used to identify insulin kinetics parameters using a grid search. Monte Carlo analysis (N = 1000) quantifies variation in simulation error for insulin assay errors of 5%. A region of parameter values around the optimum was identified whose errors are within variation due to assay error. A smaller optimal region indicates more precise practical identifiability. Trial results were compared to assess identifiability and precision. RESULTS: Trial B, without insulin modification, has optimal parameter regions 4.7 times larger on average than Trial A, with 1-U insulin bolus modification. Ranges of optimal parameter values between trials A and B increase from 0.04 to 0.12 min-1 for hepatic clearance and from 0.07 to 0.14 for first-pass clearance on average. Trial B's optimal values frequently lie outside physiological ranges, further indicating lack of distinct identifiability. CONCLUSIONS: A small 1-U insulin bolus improves identification of hepatic clearance parameters by providing a smaller region of optimal parameter values. Adding an insulin bolus in metabolic tests can significantly improve identifiability and outcome test precision. Assay errors necessitate insulin modification in clinical tests to ensure identifiability and precision.

The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Maori and Pacific ancestry.

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 Maori) 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 Maori 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.