491-P: Severe Muscle Insulin Resistance in Inuit Homozygous Carriers of the Common Greenlandic P.Arg684Ter TBC1D4 Variant Is Improved by a Single Bout of Exercise
Bibliographic record
Abstract
In the Greenlandic Inuit population a common nonsense TBC1D4 p.Arg684Ter variant in muscle is found with an allele frequency of 17%. Homozygous carriers of this variant have impaired glucose tolerance, and a 10-fold increased risk of type 2 diabetes. Here we investigate whether the TBC1D4 p.Arg684Ter affects regulation of skeletal muscle glucose uptake during exercise and during insulin stimulation in the post exercise period. Inuits carrying zero (n=8) or two (n=8) alleles of TBC1D4 p.Arg684Ter were recruited from population surveys in Greenland. Glucose tolerance was measured during a 6 hour oral glucose tolerance test (OGTT). Skeletal muscle glucose uptake was measured by applying arterial-venous balance technique across the legs during one-legged exercise and during subsequent euglycemic hyperinsulinemic clamp. Glucose uptake was measured in both the rested and the exercised leg. During the OGTT blood glucose was similar at fasting but markedly elevated (by 4.4 mM) in TBC1D4 p.Arg684Ter carriers compared to matched controls at 2 hours, and variants became hypoglycemic at 4 hours (3.3 vs. 4.7 mM) and similar to controls at 6 hours. During exercise, TBC1D4 variant carriers and controls displayed similar glucose uptake in skeletal muscle. During insulin clamp, glucose uptake in the previously rested leg was lower (~50%) in TBC1D4 variant carriers compared to controls. In the prior exercised leg, glucose uptake during the insulin clamp was higher in both groups compared to the rested leg. However, glucose uptake in the previously exercised leg from TBC1D4 variant carriers was comparable to the previously rested leg in controls and thus still markedly lower than controls. In conclusion: TBC1D4 p.Arg684Ter carriers have impaired insulin stimulated but normal exercise stimulated glucose uptake in skeletal muscle. A single bout of exercise improves muscle glucose uptake in carriers to levels seen in non-exercise muscle of controls. Disclosure J. M. Kristensen: None. T. Hansen: None. M. E. Jørgensen: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis, Stock/Shareholder; Self; Novo Nordisk A/S. J. F. P. Wojtaszewski: None. T. L. J. Larsen: None. C. S. Carl: None. A. Thorup: None. J. Hingst: None. J. Onslev: None. J. S. Olesen: None. M. L. Pedersen: None. E. A. Richter: None. Funding Novo Nordisk Foundation (NNF14OC0013057, NNF17OC0028136); Independent Research Fund Denmark (FSS802000288B5855628)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".