The HNF‐1a variant induces endogenous glucose production and Ketonuria in female mice
Bibliographic record
Abstract
BACKGROUND Type 2 diabetes (T2D) diagnoses in the Anishininiiwuk (Oji‐Cree) linguistic group of central Canada are among the highest in the world. A genetic variant in the transcription factor hepatic nuclear factor‐1a (HNF‐1a), known as HNF‐1a G319S is present in this population which has been strongly associated with earlier onset of T2D. Historically, T2D was rare in Anishininiiwuk communities provided an active lifestyle required for land‐based food procurement, and potentially with prolonged periods of fasting. As a result of colonization, this lifestyle was abruptly altered leading to a decrease in hunter‐gatherer societies. In the liver, HNF‐1a plays an important role in glucose homeostasis and suppression of hepatic steatosis, but it is unclear if the G319S variant affects liver function. We hypothesize that the G319S variant promotes greater hepatic fuel production and confers a metabolic advantage in the fasted state. METHODS CRISPR/Cas9 gene editing was used to knock‐in the HNF‐1a G319S G>A 955 single nucleotide substitution into C57BL6 mice. These mice express the G319S variant at endogenous levels and in appropriate tissues. Mice fed chow diet ad libitum were sacrificed at 6 months of age, and liver tissues were collected for gene expression analysis, glycogen content measurements, and for hematoxylin and eosin staining. In addition, pyruvate tolerance tests were performed, and urine ketone levels measured in mice fasted for 12 hours. RESULTS Differences in hepatic steatosis and glycogen content were not observed between the wildtype (G/G), heterozygous (G/S), and homozygous (S/S) HNF‐1a mice. Female mice with two copies of the variant S‐allele (S/S) displayed elevated endogenous glucose production on a pyruvate tolerance test, as well as elevated ketones in the urine. MAIN FINDINGS/CONCLUSIONS Independent of hepatic steatosis, female homozygous (S/S) HNF‐1a mice show greater endogenous glucose production, and higher ketone levels in their urine, indicative of a greater capacity to generate and mobilize endogenous fuels. Support or Funding Information This work was supported by a CIHR project grant awarded to CAD (PJT‐159633).
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.011 | 0.003 |
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".