The HNF‐1a variant induces endogenous glucose production and Ketonuria in female mice

Abstract

BACKGROUNDType 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.METHODSCRISPR/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.RESULTSDifferences 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/CONCLUSIONSIndependent 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 InformationThis work was supported by a CIHR project grant awarded to CAD (PJT‐159633).