# Gender-Associated Differences in the Regulation of Potassium Channels in Astrocytes of Type 2 Diabetic Mice

## TL;DR

Diabetes impairs potassium channels in brain cells, with a stronger effect in males, which could increase seizure risk.

## Contribution

The study reveals sex differences in Kir4.1 channel downregulation in diabetic mice, highlighting a potential target for anti-diabetic treatments.

## Key findings

- Diabetic male mice show more severe Kir4.1 channel downregulation than females.
- Hyperglycemia reduces Kir4.1 protein synthesis and potassium uptake in astrocytes.
- Barium-insensitive currents increase in diabetic mice, possibly compensating for channel dysfunction.

## Abstract

What are the main findings?
Kir4.1 channels are downregulated in diabetes in both sexes.Diabetic db/db male mice have a larger impact on their Kir4.1 channel than females.

Kir4.1 channels are downregulated in diabetes in both sexes.

Diabetic db/db male mice have a larger impact on their Kir4.1 channel than females.

What are the implications of the main findings?
Kir4.1 channels should be the focus of anti-diabetic treatments.Since Kir4.1 may be partially recovered by aminoguanidine as was recently shown, the polyamine strategy needs to be investigated further.

Kir4.1 channels should be the focus of anti-diabetic treatments.

Since Kir4.1 may be partially recovered by aminoguanidine as was recently shown, the polyamine strategy needs to be investigated further.

Hyperglycemia is linked to a higher risk of diabetes, epilepsy, and seizures, which contribute to increased mortality. Previous research has shown that hyperglycemia impairs the function of the polyamine-dependent Kir4.1 channels in cultured astrocytes, and a similar effect was observed in male astrocytes from diabetic (db/db) mice. However, whether there are sex differences in this effect remains unclear. This study aims to compare Kir4.1 channel function in 10–12 week old brains of female db/db mice with that in males and non-diabetic heterozygous (db/+). We performed mRNA analyses, Western blotting (WB), glucose level measurements, and patch-clamp recordings from hippocampal astrocytes in brain slices to assess Kir4.1 channel activity in db/db and db/+ mice of both sexes. Our results showed increased glucose levels in diabetic db/db mice, especially in males, along with (1) reduced synthesis of Kir4.1 channel protein, (2) reduced membrane potential, (3) decreased Kir currents, and (4) compromised potassium uptake. Female diabetic astrocytes exhibited significantly lower barium-blocked Kir4.1 currents compared to diabetic males. Additionally, barium-insensitive currents (leakage currents) were upregulated in db/db mice, likely as a compensatory response to hyperglycemia. In conclusion, diabetes impairs astrocyte function by downregulating Kir4.1 channels, with a more pronounced effect in male diabetic mice. This impairment may increase seizure risk by affecting the ability of astrocytes to maintain extracellular ion balance.