Outbred Mice with Streptozotocin-Induced Diabetes Show Sex Differences in Glucose Metabolism

Abstract

Outbred mice (ICR) with different genotypes and phenotypes have been reported to be more suitable for scientific testing than inbred mice because they are more similar to humans. To investigate whether the sex and genetic background of the mice are important factors in the development of hyperglycemia, we used ICR mice and divided them into male, female, and ovariectomized female (FOVX) groups and treated them with streptozotocin (STZ) for five consecutive days to induce diabetes. Our results show that fasting blood glucose and hemoglobin A1c (HbA1c) levels were significantly higher in diabetes-induced males (M-DM) and ovariectomized diabetes-induced females (FOVX-DM) than in diabetes-induced females (F-DM) at 3 and 6 weeks after STZ treatment. Furthermore, the M-DM group showed the most severe glucose tolerance, followed by the FOVX-DM and F-DM groups, suggesting that ovariectomy affects glucose tolerance in female mice. The size of pancreatic islets in the M-DM and FOVX-DM groups was significantly different from that of the F-DM group. The M-DM and FOVX-DM groups had pancreatic beta-cell dysfunction 6 weeks after STZ treatment. Urocortin 3 and somatostatin inhibited insulin secretion in the M-DM and FOVX-DM groups. Overall, our results suggest that glucose metabolism in mice is dependent on sex and/or genetic background.

Sex-based impact of pancreatic islet stressors in GluCreERT2/Rosa26-eYFP mice

“…Mechanistically, increased STZ resistance in female mice has been demonstrated to be related to higher oestrogen levels, with oestrogen known to suppress inflammation ( Abildgaard et al 2020 ), protect against inflammatory cytokine insult ( Sachs et al 2020 ), promote misfolded protein degradation ( Xu et al 2018 ) and enhance glucose-stimulated insulin secretion ( Tiano & Mauvais-Jarvis 2012 ). Indeed, upon ovariectomy, female mice become more susceptible to STZ with similar metabolic dysregulation as observed in male mice ( Kim et al 2023 ). In harmony with this, ovariectomised female mice treated with oestradiol present with an improved protection against the harmful effects of STZ ( Li et al 2018 ).…”

“…There is a belief that female mice are more tolerant to the detrimental effects of STZ than males ( Ariza et al 2014 , Chandramouli et al 2018 , Kim et al 2020 ). In that respect, several studies have already investigated the sex-specific effects of STZ treatment in mice, with a general consensus that the diabetogen causes more detrimental effects on pancreatic islet morphology in male than female mice ( Kolb 1987 , Abildgaard et al 2020 , Kim et al 2020 , 2023 ), although this has been debated ( Plesner et al 2014 ). Mechanistically, increased STZ resistance in female mice has been demonstrated to be related to higher oestrogen levels, with oestrogen known to suppress inflammation ( Abildgaard et al 2020 ), protect against inflammatory cytokine insult ( Sachs et al 2020 ), promote misfolded protein degradation ( Xu et al 2018 ) and enhance glucose-stimulated insulin secretion ( Tiano & Mauvais-Jarvis 2012 ).…”

“…Alpha-to-beta-cell transdifferentiation was increased in male STZ mice, likely as an adaptive response to help preserve beta-cell mass. Thus, in the absence of oestrogen signalling that possesses independent beta-cell protective actions ( Kim et al 2023 ), islet cell lineage alteration in the face of a specific beta-cell insult could be paramount. Whether oestrogen could be exploited as an antidiabetic therapy is debatable, and detrimental off-target side effects may ultimately limit overall effectiveness ( Sjögren et al 2016 ).…”

Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice

“…First, we only utilized male mice. Male mice have historically been used to study effects of STZ, in large part due to the difficulty of inducing hyperglycemia in female mice [94][95][96][97][98][99]. Given the higher prevalence of depressive-like behavior in female clinical populations, it is critically important to study female models of hyperglycemia-associated depression.…”

Sex-dependent effects of Canagliflozin on kidney protection in mice with combined hypertension-type 1 diabetes

“…Additionally, females are more resistant to STZ-induced diabetes type 1, thus we must take into consideration the different stages of the disease progression in males and females. Studies have shown that females treated with the same dose of STZ have lower blood glucose levels compared to males [52] but females develop a more severe diastolic dysfunction, despite lower blood glucose levels [53].…”