Biology subjects

Rick, K. R.

Publications and source records attributed to Rick, K. R..

3 recordsLinked to original sources

bioRxiv2024

Cisplatin exposure dysregulates pancreatic islet function in male mice

Cancer survivors have an increased risk of developing new-onset Type 2 diabetes compared to the general population. Moreover, patients treated with cisplatin, a commonly used chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes compared to age- and sex-matched controls. Insulin-secreting beta cells--located within pancreatic islets--are critical for maintaining glucose homeostasis, and dysregulated insulin secretion is central to Type 2 diabetes pathophysiology. Surprisingly, the impact of cisplatin treatment on pancreatic islets has not been reported. In this study, we aimed to determine if murine islet function is adversely affected by direct or systemic exposure to cisplatin. In vitro cisplatin exposure to male mouse islets profoundly dysregulated insulin release, reduced oxygen consumption, and altered the expression of genes related to insulin production, oxidative stress, and the Bcl-2 family. In vivo cisplatin exposure led to sustained hypoinsulinemia and hypoglycemia in male mice. Pancreas tissues from cisplatin-exposed male mice showed increased proinsulin accumulation and expression of DNA-damage markers in beta cells, but no change in average islet size or % insulin+ area per islet. Our data suggest both direct and systemic cisplatin exposure cause acute defects in insulin secretion and may have lasting effects on islet health in mice.

molecular biology↗

bioRxiv2020

Chronic low-dose dioxin exposure accelerates high fat diet-induced hyperglycemia in female mice

ObjectiveHuman studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka "dioxin"), and increased diabetes risk, but rarely consider potential sex differences. We previously showed that a single high-dose TCDD exposure (20 {micro}g/kg) decreased plasma insulin levels in both male and female mice in vivo, but effects on glucose homeostasis were sex-dependent. The purpose of the current study was to determine whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in either chow-fed or high fat diet (HFD)-fed mice. MethodsMale and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females at 12 weeks for Tempo-Seq(R) analysis. ResultsLow-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. TCDD caused a modest increase in islet area in males irrespective of diet, but reduced % beta cell area within islets in females. RNAseq analysis of female islets also revealed abnormal changes to endocrine and metabolic pathways in TCDD-exposed HFD-fed females compared chow-fed females. ConclusionsOur data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice, but promotes maladaptive metabolic responses in HFD-fed females.

pharmacology and toxicology↗

bioRxiv2019

Long-term metabolic consequences of acute dioxin exposure differ between male and female mice

Exposure to environmental pollutants is consistently associated with increased diabetes risk in humans. In male mice, acute dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) exposure supresses insulin secretion. This study investigated the long-term effects of a single TCDD injection (20 {micro}g/kg) on glucose metabolism and beta cell function in male and female mice. TCDD-exposed males displayed modest fasting hypoglycemia for [~]4 weeks post-injection, reduced fasting insulin levels for up to 6 weeks, increased insulin sensitivity, and decreased beta cell area. TCDD-exposed females also had long-term suppressed basal plasma insulin levels, and abnormal insulin secretion for up to 6 weeks. Unlike males, TCDD did not impact insulin sensitivity or beta cell area in females, but did cause transient glucose intolerance 4 weeks post-exposure. Our results show that a single exposure to dioxin can supress basal insulin levels long-term in both sexes, but effects on metabolism are sex-dependent.

pharmacology and toxicology↗