A novel chronic in vivo oral cadmium exposure-washout mouse model for studying cadmium toxicity and complex diabetogenic effects.

Type II diabetes mellitus (T2DM) is characterized by insulin resistance, ß-cell dysfunction and hyperglycemia. In addition to well known risk factors such as lifestyle and genetic risk score, accumulation of environmental toxicants in organs relevant to glucose metabolism is increasingly recognized as additional risk factors for T2DM. Here, we describe the development of an in vivo oral cadmium (Cd) exposure model. It was shown that oral Cd exposure in drinking water followed by washout and high fat diet (HFD) in C57BL/6N mice results in islet Cd bioaccumulation comparable to that found in native human islets while mitigating the anorexic effects of Cd to achieve the same weight gain required to induce insulin resistance as in Cd naïve control mice. Inter individual variation in plasma glucose and insulin levels as well as islet Cd bioaccumulation was observed in both female and male mice. Regression analysis showed an inverse correlation between islet Cd level and plasma insulin following a glucose challenge in males but not in females. This finding highlights the need to account for inter individual target tissue Cd concentrations when interpreting results from in vivo Cd exposure models. No effect of Cd on insulin secretion was observed in islets ex vivo, highlighting differences between in vivo and ex vivo cadmium exposure models. In summary, our oral in vivo Cd exposure-washout with HFD model resulted in islet Cd bioaccumulation that is relevant in the context of environmental cadmium exposure in humans. Here, we showed that islet Cd bioaccumulation is associated with complex cadmium-mediated changes in glucose clearance and ß-cell function. The model described here will serve as a useful tool to further examine the relationship between Cd exposure, islet Cd bioaccumulation, dysglycemia and their underlying mechanisms.

The Use of Electroconvulsive Therapy in Neuropsychiatric Complications of Coronavirus Disease 2019: A Systematic Literature Review and Case Report.

BACKGROUND: There is a significant prevalence of new onset neuropsychiatric symptoms (NPS), some severe and persistent, in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: This study reports on the use of electroconvulsive therapy (ECT) to treat NPS associated with COVID-19. METHODS: A review of the literature pertaining to the use of ECT in patients with COVID-19 and NPS was performed through PubMed, PsycINFO, and MEDLINE. Search terms included "Electroconvulsive Therapy" and "ECT," combined with "COVID-19" and "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2)." In addition, we present a case in which ECT was used to achieve complete remission in a patient who developed new onset, treatment-resistant depression, psychosis, and catatonia, associated with COVID-19. RESULTS: A total of 67 articles were reviewed with 3 selected for inclusion. These articles detailed 3 case reports of patients with new onset NPS (mania, psychosis and suicidality, and catatonia) that developed in the context of active COVID-19 and were treated successfully with ECT. CONCLUSIONS: ECT, a broad-spectrum treatment that has been found to be effective in various NPS (independent of etiology), is shown in our case report and others, to be safe and effective for NPS associated with COVID-19. Although we identified only 3 other cases in the literature, we believe that the probable antiinflammatory mechanism of ECT, its safety and tolerability, and the faster time to symptom remission support the need for more research and increased clinician awareness about this life-saving procedure.

Intraoperative valence testing to adjudicate between ventral capsule/ventral striatum and bed nucleus of the stria terminalis target selection in deep brain stimulation for obsessive-compulsive disorder.

OBJECTIVE: Deep brain stimulation (DBS) is an accepted therapy for severe, treatment-refractory obsessive-compulsive disorder (trOCD). The optimal DBS target location within the anterior limb of the internal capsule, particularly along the anterior-posterior axis, remains elusive. Empirical evidence from several studies in the past decade has suggested that the ideal target lies in the vicinity of the anterior commissure (AC), either just anterior to the AC, above the ventral striatum (VS), or just posterior to the AC, above the bed nucleus of the stria terminalis (BNST). Various methods have been utilized to optimize target selection for trOCD DBS. The authors describe their practice of planning trajectories to both the VS and BNST and adjudicating between them with awake intraoperative valence testing to individualize permanent target selection. METHODS: Eight patients with trOCD underwent awake DBS with trajectories planned for both VS and BNST targets bilaterally. The authors intraoperatively assessed the acute effects of stimulation on mood, energy, and anxiety and implanted the trajectory with the most reliable positive valence responses and least stimulation-induced side effects. The method of intraoperative target adjudication is described, and the OCD outcome at last follow-up is reported. RESULTS: The mean patient age at surgery was 41.25 ± 15.1 years, and the mean disease duration was 22.75 ± 10.2 years. The median preoperative Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score was 39 (range 34-40). Two patients had previously undergone capsulotomy, with insufficient response. Seven (44%) of 16 leads were moved to the second target based on intraoperative stimulation findings, 4 of them to avoid strong negative valence effects. Three patients had an asymmetric implant (1 lead in each target). All 8 patients (100%) met full response criteria, and the mean Y-BOCS score reduction across the full cohort was 51.2% ± 12.8%. CONCLUSIONS: Planning and intraoperatively testing trajectories flanking the AC-superjacent to the VS anteriorly and to the BNST posteriorly-allowed identification of positive valence responses and acute adverse effects. Awake testing helped to select between possible trajectories and identify individually optimized targets in DBS for trOCD.

Exploring the Association Between Demographics, SLC30A8 Genotype, and Human Islet Content of Zinc, Cadmium, Copper, Iron, Manganese and Nickel.

A widely prevalent single nucleotide polymorphism, rs13266634 in the SLC30A8 gene encoding the zinc transporter ZnT8, is associated with an increased risk for T2DM. ZnT8 is mostly expressed in pancreatic insulin-producing islets of Langerhans. The effect of this variant on the divalent metal profile in human islets is unknown. Additionally, essential and non-essential divalent metal content of human islets under normal environmental exposure conditions has not been described. We therefore examined the correlation of zinc and other divalent metals in human islets with rs13266634 genotype and demographic characteristics. We found that the diabetes risk genotype C/C at rs13266634 is associated with higher islet Zn concentration (C/C genotype: 16792 ± 1607, n = 22, C/T genotype: 11221 ± 1245, n = 18 T/T genotype: 11543 ± 6054, n = 3, all values expressed as mean nmol/g protein ± standard error of the mean, p = 0.040 by ANOVA). A positive correlation between islet cadmium content and both age (p = 0.048, R2 = 0.09) and female gender (women: 36.88 ± 4.11 vs men: 21.22 ± 3.65 nmol/g protein, p = 0.007) was observed. Our results suggest that the T2DM risk allele C is associated with higher islet zinc levels and support prior evidence of cadmium's higher bioavailability in women and its long tissue half-life.

Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice.

Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.

Developmental androgen excess disrupts reproduction and energy homeostasis in adult male mice.

Polycystic ovary syndrome is a common endocrine disorder in females of reproductive age and is believed to have a developmental origin in which gestational androgenization programs reproductive and metabolic abnormalities in offspring. During gestation, both male and female fetuses are exposed to potential androgen excess. In this study, we determined the consequences of developmental androgenization in male mice exposed to neonatal testosterone (NTM). Adult NTM displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropin concentrations. Hypothalamic KiSS1 neurons are believed to be critical to the onset of puberty and are the target of leptin. Adult NTM exhibited lower hypothalamic Kiss1 expression and a failure of leptin to upregulate Kiss1 expression. NTM displayed an early reduction in lean mass, decreased locomotor activity, and decreased energy expenditure. They displayed a delayed increase in subcutaneous white adipose tissue amounts. Thus, excessive neonatal androgenization disrupts reproduction and energy homeostasis and predisposes to hypogonadism and obesity in adult male mice.

Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice.

Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin, and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues, and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat as well as increased number of enlarged and insulin-resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure, and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction, as can be observed in women with PCOS, including increased sympathetic tone, visceral adiposity, insulin resistance, prediabetes, and hypertension.