Case Series of U-500 Insulin Use in Adults With Type 2 Diabetes and Severe Insulin Resistance.

OBJECTIVES: Severe insulin resistance results in large volumes of insulin to achieve glycemic control. These large volumes can result in patient discomfort and decreased satisfaction. Using the more concentrated U-500 insulin provides a solution to this problem. This case series demonstrates real-world use of U-500 insulin in a Canadian population. METHODS: Seventeen patients were identified to have been started on U-500 insulin at an endocrinology clinic in Vancouver, British Columbia, Canada. The retrospective chart review looked at patients' characteristics before starting U-500 insulin and at their 1-year follow-up appointment. RESULTS: At follow up, patients demonstrated improved glycated hemoglobin with a mean improvement of 1.6% at 1 year (p<0.05). There was a statistically significant increase in hypoglycemia (p<0.05), and, on average, patients gained 5.6 kg over the course of the year (p<0.05). There was no statistically significant change in number of units of insulin, injections, lipids, renal function or blood pressure. CONCLUSIONS: The initiation of U-500 insulin results in improved glycemic control at the cost of increased hypoglycemia and weight gain.

Endocrine disrupting effects of waterborne fluoxetine exposure on the reproductive axis of female goldfish, Carassius auratus.

Evidence suggests that pharmaceuticals and personal care products reach urban watersheds, bioconcentrate in fish, and potentially disrupt physiological homeostasis. These impairments often affect hormone functions. Selective serotonin reuptake inhibitors (SRRIs) are increasingly studied with regards to their endocrine disrupting effects on teleost physiological processes, including reproduction. To examine whether FLX effects on the endocrine regulation of reproductive physiology in goldfish are sex-specific, we exposed sexually recrudescent female goldfish to two waterborne concentrations of FLX (0.54µg/L and 54µg/L) using an experimental design previously used for sexually mature male goldfish. To evaluate possible endocrine disrupting effects, we quantified the gonadosomatic index, circulating hormone concentrations (luteinizing hormone, LH; growth hormone, GH; 17-ß estradiol, E2; and testosterone, T), and the expression of isotocin and vasotocin in the telencephalon, gonadotropin subunits and GH in the pituitary, and gonadotropin receptors, GH receptors, and aromatase in the ovary. Female goldfish exposed to 0.54µg/L FLX exhibited a significant decrease in circulating E2, and conversely, a significant increase in circulating LH and ovarian aromatase mRNA levels, suggesting disruption of E2-mediated feedback on LH release. These results, when compared with those previously observed in males, reveal that waterborne exposure to environmentally relevant levels of FLX sex-specifically disrupts the reproductive endocrine axis in goldfish, characterized by a decrease in E2 in females, and conversely, estrogen-like effects in males. These data emphasize the importance of studying the effect of endocrine disrupting chemicals on both sexes.

Rapid modulation of gene expression profiles in the telencephalon of male goldfish following exposure to waterborne sex pheromones.

Sex pheromones rapidly affect endocrine physiology and behaviour, but little is known about their effects on gene expression in the neural tissues that mediate olfactory processing. In this study, we exposed male goldfish for 6h to waterborne 17,20ßP (4.3 nM) and PGF2α (3 nM), the main pre-ovulatory and post-ovulatory pheromones, respectively. Both treatments elevated milt volume (P=0.001). Microarray analysis of male telencephalon following PGF2α treatment identified 71 unique transcripts that were differentially expressed (q<5%; 67 up, 4 down). Functional annotation of these regulated genes indicates that PGF2α pheromone exposure affects diverse biological processes including nervous system functions, energy metabolism, cholesterol/lipoprotein transport, translational regulation, transcription and chromatin remodelling, protein processing, cytoskeletal organization, and signalling. By using real-time RT-PCR, we further validated three candidate genes, ependymin-II, calmodulin-A and aldolase C, which exhibited 3-5-fold increase in expression following PGF2α exposure. Expression levels of some other genes that are thought to be important for reproduction were also determined using real-time RT-PCR. Expression of sGnRH was increased by PGF2α, but not 17,20ßP, whereas cGnRH expression was increased by 17,20ßP but not PGF2α. In contrast, both pheromones increase the expression of glutamate (GluR2a, NR2A) and γ-aminobutyric acid (GABAA γ2) receptor subunit mRNAs. Milt release and rapid modulation of neuronal transcription are part of the response of males to female sex pheromones.

Estrogen-like effects in male goldfish co-exposed to fluoxetine and 17 alpha-ethinylestradiol.

The antidepressant fluoxetine (FLX) and the synthetic estrogen, 17 alpha-ethinylestradiol (EE2), are present in municipal sewage discharges. To better understand possible interactions between them, male goldfish were exposed to an ethanol control or to nominal concentrations of FLX (0.54 µg/L) and EE2 (5 ng/L) alone and in combination for 14 days. Real-time reverse-transcription polymerase chain reaction was used to assess effects on hepatic gene expression and liquid chromatography tandem mass spectrometry to analyze the plasma proteome. The results showed an increase in estrogen receptor alpha (esr1) and vitellogenin (vtg) gene expression by 1.9-2.4-fold in the FLX and EE2 groups, but this did not reach statistical significance. In contrast, co-exposure up regulated esr1 and vtg gene expression by 5.5- and 5.3-fold, respectively. Fluoxetine and EE2 alone did not affect estrogen receptor beta (esr2), but the co-exposure down regulated esr2 expression by 50%. There was a significant increase in the number of plasma proteins that were related to endocrine system disorders in the FLX and FLX plus EE2 groups. The level of VTG protein was increased in the plasma from goldfish exposed to EE2, FLX, and FLX plus EE2. Our study demonstrates that low concentrations of FLX and EE2 in a simple mixture produce strong estrogen-like effects in the male goldfish.