Effect of the Fetal THRB Genotype on the Placenta.

CONTEXT: Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high thyroid hormone (TH) levels shown to be detrimental to a normal fetus (NlFe) but not to an affected fetus (AfFe). However, no information is available about differences in placental TH regulators. OBJECTIVE: To investigate whether there are differences in placentas associated with a NlFe compared with an AfFe, we had the unique opportunity to study placentas from 2 pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. METHODS: Sections of placentas were collected and frozen at -80 °C after term delivery of a NlFe and an AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. Expression of following genes was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. RESULTS: The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the TH transporters MCT10, LAT1 and LAT2, and THRA. CONCLUSION: We present the first study of the effect of the fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of TH regulators in the placenta.

The Effect of Glucagon on Protein Catabolism During Insulin Deficiency: Exchange of Amino Acids Across Skeletal Muscle and the Splanchnic Bed.

Transient insulin deprivation with concurrent hyperglucagonemia is a catabolic state that can occur in type 1 diabetes. To evaluate glucagon's catabolic effect in the setting of its glucogenic effect, we measured the regional exchanges of amino acid metabolites (amino-metabolites) across muscle and splanchnic beds in 16 healthy humans during either somatostatin followed by glucagon or saline infusion alone. Despite a twofold or greater increase in the regional exchange of amino-metabolites by glucagon, whole-body kinetics and concentrations of amino acids (AA) remained stable. Glucagon increased the splanchnic uptake of not only gluconeogenic but also essential (EAA) AA while increasing their release from the muscle bed. Regional tracer-based kinetics and 3-methylhistidine release indicate that EAA release from muscle is likely caused by reduced protein synthesis rather than increased protein degradation. Furthermore, many metabolites known to affect insulin action and metabolism were altered by hyperglucagonemia including increase in branched-chain AA and keto acids of leucine and isoleucine in arterial plasma. Further, an increase in arterial concentrations of α-aminoadipic acid arising from increased conversion from lysine in the splanchnic bed was noted. These results demonstrate that hyperglucagonemia during hypoinsulinemia increases net muscle protein catabolism and substantially increases the exchange of amino metabolites across splanchnic and muscle beds.

A community-based study of demographics, medical and psychiatric conditions, and gender dysphoria/incongruence treatment in transgender/gender diverse individuals.

BACKGROUND: Current understanding about health care in the gender diverse population is limited by the lack of community-based, longitudinal data, especially in the USA. We sought to characterize a community-based cohort of transgender individuals including demographics, gender identities, social characteristics, psychiatric and medical conditions, and medical therapy for gender dysphoria/incongruence. PATIENTS AND METHODS: We performed a retrospective chart review of gender diverse residents of Olmsted County, Minnesota, who sought gender-specific healthcare from January 1, 1974, through December 31, 2015, using an infrastructure that links medical records of Olmsted County residents from multiple institutions. RESULTS: The number of patients seeking gender-specific healthcare increased from 1 to 2 per 5-year interval during the 1970s-1990s to 41 from 2011 to 2015 (n = 82). Forty-nine (59.8%) were assigned male sex at birth (AMAB), 31 (37.8%) were assigned female (AFAB), and 2 (2.4%) were intersex. Gender identities evolved over time in 16.3% and 16.1% of patients AMAB and AFAB, respectively, and at most recent follow-up, 8.2% and 12.9% of patients AMAB and AFAB, respectively, were non-binary. Depression affected 78%, followed by anxiety (62.2%), personality disorder (22%), and post-traumatic stress disorder (14.6%). 58.5% experienced suicidal ideation, 22% attempted suicide, and 36.6% were victims of abuse. The most prevalent medical conditions and cardiovascular (CV) risk factors included obesity (42.7%), tobacco use (40.2%), fracture [34.1% (86.2% traumatic)], hypertension (25.6%), hyperlipidemia (25.6%), and hypertriglyceridemia (15.9%). 67.3% of patients AMAB used feminizing and 48.4% of patients AFAB used masculinizing hormone therapy. When compared to US CDC National Health Statistics, there was a significantly greater prevalence of depression and anxiety but no difference in the prevalence of obesity, hypertension, hypercholesterolemia, type 2 diabetes, or stroke. CONCLUSION: Transgender and gender diverse individuals represent a population who express various gender identities and are seeking gender-specific healthcare at increasing rates. Psychiatric illness is highly prevalent compared to the US population but there is no difference in the prevalence of CV risk factors including obesity, type 2 diabetes, hypertension, and dyslipidemia.

Insulin Regulation of Proteostasis and Clinical Implications.

Maintenance and modification of the cellular proteome are at the core of normal cellular physiology. Although insulin is well known for its control of glucose homeostasis, its critical role in maintaining proteome homeostasis (proteostasis) is less appreciated. Insulin signaling regulates protein synthesis and degradation as well as posttranslational modifications at the tissue level and coordinates proteostasis at the organism level. Here, we review regulation of proteostasis by insulin in postabsorptive, postprandial, and diabetic states. We present the effects of insulin on amino acid flux in skeletal muscle and splanchnic tissues, the regulation of protein quality control, and turnover of mitochondrial protein pools in humans. We also review the current evidence for the mechanistic control of proteostasis by insulin and insulin-like growth factor 1 receptors based on preclinical studies. Finally, we discuss irreversible posttranslational modifications of the proteome in diabetes and how future investigations will provide new insights into mechanisms of diabetic complications.

Patient-Reported Adherence to Empiric Vitamin/Mineral Supplementation and Related Nutrient Deficiencies After Roux-en-Y Gastric Bypass.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is associated with nutrient deficiencies, but the optimal supplement regimen remains unclear. We assessed patient-reported adherence to and efficacy of Mayo Clinic's post-RYGB vitamin/mineral supplement protocol and the related incidence of common nutrient deficiencies. METHODS: Data were collected on 287 obese patients who underwent RYGB. Patient-reported supplement adherence was assessed via medication/supplement lists generated by medication reconciliation in hospital dismissal summaries and clinic notes at 6, 12, and 18-36 months postsurgery. Deficiencies were assessed via measurements of hemoglobin, ferritin, 25-hydroxyvitamin D, and vitamins A, E, and B12 in the setting of our supplementation protocol. RESULTS: Patient-reported adherence to multivitamin/minerals and subcutaneous vitamin B12 was sustained in >92 % of patients, correlating with low rates of vitamin A, E, and B12 deficiencies (4.9, 0, and 3.7 %, respectively). Rates of calcium supplementation decreased (94.1 to 78.7 %) while rates of vitamin D and iron use increased over time (39.7 to 65.8 and 6.3 to 23.1 %, respectively). At 18-36 months, vitamin D deficiency persisted in 16.2 % of patients, iron deficiency in 6.7 % of women and 17.2 % of men, and anemia in 12.2 % of women and 34.3 % of men. CONCLUSION: Compared to previous reports, we found a lower prevalence of micronutrient deficiencies and excellent patient-reported adherence to a standardized multivitamin/mineral and vitamin B12 regimen. Continued prevalence of vitamin D deficiency prompts consideration of standardized vitamin D supplementation after RYGB. Anemia and iron deficiency were observed at lower rates than previously reported, but were more common in men compared to women.

Delayed post-operative cardiac tamponade manifesting as cardiogenic shock.

We describe the case of a 32-year-old woman with a history of cardiac surgery two weeks previously who presented with an upper gastrointestinal bleed. She also had symptoms of syncope and abdominal pain, as well as elevated liver enzymes. She had cool, clammy extremities, bilateral lower extremity edema, and oliguria. An echocardiogram was obtained, which revealed a large posterior pericardial effusion with evidence of tamponade physiology, and an emergent pericardiocentesis was performed with insertion of a drainage catheter, which drained bloody fluid, with subsequent hemodynamic improvement. 7 days after open-heart surgery, a challenging diagnosis given its vague symptoms and signs not classically associated with the condition.>.