IER3IP1 is critical for maintaining glucose homeostasis through regulating the endoplasmic reticulum function and survival of ß cells.

Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in ß cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in ß cells, named IER3IP1-ßKO and IER3IP1-ißKO, respectively. We found that IER3IP1-ßKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated ß-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with ß-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-ßKO impaired ß-cell maturation and proliferation, along with increased condensation of ß-cell nuclear chromatin. Inducible ß-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after ß-cell early development. Importantly, IER3IP1 was decreased in ß cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with ß-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in ß cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.

Evolution of insulin at the edge of foldability and its medical implications.

Proteins have evolved to be foldable, and yet determinants of foldability may be inapparent once the native state is reached. Insight has emerged from studies of diseases of protein misfolding, exemplified by monogenic diabetes mellitus due to mutations in proinsulin leading to endoplasmic reticulum stress and ß-cell death. Cellular foldability of human proinsulin requires an invariant Phe within a conserved crevice at the receptor-binding surface (position B24). Any substitution, even related aromatic residue TyrB24, impairs insulin biosynthesis and secretion. As a seeming paradox, a monomeric TyrB24 insulin analog exhibits a native-like structure in solution with only a modest decrement in stability. Packing of TyrB24 is similar to that of PheB24, adjoining core cystine B19-A20 to seal the core; the analog also exhibits native self-assembly. Although affinity for the insulin receptor is decreased ∼20-fold, biological activities in cells and rats were within the range of natural variation. Together, our findings suggest that the invariance of PheB24 among vertebrate insulins and insulin-like growth factors reflects an essential role in enabling efficient protein folding, trafficking, and secretion, a function that is inapparent in native structures. In particular, we envision that the para-hydroxyl group of TyrB24 hinders pairing of cystine B19-A20 in an obligatory on-pathway folding intermediate. The absence of genetic variation at B24 and other conserved sites near this disulfide bridge-excluded due to ß-cell dysfunction-suggests that insulin has evolved to the edge of foldability. Nonrobustness of a protein's fitness landscape underlies both a rare monogenic syndrome and "diabesity" as a pandemic disease of civilization.

"Register-shift" insulin analogs uncover constraints of proteotoxicity in protein evolution.

Globular protein sequences encode not only functional structures (the native state) but also protein foldability, i.e. a conformational search that is both efficient and robustly minimizes misfolding. Studies of mutations associated with toxic misfolding have yielded insights into molecular determinants of protein foldability. Of particular interest are residues that are conserved yet dispensable in the native state. Here, we exploited the mutant proinsulin syndrome (a major cause of permanent neonatal-onset diabetes mellitus) to investigate whether toxic misfolding poses an evolutionary constraint. Our experiments focused on an invariant aromatic motif (PheB24-PheB25-TyrB26) with complementary roles in native self-assembly and receptor binding. A novel class of mutations provided evidence that insulin can bind to the insulin receptor (IR) in two different modes, distinguished by a "register shift" in this motif, as visualized by molecular dynamics (MD) simulations. Register-shift variants are active but defective in cellular foldability and exquisitely susceptible to fibrillation in vitro Indeed, expression of the corresponding proinsulin variant induced endoplasmic reticulum stress, a general feature of the mutant proinsulin syndrome. Although not present among vertebrate insulin and insulin-like sequences, a prototypical variant ([GlyB24]insulin) was as potent as WT insulin in a rat model of diabetes. Although in MD simulations the shifted register of receptor engagement is compatible with the structure and allosteric reorganization of the IR-signaling complex, our results suggest that this binding mode is associated with toxic misfolding and so is disallowed in evolution. The implicit threat of proteotoxicity limits sequence variation among vertebrate insulins and insulin-like growth factors.

Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in ß cells.

Insulin resistance in classic insulin-responsive tissues is a hallmark of type 2 diabetes (T2D). However, the pathologic significance of ß-cell insulin resistance and the underlying mechanisms contributing to defective insulin signaling in ß cells remain largely unknown. Emerging evidence indicates that proinsulin misfolding is not only the molecular basis of mutant INS-gene-induced diabetes of youth (MIDY) but also an important contributor in the development and progression of T2D. However, the molecular basis of ß-cell failure caused by misfolded proinsulin is still incompletely understood. Herein, using Akita mice expressing diabetes-causing mutant proinsulin, we found that misfolded proinsulin abnormally interacted with the precursor of insulin receptor (ProIR) in the endoplasmic reticulum (ER), impaired ProIR maturation to insulin receptor (IR), and decreased insulin signaling in ß cells. Importantly, using db/db insulin-resistant mice, we found that oversynthesis of proinsulin led to an increased proinsulin misfolding, which resulted in impairments of ProIR processing and insulin signaling in ß cells. These results reveal for the first time that misfolded proinsulin can interact with ProIR in the ER, impairing intracellular processing of ProIR and leading to defective insulin signaling that may contribute to ß-cell failure in both MIDY and T2D.-Liu, S., Li, X., Yang, J., Zhu, R., Fan, Z., Xu, X., Feng, W., Cui, J., Sun, J., Liu, M. Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in ß cells.

Liraglutide improves obesity-induced renal injury by alleviating uncoupling of the glomerular VEGF-NO axis in obese mice.

Obesity-related kidney disease is associated with generalized endothelial dysfunction. Liraglutide, a glucagon-like peptide-1 agonist, has cardiovascular-renal protective effects in patients with diabetes. In this study, the ability of liraglutide to reduce urinary albumin excretion by alleviating glomerular vascular endothelial growth factor-nitric oxide (VEGF-NO) axis uncoupling was assessed in high fat diet-induced obese mice. C57BL/6J mice were divided into control and obesity groups, treated with or without liraglutide (200 µg/kg/day). Blood biochemistry and urinary albumin excretion were measured. Glomerular VEGF and the AMPK-endothelial nitric oxide synthase (eNOS) pathway were assayed by western blotting. Glomerular NO, renal haeme oxygenase-1 activity, and malondialdehyde levels were also measured. Treatment of obese mice with liraglutide led to significant reductions in body weight gain (46 ± 1 g vs 55 ± 1 g, P < .0001), visceral fat (8.9 ± 0.6 g vs 14.5 ± 0.6 g, P < .0001), perirenal fat (2.9 ± 0.2 g vs 5.4 ± 0.3 g, P < .0001), and free fatty acid (1.71 ± 0.12 mmol/L vs 1.02 ± 0.08 mmol/L, P < .0001). Liraglutide significantly improved glucose homeostasis, which was impaired in obese mice. Liraglutide reduced urinary albumin excretion and glomerular hypertrophy in obese mice. Additionally, liraglutide significantly decreased VEGF and increased glomerular NO production in glomeruli, indicating restoration of the glomerular VEGF-NO axis. Furthermore, liraglutide activated the glomerular AMPK-eNOS pathway in obese mice, upregulated renal haeme oxygenase-1 activity, and reduced the renal malondialdehyde levels in obese mice. In conclusion, liraglutide reduced microalbuminuria and ameliorated renal injury by alleviating the uncoupling of the glomerular VEGF-NO axis.

[Preliminary result of stents implantation for spontaneous isolated dissection of the superior mesenteric artery: a prospective single-arm study].

ObjectiveTo access the efficacy of stents for spontaneous isolated dissection of the superior mesenteric artery (SIDSMA). MethodThe study is a prospective single-arm study which has been registered on Clinical Trials (NCT03916965). Clinical data and follow-up information of the SIDSMA patients who received stent implantation in the First Affiliated Hospital of Zhejiang University during April 1, 2019 and September 30, 2019 were collected. The patients were recommended to be followed up at 1, 3, 6 and 12 months. ResultsA total of 34 patients were enrolled. Their mean age was (54±8) years. Abdominal pain was the most common symptom. Patients received (2.1±0.6) stents on the average. Post-operation hospital stay was (2.7±1.6) days, and the patients were followed up for (2.3±1.9) months (CT angiography) and (5.5±1.7) months (clinical visit/phone call). There was no recurrence of abdominal pain. The CT angiography showed complete remodeling and incomplete remodeling took place in 23 and 9 patients (69.7% and 27.3%), respectively. Two patients (6.1%) had mild in-stent stenosis. No stent rupture or migration was reported. ConclusionThis study demonstrated a satisfactory short-term result of stents implantation for SIDSMA, which indicated the endovascular treatment could be the first-line therapy for SIDSMA.

Positive charge in the n-region of the signal peptide contributes to efficient post-translational translocation of small secretory preproteins.

Increasing evidence indicates that many small secretory preproteins can undergo post-translational translocation across the membrane of the endoplasmic reticulum. Although the cellular machinery involved in post-translational translocation of small secretory preproteins has begun to be elucidated, the intrinsic signals contained within these small secretory preproteins that contribute to their efficient post-translational translocation remain unknown. Here, we analyzed the eukaryotic secretory proteome and discovered the small secretory preproteins tend to have a higher probability to harbor the positive charge in the n-region of the signal peptide (SP). Eliminating the positive charge of the n-region blocked post-translational translocation of newly synthesized preproteins and selectively impaired translocation efficiency of small secretory preproteins. The pathophysiological significance of the positive charge in the n-region of SP was underscored by recently identified preproinsulin SP mutations that impair translocation of preproinsulin and cause maturity onset diabetes of youth (MODY). Remarkably, we have found that slowing the polypeptide elongation rate of small secretory preproteins could alleviate the translocation defect caused by loss of the n-region positive charge of the signal peptide. Together, these data reveal not only a previously unrecognized role of the n-region's positive charge in ensuring efficient post-translational translocation of small secretory preproteins, but they also highlight the molecular contribution of defects in this process to the pathogenesis of genetic disorders such as MODY.

THE ASSOCIATION BETWEEN BODY MASS INDEX AND SUBCLINICAL THYROID DYSFUNCTION IN DIFFERENT SEXES OF CHINESE.

Objective: To study subclinical thyroid dysfunction (SCTD)-subclinical hyperthyroidism and subclinical hypothyroidism-in Chinese patients in relation to body mass index (BMI) and to determine whether a difference between sexes exists. Methods: This cross-sectional study recruited 13,503 healthy participants (8,345 male, 5,158 female) who participated in a health examination. Clinical data, including anthropometric measurements and serum parameters, were collected. The association between SCTD and the BMI of each sex was analyzed separately by stratifying the data by SCTD type and regarding BMI as a categorical or as a continuous variable in different models. The odds ratio of SCTD was calculated from binary logistic regression models. Results: The prevalence of both subclinical hyperthyroidism and subclinical hypothyroidism was significantly lower in males compared to females. For subclinical hypothyroidism, we found no significant association with BMI in females. In males, there was a significant negative relationship between BMI and subclinical hypothyroidism. For subclinical hyperthyroidism, we did not find any significant relationship with BMI in either sex after stratifying the data and treating BMI as a categorical or as a continuous variable. Conclusion: For subclinical hyperthyroidism, no significant effect was found in either sex. For subclinical hypothyroidism, high BMI was associated with lower rates of subclinical hypothyroidism in males, and no significant correlation was found in females. The mechanism of this sex-specific association between BMI and SCTD needs more verification. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; BUN = blood urea nitrogen; CI = confidence interval; Cr = creatinine; DBP = diastolic blood pressure; FG = fasting glucose; FT3 = free triiodothyronine; FT4 = free thyroxine; HDL = high-density lipoprotein; LDL = low-density lipoprotein; OR = odds ratio; SBP = systolic blood pressure; SCTD = subclinical thyroid dysfunction; TBIL = total bilirubin; TC = total cholesterol; TG = triglyceride; TSH = thyroid-stimulating hormone; UA = uric acid; WBC = white blood cell; WC = waist circumference.

Biosynthesis, structure, and folding of the insulin precursor protein.

Insulin synthesis in pancreatic ß-cells is initiated as preproinsulin. Prevailing glucose concentrations, which oscillate pre- and postprandially, exert major dynamic variation in preproinsulin biosynthesis. Accompanying upregulated translation of the insulin precursor includes elements of the endoplasmic reticulum (ER) translocation apparatus linked to successful orientation of the signal peptide, translocation and signal peptide cleavage of preproinsulin-all of which are necessary to initiate the pathway of proper proinsulin folding. Evolutionary pressures on the primary structure of proinsulin itself have preserved the efficiency of folding ("foldability"), and remarkably, these evolutionary pressures are distinct from those protecting the ultimate biological activity of insulin. Proinsulin foldability is manifest in the ER, in which the local environment is designed to assist in the overall load of proinsulin folding and to favour its disulphide bond formation (while limiting misfolding), all of which is closely tuned to ER stress response pathways that have complex (beneficial, as well as potentially damaging) effects on pancreatic ß-cells. Proinsulin misfolding may occur as a consequence of exuberant proinsulin biosynthetic load in the ER, proinsulin coding sequence mutations, or genetic predispositions that lead to an altered ER folding environment. Proinsulin misfolding is a phenotype that is very much linked to deficient insulin production and diabetes, as is seen in a variety of contexts: rodent models bearing proinsulin-misfolding mutants, human patients with Mutant INS-gene-induced Diabetes of Youth (MIDY), animal models and human patients bearing mutations in critical ER resident proteins, and, quite possibly, in more common variety type 2 diabetes.

Competitive Inhibition of the Endoplasmic Reticulum Signal Peptidase by Non-cleavable Mutant Preprotein Cargos.

Upon translocation across the endoplasmic reticulum (ER) membrane, secretory proteins are proteolytically processed to remove their signal peptide by signal peptidase (SPase). This process is critical for subsequent folding, intracellular trafficking, and maturation of secretory proteins. Prokaryotic SPase has been shown to be a promising antibiotic target. In contrast, to date, no eukaryotic SPase inhibitors have been reported. Here we report that introducing a proline immediately following the natural signal peptide cleavage site not only blocks preprotein cleavage but also, in trans, impairs the processing and maturation of co-expressed preproteins in the ER. Specifically, we find that a variant preproinsulin, pPI-F25P, is translocated across the ER membrane, where it binds to the catalytic SPase subunit SEC11A, inhibiting SPase activity in a dose-dependent manner. Similar findings were obtained with an analogous variant of preproparathyroid hormone, demonstrating that inhibition of the SPase does not depend strictly on the sequence or structure of the downstream mature protein. We further show that inhibiting SPase in the ER impairs intracellular processing of viral polypeptides and their subsequent maturation. These observations suggest that eukaryotic SPases (including the human ortholog) are, in principle, suitable therapeutic targets for antiviral drug design.

Inefficient translocation of preproinsulin contributes to pancreatic ß cell failure and late-onset diabetes.

Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of ß cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to ß cell failure and diabetes. Specifically, we find that, after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized, untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes ß cell death. Restoring an N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of ß cell failure and diabetes but also provide the first evidence of the physiological and pathological significance of the SP n region positive charge of secretory proteins.

Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity.

We investigated GH action on macrophage (MΦ) by creating a MΦ-specific GH receptor-null mouse model (MacGHR KO). On a normal diet (10% fat), MacGHR KO and littermate controls exhibited similar growth profiles and glucose excursions on intraperitoneal glucose (ipGTT) and insulin tolerance (ITT) tests. However, when challenged with high fat diet (HFD, 45% fat) for 18 weeks, MacGHR KO mice exhibited impaired ipGTT and ITT compared with controls. In MacGHR KO, adipose-tissue (AT) MΦ abundance was increased with skewing toward M1 polarization. Expression of pro-inflammatory cytokines (IL1ß, TNF-α, IL6, and osteopontin (OPN)) were increased in MacGHR KO AT stromal vascular fraction (SVF). In MacGHR KO AT, crown-like-structures were increased with decreased insulin-dependent Akt phosphorylation. The abundance of phosphorylated NF-κB and of OPN was increased in SVF and bone-marrow-derived MΦ in MacGHR KO. GH, acting via an NF-κB site in the distal OPN promoter, inhibited the OPN promoter. Thus in diet-induced obesity (DIO), lack of GH action on the MΦ exerts an unexpected deleterious effect on glucose homeostasis by accentuating AT inflammation and NF-κB-dependent activation of OPN expression. These novel results in mice support the possibility that administration of GH could have salutary effects on DIO-associated chronic inflammation and insulin resistance in humans.

Downregulation of RCN1 inhibits esophageal squamous cell carcinoma progression and M2 macrophage polarization.

Reticulocalbin 1 (RCN1) is a calcium-binding protein involved in the regulation of calcium homeostasis in the endoplasmic reticulum. The aim of this study was to explore the clinical value and biological role of RCN1 in esophageal squamous cell carcinoma (ESCC). In addition, we investigated the effect of RCN1 on the polarization of tumor-associated macrophages (TAMs). The GSE53625 dataset from the Gene Expression Omnibus database was used to analyze the expression of RCN1 mRNA and its relationship with clinical value and immune cell infiltration. Immunohistochemistry was used to validate the expression of RCN1 and its correlation with clinicopathological characteristics. Subsequently, transwell and cell scratch assays were conducted to evaluate the migration and invasion abilities of ESCC cells. The expression levels of epithelial-mesenchymal transition (EMT)-related proteins were evaluated by western blot, while apoptosis was detected by flow cytometry and western blot. Additionally, qRT‒PCR was utilized to evaluate the role of RCN1 in macrophage polarization. RCN1 was significantly upregulated in ESCC tissues and was closely associated with lymphatic metastasis and a poor prognosis, and was an independent prognostic factor for ESCC in patients. Knockdown of RCN1 significantly inhibited the migration, invasion, and EMT of ESCC cells, and promoted cell apoptosis. In addition, RCN1 downregulation inhibited M2 polarization. RCN1 is upregulated in ESCC patients and is negatively correlated with patient prognosis. Knocking down RCN1 inhibits ESCC progression and M2 polarization. RCN1 can serve as a potential diagnostic and prognostic indicator for ESCC, and targeting RCN1 is a very promising therapeutic strategy.

Clinical Characteristics of Patients With HNF1-alpha MODY: A Literature Review and Retrospective Chart Review.

The clinical manifestation of hepatocyte nuclear factor-1-alpha (HNF1-alpha) maturity-onset diabetes of the young (MODY) is highly variable. This study aims to investigate the clinical characteristics of patients with HNF1-alpha MODY in general, by geographical regions (Asian or non-Asian), HNF1-alpha mutations, and islet autoantibody status. A literature review and a chart review of patients with HNF1-alpha MODY were performed. The means and proportions from studies were pooled using the inverse variance method for pooling, and subgroup analyses were performed. A total of 109 studies involving 1,325 patients [41.5%, 95% confidence interval (CI): 35.2, 48.1; male] were identified. The mean age of diagnosis was 20.3 years (95% CI: 18.3-22.2), and the mean glycated hemoglobin was 7.3% (95% CI: 7.2-7.5). In comparison, Asian patients exhibited significantly higher HbA1c (p = 0.007) and 2-h post-load C-peptide (p = 0.012) levels and lower levels of triglyceride (TG) (p < 0.001), total cholesterol (TC) (p < 0.001), and high-density lipoprotein cholesterol (HDL-c) (p < 0.001) and less often had macrovascular complications (p = 0.014). The age of diagnosis was oldest in patients with mutations in the transactivation domain (p < 0.001). The levels of 2-h post-load C-peptide (p < 0.001), TG (p = 0.007), TC (p = 0.017), and HDL-c (p = 0.001) were highest and the prevalence of diabetic neuropathy was lowest (p = 0.024) in patients with DNA-binding domain mutations. The fasting (p = 0.004) and 2-h post-load glucose (p = 0.003) levels and the prevalence of diabetic neuropathy (p = 0.010) were higher among patients with positive islet autoantibodies. The study demonstrated that the clinical manifestations of HNF1-alpha MODY differed by geographical regions, HNF1-alpha mutations, and islet autoantibody status.

Prediction model of random forest for the risk of hyperuricemia in a Chinese basic health checkup test.

OBJECTIVES: The present study aimed to develop a random forest (RF) based prediction model for hyperuricemia (HUA) and compare its performance with the conventional logistic regression (LR) model. METHODS: This cross-sectional study recruited 91,690 participants (14,032 with HUA, 77,658 without HUA). We constructed a RF-based prediction model in the training sets and evaluated it in the validation sets. Performance of the RF model was compared with the LR model by receiver operating characteristic (ROC) curve analysis. RESULTS: The sensitivity and specificity of the RF models were 0.702 and 0.650 in males, 0.767 and 0.721 in females. The positive predictive value (PPV) and negative predictive value (NPV) were 0.372 and 0.881 in males, 0.159 and 0.978 in females. AUC of the RF models was 0.739 (0.728-0.750) in males and 0.818 (0.799-0.837) in females. AUC of the LR models were 0.730 (0.718-0.741) for males and 0.815 (0.795-0.835) for females. The predictive power of RF was slightly higher than that of LR, but was not statistically significant in females (Delong tests, P=0.0015 for males, P=0.5415 for females). CONCLUSION: Compared with LR, the good performance in HUA status prediction and the tolerance of features associations or interactions showed great potential of RF in further application. A prospective cohort is necessary for HUA developing prediction. People with high risk factors should be encouraged to actively control to reduce the probability of developing HUA.

A Novel Nonsense INS Mutation Causes Inefficient Preproinsulin Translocation Into the Endoplasmic Reticulum.

Preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) is the first and critical step of insulin biosynthesis. Inefficient PPI translocation caused by signal peptide (SP) mutations can lead to ß-cell failure and diabetes. However, the effect of proinsulin domain on the efficiency of PPI translocation remains unknown. With whole exome sequencing, we identified a novel INS nonsense mutation resulting in an early termination at the 46th residue of PPI (PPI-R46X) in two unrelated patients with early-onset diabetes. We examined biological behaviors of the mutant and compared them to that of an established neonatal diabetes causing mutant PPI-C96Y. Although both mutants were retained in the cells, unlike C96Y, R46X did not induce ER stress or form abnormal disulfide-linked proinsulin complexes. More importantly, R46X did not interact with co-expressed wild-type (WT) proinsulin in the ER, and did not impair proinsulin-WT folding, trafficking, and insulin production. Metabolic labeling experiments established that, despite with an intact SP, R46X failed to be efficiently translocated into the ER, suggesting that proinsulin domain downstream of SP plays an important unrecognized role in PPI translocation across the ER membrane. The study not only expends the list of INS mutations associated with diabetes, but also provides genetic and biological evidence underlying the regulation mechanism of PPI translocation.

A Meta-Analysis of Pregnancy Outcomes With Levothyroxine Treatment in Euthyroid Women With Thyroid Autoimmunity.

CONTEXT: Thyroid autoimmunity (TAI), the most common cause of (sub)clinical hypothyroidism, is associated with adverse pregnancy outcomes. The benefits of levothyroxine (LT4) intervention in women with TAI remain controversial. OBJECTIVE: The purpose of this analysis is to determine the effect of LT4 on pregnancy outcomes in euthyroid women with TAI. DATA SOURCES: Databases were searched up to May 2019. STUDY SELECTION: Randomized controlled trails (RCTs) and retrospective studies that reported effects of LT4 administration on pregnancy outcomes in euthyroid women with TAI were screened. DATA EXTRACTION: Quality assessment and data extraction were conducted independently by 2 researchers. Conflicts were settled by a third researcher. DATA SYNTHESIS: Six trials comprising 2249 women were included. Overall, no beneficial effect on pregnancy outcomes was observed with LT4 supplementation. For women with individualized initial LT4 dosages, the risk of miscarriage decreased (relative risk [RR] 0.62, 95% CI: 0.41-0.93, I2 = 28%); there was no difference among women with fixed LT4 dosages (RR 0.96, 95% CI: 0.74-1.24, I2 = 0%). Women who initiated LT4 treatment in early pregnancy had a significantly lower preterm birth rate (RR 0.54, 95% CI: 0.31-0.92, I2 = 0%) than those who received no treatment or placebo. No improvement was observed among women who initiated treatment before conception (RR 1.14, 95% CI: 0.71-1.84, I2 = 0%). CONCLUSION: No definitive evidence showed improvement of pregnancy outcomes with LT4 supplementation in euthyroid women with TAI. However, therapeutic strategies, especially dosages and initial times of intervention, may be of great importance. Additional large RCTs are needed in the future.

Role of Proinsulin Self-Association in Mutant INS Gene-Induced Diabetes of Youth.

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin (PI) in the endoplasmic reticulum (ER) drive the molecular pathogenesis of mutant INS gene-induced diabetes of youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, PI-WT dimerizes in the ER. Here, we suggest that the normal PI-PI contact surface, involving the B-chain, contributes to dominant-negative effects of misfolded MIDY mutants. Specifically, we find that PI B-chain tyrosine-16 (Tyr-B16), which is a key residue in normal PI dimerization, helps confer dominant-negative behavior of MIDY mutant PI-C(A7)Y. Substitutions of Tyr-B16 with either Ala, Asp, or Pro in PI-C(A7)Y decrease the abnormal interactions between the MIDY mutant and PI-WT, rescuing PI-WT export, limiting ER stress, and increasing insulin production in ß-cells and human islets. This study reveals the first evidence indicating that noncovalent PI-PI contact initiates dominant-negative behavior of misfolded PI, pointing to a novel therapeutic target to enhance PI-WT export and increase insulin production.

A left femoral artery to right femoral vein bypass graft for hemodialysis access: A case report.

RATIONALE: As survival prospects improve for long-term patients with hemodialysis, it is common for patients to exhaust all upper extremity access options before other avenues need exploration. The purpose of this case report was to describe our experience in creating a prosthetic graft between left femoral artery and right femoral vein in a patient with history of central venous occlusion and bilateral femoral neck fracture. PATIENT CONCERNS: A female patient with hemodialysis exhausted all upper extremity access options along with bilateral femoral neck fracture. DIAGNOSES: Patients with end-stage renal disease exhausted all upper extremity access options. INTERVENTIONS: We performed a left femoral artery to right femoral vein dialysis access utilizing a prosthetic graft and autologous cephalic vein. OUTCOME: The graft was used for hemodialysis 3 weeks after the operation. There was no edema of the lower extremity through the immediate postoperative period as well as at follow up. The patient has been using the access for 9 months with no complication of thrombosis, infection, or bleeding. LESSONS: Prosthetic graft between the left femoral artery and right femoral vein is a simple, safe and novel approach to creating lower extremity access. This method could be a viable means of hemodialysis access in selected patients.

No obvious association exists between red blood cell distribution width and thyroid function.

Aim: We aimed to explore gender impacts on the associations between red blood cell distribution width (RDW) and thyroid function in the Chinese population. Methods/results: Gender impacts on the associations between RDW and thyroid function in 8424 males and 5198 females were investigated. RDW was found significantly lower in males than in females. An increasing trend of RDW along with aging was demonstrated in males. For females, an obvious decrease was shown during menopause period. From binary logistic regression, RDW displayed negative relationship with hypothyroidism in both genders as a single factor. However, if RDW was analyzed as a categorical variable (in RDW width quartiles) and as a continuous variable in models with covariates, all the odds ratios were negative, except for a weak-negative relationship with hypothyroidism in women in a continuous RDW model. Conclusion: The current study suggests that anisocytosis could be a contributing factor in thyroid dysfunction.