bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two Cases of Statin Induced Necrotizing Autoimmune Myopathy
Authors: Alam Mustafa , Asad Omar , Lababidi Hashim , Alam Mahad , Shahlapour Mahmoud , Horani Mohamad Hosam 
Published: May 2021

Abstract
Case 1: Six months ago, patient 1 presented with rhabdomyolysis with a CK of 17,622 Units/L. The statin was discontinued at that time, after which the patient noted substantial improvement in muscle symptoms. Two months later the patient was readmitted for complaints related to continued rhabdomyolysis. CK was elevated at 9800 Units/L, raising suspicion for SINAM. Physical exam findings on readmission were pertinent for 4/5 strength in proximal flexion and extension of the upper extremities bilaterally and 4/5 strength in hip flexion. Pertinent lab values on readmission include increased ALT of 122 Units/L, AST of 103 Units/L, TSH of 7.4 mIU/L, HbA1c of 6.6%, and BUN of 14.5 mg/dL. Urinalysis is positive 3+ for glucose, 1+ for ketones, and 2+ for blood. Brain MRI without contrast negative for any brain malignancies or abnormalities. Case 2: Patient 2 presented with gradual proximal muscle weakness while taking a statin for the past six months. Physical exam was notable for 4/5 strength in the biceps and triceps and 3/5 deltoid strength bilaterally. There was 4/5 strength in the knee flexors and extensors with 3/5 strength in the hip flexors bilaterally. Notable lab values include CK of 10,449 Units/L, CK-MB of 492ng/mL, fasting glucose of 160 mg/dL, ALT of 229 Units/L, and HgbA1C of 7.3%. Urinalysis was positive 3+ for glucose, 1+ for ketones, and 2+ for blood. Discussion: Statin induced necrotizing autoimmune myopathy (SINAM) is a rare complication of statin therapy in which subjects develop an immune response to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). SINAM’s pathophysiology remains poorly understood. Studies have shown that statins upregulate expression of HMGCR which serve as antibody targets in SINAM (Mohassel & Mammen, 2013). The HMGCR protein is upregulated in regenerating muscle fibers thus preferentially allowing autoantibodies to bind (Mammen et al, 2011). Additionally, complement is implicated in pathogenicity of SINAM with a study showing that C3 deficient mice had less pronounced deficiency in muscle strength (Bergua et al, 2019). This is further reinforced with a muscle biopsy in another SINAM confirmed patient showed C5b-9 sarcolemmal deposits (Sharma et al, 2019). This implicates the formation of antigen-antibody-complement complexes typical of a type III hypersensitivity reaction. Additionally, genetic risk factors for autoimmunity are important to consider. There is an association of SINAM occurrence in individuals with single nucleotide polymorphism in the SLCO1B1 that regulates hepatic uptake of drugs such as statins (SEARCH, 2008). HLA- DRB1*11:01 is associated with the formation of autoantibodies in SINAM (Mammen, 2016). Recent studies show the triple induction therapy of steroids, IVIG, and a steroid sparing immunosuppressant has been very effective (Meyer et al, 2020).
The Impact of ACTH on Peripheral Steroids Differs between Unilateral and Bilateral Primary Aldosteronism
Authors: Tezuka Yuta , Ishii Kae , Zhao Lili , Yamazaki Yuto , Morimoto Ryo , Sasano Hironobu , Udager Aaron , Satoh Fumitoshi , Turcu Adina 
Published: May 2021

Abstract
Background: ACTH is thought to contribute to aldosterone excess in primary aldosteronism (PA), possibly via aberrant melanocortin type 2 receptor (MC2R) expression in aldosterone producing adenomas (APAs). Dynamic manipulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a non-invasive tool for distinguishing unilateral PA (UPA) from bilateral PA (BPA), but existing data are minimal. Objective: To characterize the steroid responses to intrinsic ACTH variations and extrinsic HPA manipulation in UPA and BPA. Methods: We conducted comprehensive dynamic testing in PA patients, who were subtyped based on adrenal vein sampling. Peripheral plasma samples were collected from each patient at 6 time-points: morning; midnight; after 1 mg dexamethasone suppression (DST); and after cosyntropin stimulation (at 15’, 30’, and 60’). We quantified 15 steroids by mass spectrometry in each sample. Next generation sequencing was used to detect aldosterone-driver somatic mutations in APAs from 39 cases with available tissue. The Mann-Whitney test, Wilcoxon signed rank test, and repeated measures two-way ANOVA were employed, as appropriate. Penalized logistic regression was used to select steroids that best distinguished UPA from BPA. Receiver operating characteristic (ROC) curves were then plotted using the predicted score from the logistic regression model with the selected steroids, and area under the curves (AUC) were computed. Results: We included 80 PA patients, median age 51 (range, 26–76), 50% men, 40 with each subtype, both groups with similar age and sex distribution. Morning and midnight concentrations of 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), aldosterone, and 18-hydroxycorticosterone (18OHB) were higher in patients with UPA vs. BPA (p&lt;0.001 for all). In response to cosyntropin stimulation, the UPA group had larger increments of aldosterone, 18oxoF, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol than the BPA group (p&lt;0.05 for all). Following DST, aldosterone,18OHF, and 18oxoF were higher in UPA than in BPA patients (p&lt;0.01 for all). Overall, cortisol and cortisone serum concentrations were similar between the two subtypes. Of the UPA cases, 27 (69%) had KCNJ5 mutations. Relative to UPA patients with other mutations, the KCNJ5 group had higher 18oxoF and 18OHF at baseline; higher 18oxoF and corticosterone after both dynamic tests; and lower aldosterone after DST. The highest AUC for PA subtyping was achieved using cosyntropin stimulated steroids (0.957), while baseline data reached an AUC of 0.909. Conclusions: Steroid responses to dynamic HPA testing differs between UPA and BPA: 18oxoF and 18OHF are less suppressible, while several steroids are disproportionally amplified by ACTH in patients with UPA vs. BPA. Such non-invasive tests could circumvent the need for adrenal vein sampling in a subset of PA patients.
AZP-3404, a Peptide Analog of IGFBP-2, Induces Weight Loss and Improves Glucose Metabolism in Leptin-Resistant db/db Mice
Authors: Culler Michael D , Milano Stéphane , Delale Thomas , Ovize Michel , van der Lelij Aart Jan , Clemmons David R 
Published: May 2021

Abstract
Insulin-like growth factor binding protein-2 (IGFBP-2) has been demonstrated to be a key mediator of the peripheral metabolic actions of leptin. The metabolic activity of IGFBP-2 is independent of IGF1 binding, and can be localized to a unique heparin-binding domain (HBD-1) within its structure. AZP-3404 is a 9-amino acid analog of the IGFBP-2 HBD-1 that reproduces the activity of IGFBP-2 on adipocyte and osteoblast differentiation. In addition, AZP-3404 has been demonstrated to increase glucose uptake by differentiated mouse myotubes in vitro, and to increase glucose disposal following an intraperitoneal glucose tolerance test (IPGTT) in leptin-deficient ob/ob mice. In the present study, we hypothesized that AZP-3404 should be able to improve metabolic regulation in the db/db mouse, which is leptin-resistant due to a mutation in the leptin receptor, and, as a result, is also IGFBP-2 deficient. Following pre-treatment with vehicle for 1 week to establish a baseline, 9-week old male db/db mice were treated with either vehicle or AZP-3404 at doses of 1, 3 or 6 mg/kg, sc, bid (n=10/group) for 8 weeks. At the initiation of treatment, the mice weighed an average of 39.7 + 0.3 grams, and after 8 weeks, vehicle-treated mice had gained an average 8.2 + 1.6 grams of body weight. Mice treated with AZP-3404 displayed a progressive decrease in body weight gain that began after 2 weeks and that continued through the 8 weeks of treatment, ultimately resulting in less than 50% of the weight gain observed in the vehicle-treated mice, and without an apparent change in food intake. To assess the impact on glucose disposal, after both 4 and 8 weeks of treatment, and following an overnight fast, the mice were administered an IPGTT (blood glucose measured 0, 30, 60, 90, 120 and 240 minutes post-ip injection of 1 g glucose/kg). By 4 weeks of treatment, a significant increase in glucose disposal was observed in mice treated with the 6 mg/kg dose of AZP-3404 (AUC glucose decreased by 28.7%) versus vehicle-treated controls. By 8 weeks of treatment, all three doses produced similar increases in glucose disposal (AUC glucose decreased by 18.8, 21.4 and 23.1% with 1, 3 and 6 mg/kg AZP-3404, respectively) versus vehicle controls. Correspondingly, 4-hour fasted plasma insulin was decreased by 54, 48 and 52%, and the HOMA measure of insulin resistance was decreased by 55, 52 and 67%, in mice treated for 8 weeks with 1, 3 and 6 mg/kg AZP-3404, respectively, as compared with vehicle-treated mice. These results, demonstrating both improved glucose metabolism and decreased body weight gain in the leptin-resistant db/db mouse, further confirm the ability of AZP-3404 to reproduce the metabolic activity of IGFBP-2, and support the development of AZP-3404 as a novel therapy for disease states characterized by insulin resistance and/or obesity.
Functional Heterogeneity Among Pancreatic Alpha Cells
Authors: Noguchi Glyn M , Ou Rosie , Castillo Vincent , Donaldson Cynthia J , Mawla Alexander M , Huising Mark O 
Published: May 2021

Abstract
Historically, endocrine cells in the pancreatic islets have been assumed to function as relatively homogenous populations largely because we lacked the ability to measure individual cell activity with sufficient throughput to reliably detect heterogeneity within each population. The glucagon-secreting alpha cells play a vital role in regulating glycemia, but the mechanisms that control alpha cell activity and whether the alpha cells behave as a single unit or heterogeneously remain incompletely understood. To overcome the limitations in throughput that have to date prevented the study of alpha cells at the population level, we used genetically-encoded fluorescent indicators selectively expressed in alpha cells. Imaging intact mouse islets with these indicators in 3D responding to treatments in real time yields hundreds of individual alpha cell recordings per experiment. Calcium imaging showed reproducible heterogeneous responses to a panel of known physiological potentiators of glucagon secretion such as arginine vasopressin, epinephrine, and amino acids. Separate dose response experiments revealed that the proportion of alpha cells responding to each signal plateaus at different proportions of alpha cells. The calcium data correlate both with direct glucagon secretion levels as well as cAMP measurement. Our findings highlight previously unappreciated levels of functional heterogeneity among alpha cells and demonstrate that alpha cells are not a single uniform unit. Our observations suggest that dose-dependent increases in glucagon secretion in response to different physiological cues may be the result of mobilizing progressively larger proportions of the total alpha cell mass. We hypothesize that this functional heterogeneity is a built-in mechanism through which different physiological cues elicit graded glucagon responses from the alpha cells.
Pre-Conception Weight Loss Improves Reproductive, Metabolic and Kidney Health in Obese Mice and Their Offspring
Authors: Rodrigo Natassia , Chen Hui , Pollock Carol , Glastras Sarah 
Published: May 2021

Abstract
Background and Aims: An alarming 40% of women of reproductive age have obesity and during pregnancy obesity adversely impacts metabolic health in mothers and offspring. Maternal complications include diabetes, preeclampsia and chronic kidney disease (CKD). Our previous work showed that offspring have increased risks of obesity, diabetes, and CKD. While pre-pregnancy weight optimisation is advocated, evidence of benefits for mother and offspring are lacking. We aimed to determine if weight loss prior to pregnancy, either with diet modification or liraglutide, improves maternal and offspring metabolic outcomes, and reduces kidney complications in obese mothers and the offspring.
Methods: C57BL/6 female mice were fed a high-fat-diet (HFD) for 8 weeks and compared to lean chow-fed controls. HFD-fed dams were administered liraglutide (0.3mg/kg, s.c., for 4weeks) or switched to chow, to induce pre-conception weight loss. Pregnancy rates were observed after mating. Maternal anthropometry and glucose tolerance were measured before and after intervention, and at late gestation. Pregnant dams were either culled at gestational day 18–20 with blood and kidney harvested, or allowed to deliver their offspring. Offspring anthropometry, and glucose tolerance were assessed at postnatal week 12 after either HFD or chow feeding. Immunohistochemistry (IHC), western blotting and RT-PCR were used to measure kidney metabolic (FAS, SREBP) and inflammatory markers (CD-68,TGF-b). Results: HFD-fed dams had reduced glucose tolerance compared to chow-fed dams (p&lt;0.0001), and higher expression of renal metabolic and inflammatory markers in late gestation (eg FAS &lt;0.05, TGFb &lt;0.05). Intervention with liraglutide or diet lowered body weight, improving glucose tolerance (both p&lt;0.001), and fecundity. Markers of kidney damage, namely albuminuria and fibronectin (by RT-PCR and IHC) were reduced (both p&lt;0.05). Liraglutide treated mice exhibited greater gestational weight gain than mice switched to chow (P&lt;0.001). Markers of inflammation and oxidative stress were significantly lower in obese mice with preconception weight loss via diet compared to liraglutide (eg. MnSOD, PGC1α p&lt;0.05). The offspring of obese mothers with pre-conception weight loss had lower body weight (p&lt;0.001) and improved glucose tolerance (p&lt;0.01). Kidney metabolic and inflammatory markers (MCP-1, FAS, SREBP, CD68) were significantly altered in HFD-fed offspring of obese mothers administered liraglutide pre pregnancy (p&lt;0.05). Conclusions: Preconception weight loss improves fertility, weight and metabolic outcomes in mothers and the offspring, with benefits on reproduction, metabolic health, and chronic kidney disease risk. Therefore, obese women should be targeted for pre-conception weight loss to improve intergenerational metabolic health.
Predictors of Normalization of Fasting Glucose in Patients With Prediabetes Using Remote Continuous Care Emphasizing Low Carbohydrate Intake
Authors: McKenzie Amy , Athinarayanan Shaminie , Adams Rebecca , Hallberg Sarah , Volek Jeff , Phinney Stephen D 
Published: May 2021

Abstract
Background: Prediabetes phenotypes differ based on whether an individual exhibits impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or both. The traditional diabetes prevention approach focused on weight loss via fat/caloric restriction and exercise appears less effective in those with IFG. Given that even transient regression to normal glucose regulation is associated with reduced risk of progression to type 2 diabetes, interventions that elicit normal fasting glucose (NFG) may be beneficial. Here, we explored predictors of normalization of fasting glucose (FG) over one-year treatment with carbohydrate restricted nutrition therapy (Carb-R) delivered via a continuous remote care model.
Methods: Data were obtained from medical records of adults with prediabetes who were treated at least one year at time of analysis. Of 738 patients with an antecedent prediabetes diagnosis, 460 had IFG (100mg/dL to 125mg/dL) at enrollment in the clinic and were included in this analysis. Patients were counseled on Carb-R targeting nutritional ketosis (NK) and reported fasting blood glucose, blood beta-hydroxybutyrate (BHB), and weight via an app facilitating remote monitoring and medical/coaching support. BHB ≥0.5 mM indicated NK. Cox proportional hazard regression was used to model time of first incidence of NFG at 3, 6, 9, and 12 months and to assess if normalization of fasting glucose was associated with baseline factors, weight change, metformin use, and degree or frequency of NK achieved, analyzed separately. Mean±SE is reported.
Results: Patients with IFG were 53.9±0.4 years of age, 64.0% female, HbA1c 5.92±0.02%, and fasting glucose 114.5±0.8 mg/dL at enrollment. During treatment, 199 (43.3%) patients normalized FG at ≥1 time point with mean weight loss of 10.0±0.4 kg (-8.9%) at time of normalization, 192 (41.7%) did not, and 69 (15.0%) were missing glucose data. In an adjusted multivariate model, lower baseline HbA1c (HR 0.60, p=0.03), female sex (HR 1.39, p=0.04), and greater mean BHB value (HR 1.83, p&lt;0.001) or higher proportion of days on which NK was reported (HR 3.23, p&lt;0.001) were associated with reversion to NFG. Age, metformin use, weight change, and baseline fasting glucose, weight, triglycerides, HDL-C, and LDL-C were not associated with reversion to NFG (p&gt;0.05). Conclusions: Greater adherence to Carb-R indicated by greater BHB values and a greater proportion of days in NK were strongly associated with normalization of FG in prediabetes patients with IFG. Weight loss, a common goal for diabetes prevention, was not associated with reversion to NFG. Future studies should assess the effects of Carb-R including NK in other prediabetes phenotypes and on progression to type 2 diabetes.
Renal GLUT2 is Essential in Regulating Systemic Glucose Homeostasis by Glycosuria
Authors: de Souza Cordeiro Leticia M , Devisetty Nagavardhini , McDougal David , Peters Dorien J M , Chhabra Kavaljit H 
Published: May 2021

Abstract
Diabetes increases renal GLUT2 levels and consequently, worsens hyperglycemia by enhancing glucose reabsorption. We recently demonstrated that renal GLUT2 is a primary effector of the central melanocortin system in regulating glucose homeostasis. Therefore, we hypothesized that renal GLUT2 is essential for maintaining systemic glucose homeostasis by regulating glycosuria. To test the hypothesis, we generated kidney-specific inducible Glut2 knockout (KO) mice [Glut2LoxP/LoxP x KspCadCreERT2 (inducible by tamoxifen)]. These mice exhibited 90% reduction in Glut2 expression selectively in the kidneys, without affecting the expressions of other renal glucose transporters, such as Glut1, Sglt1, and Sglt2. To evaluate the physiological contribution of renal GLUT2 in systemic glucose homeostasis, we performed oral glucose tolerance tests (OGTT) in kidney-specific Glut2 KO mice and their control littermates (Ctrl). We observed that the kidney-specific GLUT2 deficient mice exhibited improved glucose tolerance compared to their Ctrls (AUC for OGTT, 41,950 ±2,014 vs. 52,165 ±1,686 mg/dL.min). To measure glycosuria in the kidney-specific Glut2 KO mice, we placed the mice in metabolic cages and collected 24h urine after acclimating the mice in the new cages. Indeed, the GLUT2 deficient mice had ~1,800-fold increase in urine glucose levels (53.5 ±11 vs. 0.03 ±0.005 mg/24h) and exhibited an increased urine volume (2.5 ±0.3 vs. 0.9 ±0.3 mL/24h) and water intake (7.6 ±0.7 vs. 4.9 ±0.7 mL/24h) compared to their Ctrl littermates. The improvement in glucose tolerance in the kidney-specific Glut2 KO mice was independent of the insulin signaling because we did not observe any changes in insulin tolerance tests (ITT) (AUC for ITT, 10,982 ±414 vs. 11,275 ±583 mg/dL.min) and serum insulin levels (1.07 ±0.14 vs. 1.05 ±0.13 ng/mL) between the groups. Importantly, the kidney-specific GLUT2 deficient mice had normal serum creatinine (0.42 ±0.02 vs. 0.41 ±0.03 mg/dL), free fatty acid (0.43 ±0.14 vs. 0.53±0.14 nmol/µL), β-hydroxybutyrate (0.29 ±0.01 vs. 0.27 ±0.02 mM) and glucagon (14 ±4 vs. 10 ±1 pg/mL) levels. Moreover, the kidney-specific Glut2 KO mice had normal glomerular area (4,190 ±119 vs. 4,219 ±186 µm2) as measured by kidney histology and normal glomerular filtration rate (153 ±9 vs. 173 ±10 [µL/min/b.w.]/100) compared with their Ctrl littermates, indicating the absence of any known renal injury. Altogether, we have developed a new mouse model in which we can knockout Glut2 selectively in the kidneys in adult mice. We show that loss-of-function of kidney-specific GLUT2 improves glucose tolerance due to elevated glycosuria without producing any known side effects. In conclusion, blocking kidney-specific GLUT2 has the potential to treat diabetes.
Serum Sclerostin Is Associated With Central Fat Distribution in Patients With Type 2 Diabetes and Peripheral Neuropathy
Authors: Costi Bruna , Correia Carolina , Medeiros Karoline , Filho Paulo Barros , Bandeira Francisco 
Published: May 2021

Abstract
Background: Peripheral neuropathy (PN) is the most common chronic diabetic complication occurring in both type 1 and type 2 (T2DM) patients as well as in prediabetes states. Metabolic syndrome seems to be as important as glycemic control in determining the onset and course of DPN, but the mechanisms underlying this association is far from conclusive. Sclerostin (SCL) is a glycoprotein secreted by osteocytes that has an antagonistic effect on the Wnt/beta-catenin pathway which is related to bone formation as well as to increased ectopic fat including marrow fat. Besides to its well-documented role in bone metabolism, the relationship between SCL and adiposity and metabolic syndrome is poorly understood. Objective: To determine SCL levels in patients with T2DM and DPN and evaluate their relationship with metabolic and body composition parameters. Design: Cross-sectional study including 56 patients with T2DM and DPN. Serum SCL levels, glycemic and lipid profile, anthropometric measurements, and percent body fat (PBF) were determined. Results: Mean age was 61.80 ± 10.67 years, duration of T2DM 13.30 ± 8.13 years, 57.1% men, 78.6% hypertensive, body mass index 28.74 ± 5.04 kg/m2, abdominal circumference 99.86 ± 13.37 cm, waist-to-hip ratio (WHR) 0.97 ± 0.08, fasting plasma glucose 169.73 ± 83.13 mg/dL, HbA1c 8.88 ± 2.09%, Triglycerides (TG) 163.54 ± 75.93 mg/dL, SCL 207.41 ± 215.13 pg/mL, and PBF 34.45 ± 8.42%. There were significant correlations between SCL and TG (r=0.407, p=0.003) and significant differences in TG according to quartiles (&lt; p25 vs &gt;p75) of SCL: 125.15 ± 47.45 mg/dL vs 223.50 ± 88.77 mg/dL, p = 0.002; and in WHR: 0.97 ± 0.07 vs 1.01 ± 0.07, p = 0.027. Conclusion: We found that increased levels of SCL were associated with WHR and TG in T2DM patients with DPN.