bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type 2 Diabetes Clusters Indicate Diabetes Duration Key in Fracture Risk
Authors: Ghatan Sam , Ahmadizar Fariba , Li Ruolin , Medina-Gomez Carolina , Zillikens Maria Carola , Rivadeneira Fernando , Kavousi Maryam , Oei Ling 
Published: May 2021

Abstract
Introduction: Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk of developing fractures, despite higher mean BMI and BMD. Recently, clinically-relevant sub-groups of T2DM have been characterised using biomarkers of glycemic metabolism. Aim: Characterise T2DM sub-groups in a population-based setting and test for differences in fracture risk. Methods: A total of 10019 Rotterdam Study participants were available with glycemic and (incident) fracture follow-up. Participants with T2DM (n=1678) were partitioned in subgroups using K-means clustering based on: HOMA-B, HOMA-IR, age of diabetes onset, BMI and waist circumference measurements. Non-vertebral fracture risk was estimated across T2D subgroups using Cox proportional hazard models, adjusted for sex, age, BMI, collection cohort and prevalent T2DM. Results: Four T2D clusters were defined each with relatively-unique clinical characteristics namely, 1) advanced age of onset; 2) decreased insulin sensitivity; 3) beta-cell disfunction; 4) Obesity/high BMI. Individuals with prevalent and incident T2DM (independent of cluster) had lower risk of fracture than non-diabetics (see Forest plot). In contrast, individuals with prevalent T2DM (n=1152) had increased risk of non-vertebral fracture (HR: 2.1, 95%CI: 1.65–2.76), than individuals without T2DM. Conclusion: Despite that partitioning the heterogeneity of T2DM in clinically-meaningful clusters opens the road to tailored prevention and care, our findings with prevalent T2DM indicate that disease duration (likely with inadequate glycemic control) is the main determinant of fracture risk. In line with this contention, the association between T2DM and fracture risk is not causal, as causality requires association with incident cases, as also confirmed by earlier Mendelian randomization studies. Future work, using genetically-determined disease definitions and biomarkers will help unveil clusters of individuals with T2DM at increased risk of fracture.
Volanesorsen, an Antisense Oligonucleotide to Apolipoprotein-CIII, Decreases Triglycerides and Increases Lipoprotein Lipase Activity in Partial Lipodystrophy
Authors: Lightbourne Marissa , Brite Brianna , Startzell Megan S , Kimberley Bruce , Eckel Robert , Brown Rebecca J 
Published: May 2021

Abstract
Partial lipodystrophy syndromes (PL) involve selective deficiency of adipose tissue, with regional deficiency of fat in the lower extremities and preservation or even excess fat in the face and neck. Clinical features typical of PL include severe insulin resistance, diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. Apolipoprotein CIII (Apo-CIII) is elevated in PL, and is thought to contribute to high TG by inhibiting lipoprotein lipase (LPL). However, prior studies of this drug in patients with LPL mutations demonstrated LPL-independent mechanisms of TG-lowering. We hypothesized that Volanesorsen, an antisense oligonucleotide (ASO) to apo-CIII, would decrease apo-CIII, increase LPL activity, and lower TG in PL. We further hypothesized that Volanesorsen would improve insulin resistance and glycemia by directing free fatty acids (FFA) into adipose tissue, rather than ectopic sites (e.g. liver) associated with insulin resistance. Five adults with PL and TG ≥500 mg/dL or TG≥200 with A1c &gt;7.0% were enrolled in a 16-week placebo-controlled, randomized, double blind study of Volanesorsen, 300 mg SC weekly, followed by a 1-year open label extension. Here, we report within-subject effects of Volanesorsen lipids, glycemia and lipolysis, before and after 16 weeks of active drug. From week 0 to week 16, apoC-III decreased from 380 (246, 600) to 75 (26, 232) ng/mL, TG decreased from 503 (330, 1040) to 116 (86, 355) mg/dL; and LPL activity measured in post-heparin plasma utilizing the subject’s serum as activator increased from 22.0±3.0 to 35.5±5.9 nEq/ml/min. Free fatty acid turnover (measured by palmitate tracer studies) decreased from 0.41 (0.35, 0.45) to 0.25 (0.23, 0.29) mg/kg/min. There was no change in A1c (8.4±1.2 to 8.3±0.9%), however there was a decrease in HOMA-IR from 26 (20, 54) to 13 (9, 43) and an increase in peripheral insulin sensitivity (glucose infusion rate during euglycemic hyperinsulinemic clamp, 120 mU/m2/min) from 3.6±2.4 to 4.4±1.5 mg/kgFFM/min and in hepatic insulin sensitivity (% suppression of hepatic glucose production during clamp) from 78±19 to 90±13%. Adverse events include injection site reactions and decreased platelets. Volanesorsen decreased apo-CIII and triglycerides, at least in part through an LPL dependent mechanism, and may improve insulin resistance.
PCSK9 Inhibitors for the Management of Mitotane-Induced Hypercholesterolemia in Adrenocortical Carcinoma
Authors: Aurora John A , Erenler Feyza , Matta Stephany , Lechan Ronald M 
Published: May 2021

Abstract
Background: After surgical resection in adrenocortical carcinoma (ACC), mitotane is often used as adjuvant therapy. However, mitotane can cause adverse effects, such as inducing hypercholesterolemia by stimulating HMG-CoA reductase. In addition, mitotane is a strong CYP3A4 inducer which presents a challenge with statins, such as lovastatin, simvastatin, and atorvastatin. We present a case using a PCSK9 inhibitor in mitotane-induced hypercholesterolemia which was refractory to the maximum dose of rosuvastatin.
Clinical Case: A laparoscopic left adrenalectomy was performed on a 45-year old female with Stage 3 (T3, NX, M0) ACC (4.5 x 3.4 x 3.2 cm). Her ACC was determined to be high grade with a mitotic rate 20/50 HPF and Ki-67 of 18.7% with lymphovascular invasion and tumor invasion of periadrenal adipose tissue. Following surgical resection, she started adjuvant therapy mitotane and oral hydrocortisone replacement, as well as 6 weeks of radiation therapy. Prior to starting mitotane, her LDL-C was 133 mg/dL (normal range &lt;130 mg/dL) and treated with simvastatin 40 mg daily. A drug interaction was identified between simvastatin and mitotane, with mitotane reducing effects of simvastatin via CYP3A4 induction, so rosuvastatin 10 mg daily was started instead. A trial of combination rosuvastatin and ezetimibe was used; however, patient discontinued ezetimibe due to reported side effects. As the dose of mitotane increased to achieve a blood concentration of 14–20 mcg/mL, LDL-C simultaneously increased along with a corresponding dose increase of rosuvastatin. While being on mitotane 2 g daily and rosuvastatin 40 mg daily, her lipids peaked with LDL-C 219 mg/dL. The decision was made to start evolocumab administered as 140 mg subcutaneously every 2 weeks in addition to rosuvastatin 40 mg daily. After 4 months of therapy with combination evolocumab and rosuvastatin, her LDL-C decreased to 111 mg/dL, a 49% reduction, while achieving a mitotane concentration of 13 mcg/mL using 4 g daily.
Conclusion: Utilizing a PCSK9 inhibitor, such as evolocumab, allows the dose of mitotane to be increased to achieve a therapeutic level while maintaining adequate control of cholesterol. With options for management of mitotane-induced hypercholesterolemia being limited, off-label use of a PCSK9 inhibitor can be justified clinically as moderate LDL-C reduction has also been shown in a prior published case report (1). Evolocumab is a well-tolerated subcutaneous injection, and should be considered for patients with resistant hypercholesterolemia while on mitotane.
References: (1) Tsakiridou ED, Liberopoulos E, Giotaki Z, et al. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor use in the management of resistant hypercholesterolemia induced by mitotane treatment for adrenocortical cancer. J Clin Lipidol. 2018;12(3):826–829.
Study of Patients’ Characteristics and Mutual Impact Between Covid-19 and Hyperglycemia at a Community Hospital in Central Brooklyn
Authors: Myint Myat S , Htun Kyaw W , Asfaw Menilik , Chakravartty Eesha , Mukherji Rajat , Kazeem Saka 
Published: May 2021

Abstract
Background: Studies have shown that poorly-controlled hyperglycemia worsens the outcomes in patients with COVID-19 (C-19) and C-19 may damage pancreatic islets via ACE2 receptors causing acute hyperglycemia. The major population we serve at Kingsbrook Jewish Medical Center (KJMC) are underprivileged with many of them having multiple comorbidities. Methods: This is a retrospective study wherein patients, admitted from February 2020 to April 2020 with hyperglycemia, were selected and divided into 2 groups based on presence or absence of C-19. Data include demographics, comorbidities, blood glucose level, serum osmolality, serum bicarbonate, anion gap, acute kidney injury (AKI), serum creatinine, ICU admission, length of stay (LOS) and mortality. Data were analyzed using descriptive study and T-test. Results: 100 patients were included in the C-19 group (CG) and 88 patients were included in the Non C-19 group (NCG). Major comorbidities were similar in both groups including HTN, DM, CKD followed by ESRD. Mean age of patients (years) was 65.68 in CG and 61.17 in NCG. 61% were male in CG and 53.41% were male in NCG. 16% and 9% developed DKA and HHS in CG, and 13.64% and 6.82% developed DKA and HHS in NCG respectively. 15% in CG had combined DKA & HHS and 3.41% had same in NCG. Mean blood glucose level (mg/dl) was 541.6 in CG and 460.0 in NCG (p=0.03). Mean serum osmolality (mOsm/kg) was 335.7 (SD±41.01) in CG and 317.1 (SD±30.54) in NCG (p=0.01). Mean serum bicarbonate (mEq/L) was 17.73 (SD±6.31) in CG and 21.46 (SD±5.94) in NCG (p&lt;0.0001). Mean anion gap was 17.93 (SD±7.6) in CG and 13.10 (SD±7.2) in NCG (p&lt;0.0001). 56% in CG and 37% in NCG developed AKI respectively (p=0.01). Mean serum creatinine (mg/dl) was 4.22 in CG and 1.65 in NCG (p=0.004). 55% of CG were admitted to ICU and 34% of NCG were admitted to ICU (p=0.003). Median LOS (days) in discharged patients was 8 in CG and 5 in NCG (p=0.02). Mortality was 40% in CG and 3.41% in NCG (p&lt;0.0001). 12 patients in CG and 2 patients in NCG developed new-onset diabetes. In the subset of DKA, interestingly, mean age (years) was 61.63 (SD±17.73) in CG and 39.67 in NCG (SD±13.39) (p=0.001). Conclusion: In our study, patients in the CG carry worse laboratory parameters, unfavorable clinical outcomes and strikingly higher mortality. We discovered increased incidence of new-onset diabetes and elderly DKA in CG. In an inner city population like ours, the burden of DM with significant social and health care disparities is quite severe. Diabetic patients with concurrent C-19 infection can have particularly negative outcomes and C-19 possibly damages the pancreatic islets resulting in acute hyperglycemic crisis. Further research on larger population is required. References: (1)https://dx.doi.org/10.1016%2Fj.diabres.2020.108142(2) https://doi.org/10.2337/dc20-0723(3)https://www.nejm.org/doi/full/10.1056/NEJMc2018688
Efficacy of High-Intensity Intermittent Training for Improving Cardio-Metabolic Health in Women With Polycystic Ovary Syndrome
Authors: Patten Rhiannon Kate , McIlvenna Luke Colin , Hiam Danielle S , Moreno-Asso Alba , Stepto Nigel Keith 
Published: May 2021

Abstract
Polycystic ovary syndrome (PCOS) is a common and complex endocrinopathy with significant metabolic and reproductive manifestations, carrying a major health and economic burden. Consistent improvements in clinical outcomes have been reported as a result of exercise training, but shortfalls with exercise prescription are evident. Research suggests that high-intensity intermittent training (HIIT) is feasible, well tolerated and enjoyable for people with or at risk of chronic disease and can address many of the shortfalls and barriers to exercise participation. To investigate the effects of high-intensity exercise on cardio-metabolic health, twenty-four reproductive aged, overweight or obese, sedentary women with PCOS were recruited from the community and randomised to complete either 12 weeks of moderate intensity continuous cycling training (MICT; 60–65% of maximal heart rate [HRmax]; n=11) or HIIT (90–100% HRmax; n=13). All exercise was supervised by an exercise physiologist and completed 3 times per week on a cycle ergometer. Baseline and post-testing measures consisted of peak oxygen consumption (VO2peak) determined by a graded maximal exercise test, body composition by DXA scan and insulin sensitivity determined by euglycaemic-hyperinsulinaemic clamp. Significant improvements in VO2peak were seen after both HIIT (P &lt;0.001) and MICT (P &lt;0.013) with a significant between-group interaction favouring HIIT (P = 0.014). The insulin sensitivity index significantly improved after HIIT (P = 0.009) with no changes observed after MICT (P = 0.860), also resulting in a significant between-group difference favouring HIIT (P = 0.046). No changes were observed for body weight, BMI or fat mass, however, there was a significant increase in percentage of lean mass after HIIT (P = 0.026). The present study is the first to compare current exercise recommendations of moderate and vigorous intensities in women with PCOS. The results of this study provide preliminary validation of HIIT, suggesting that vigorous intensity exercise should be considered in order to improve cardio-metabolic health in women with PCOS.
How Novel is Dapagliflozin?
Authors: Vachhani Shyamsunder , Das Gautam 
Published: May 2021

Abstract
Introduction: Dapagliflozin is one of the novel class of glucose-lowering agents known as sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. Diabetes Ketoacidosis (DKA) is defined by the triad of hyperglycaemia, anion-gap acidosis, and increased plasma ketones. Euglycemic DKA is an uncommon form of ketoacidosis which is characterized by metabolic acidosis with a pH &lt;7.3 and a serum bicarbonate of &lt;18mEq/L, ketosis, and a blood glucose level of &lt;200 mg/dl. This can be caused by SGLT2 inhibitors. Euglycemic diabetes ketoacidosis is a rare complication that occurs in patient taking SGLT2 inhibitors. Here we describe a patient with euglycemic DKA. The incidence of DKA associated with dapagliflozin has been reported to be &lt; 0.1%.
Case Presentation: This 55 years old gentleman has past medical history of obesity, type 2 diabetes (since age of 27 yrs.), hypercholesterolemia, hypertension and osteoarthritis. He recently suffered from myocardial infarction discharged 2 days back and presented to emergency department with central chest pain radiating to both arms in the morning. ECG reported as normal and venous blood gas showed pH- 7.10, pCo2- 3.84, pO2- 5.54, glucose- 10, lactate-1.8, bicarbonate- 8.5, base excess 19.2, anion gap 25. And dapagliflozin was stopped as a part of discharge planning and followed up in our diabetes clinic. Urine dipstick revealed Glucose +2, ketone +4, pH 5. He was diagnosed to be suffering from euglycemic diabetic ketoacidosis & treated as per protocol. When he recovered from DKA his insulin was optimised and dapagliflozin was stopped as a part of discharge planning and was followed up in our diabetes clinic.
Discussion: In patients on dapagliflozin, cases of euglycemic diabetes ketoacidosis are increasingly being reported. Diagnosis of euglycemic diabetes ketoacidosis can be easily missed in the emergency department due to absence of marked hyperglycemia, often leading to delayed diagnosis and treatment. Mechanism of action of dapagliflozin is by selectively inhibiting the transporter protein SGLT2 in the renal proximal, which prevents glucose reabsorption and subsequently induces the elimination of filtered glucose via urine, the process is known as ‘glycuresis’ which reduces the blood glucose levels. SGLT-2 inhibitors should be initiated by a clinician cautiously and only after adequately weighing the risks and benefits of treatment. It is advisable to do urine test on patient taking dapagliflozin on admission which will help diagnose euglycemic DKA early. To prevent this potentially dangerous complication, patients taking SGLT2 inhibitors who become ill should discontinue the medication, undergo ketone evaluation, and start basal insulin, if ketones are positive. In addition, patients should be educated to stop their SGLT2 inhibitor at least 1 week prior to elective procedures.
A Possible Advantage of Glucagon-Like Peptide 1 Receptor Agonist in Kidney Transplant Recipients With Type 2 Diabetes
Authors: Sato Tetsuhiko , Ohara Emi , Ozone Chikafumi , Okazaki Mikako , Fuse Sachiho , Sasaki Rie , Azuma Yoshinori 
Published: May 2021

Abstract
Diabetic kidney disease (DKD), a devastating complication of diabetes, is one of the leading causes of end stage kidney disease (ESKD). Kidney transplantation provides superior outcomes for ESKD patients with type 2 diabetes, giving opportunities to be free from dialysis, but needs lifetime immunosuppressive medications to avoid graft kidney rejection. Post-transplant hyperglycemia, however, remains to be unsolved, because immunosuppressive agents, including glucocorticoids and calcineurin inhibitors, may result in impaired insulin secretion and sensitivity. Safe and promising anti-diabetic strategy is long-awaited among kidney transplant recipients (KTRs) with type 2 diabetes. Enormous evidence has accumulated that Glucagon-like peptide 1 (GLP-1) receptor agonists have potential to maintain kidney function as well as improve glucose tolerance in patients with DKD. The present study was designed to elucidate the association between GLP-1 receptor agonist use and better graft kidney function in KTRs with type 2 diabetes. Among KTRs with type 2 diabetes between 2012 and 2019, 73 with GLP-1 receptor agonist use and 73 without GLP-1 receptor use were identified in our center. After propensity matching, 50 KTRs were newly initiated with GLP-1 receptor agonist use or other antidiabetic medications. Baseline characteristics were well-balanced in the 2 groups. KTRs with GLP-1 receptor agonist use had greater kidney function 12 months after initiation of GLP-1 receptor agonists, compared to their counterpart KTRs without GLP-1 receptor agonists, according to estimated glomerular filtration ratio (p=0.01). Interestingly, transient decrease of body mass index was observed in KTRs with GLP-1 receptor agonist use during the 12 months. All GLP-1 receptor agonist-initiated KTRs were followed up through December 31, 2019. In conclusion, GLP-1 receptor agonist treatment was associated with better graft kidney function in KTRs with type 2 diabetes. Pharmacological GLP-1 receptor activation showed favorable tolerability and may alleviate graft kidney damage in KTRs with type 2 diabetes.
Clinical Practice Gap Analysis of CKD in T2D From Identification to Diagnosis to Management
Authors: Larkin Amy , Hanley Kelly , Le Anne 
Published: May 2021

Abstract
Understanding clinical practice gaps in the identification, diagnosis and management of CKD in patients with T2D can inform development of tools to improve physician practices. A survey instrument of 25 multiple choice, knowledge- and case-based questions allowed participants to assess their knowledge, attitudes, and confidence with regard to CKD in T2D. The CME-certified activity was available online to physicians across the globe without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. Initial data collection occurred from February 26, 2020, to April 20, 2020. 241 diabetologists/endocrinologists completed the full assessment. Physicians demonstrated gaps in the following areas: Assessment to diagnose kidney disease stage: 47% gap Evidence-based strategies to delay progression of CKD in patients with diabetes: 72% gap SGLT2 inhibitors CVOT data comparisons: 73% gap Results from CREDENCE trial: 43% gap Mechanism of cardiorenal syndrome: 95% gap Link between diabetes, kidney disease, and the cardiorenal syndrome: 42% gap Fibrosis as a component of progression of CKD: 61% gap Knowledge of billing procedure for CKD screening: 64% gap Comparison of safety profiles for approved MRAs: 45% gap Differences in emerging MRAs compared to traditional MRAs: 53% gap Clinical trial data for emerging MRA: 32% gap When asked about satisfaction with current treatment approaches for managing CKD in patients with T2D, 9% selected very satisfied, 75% selected moderately-mostly satisfied, and 17% slightly-not satisfied. This educational research on assessment of physicians’ clinical practices yielded important insights into clinical gaps related to identification, screening, diagnosis, and management of CKD in patients with T2D. Further studies are planned to assess the effect of medical education on decreasing these clinical practice gaps.
Development of the University of Colorado Endocrine ECHO Program
Authors: Lorton Eleanor , Coluzzi Alexandra , Maurer Laura , Pitzer Lauren , Saxon David 
Published: May 2021

Abstract
Background: The Extension for Community Health Outcomes (ECHO) model aims to improve rural community healthcare by providing specialist-lead telementoring for primary care providers (PCPs) in a didactic and discussion-based format.1 There is a notable shortage of endocrinologists in Colorado, particularly in rural and frontier counties. Best estimate is that 14 of 64 Colorado counties have at least one practicing endocrinologist. Here we describe the development and initial experience with an endocrine-specific ECHO program.
Methods: Grant-funding was obtained to develop a longitudinal endocrine ECHO program to support PCPs who care for a large proportion of patients with Medicaid insurance. Program development occurred with input from endocrinologists, primary care physicians, and ECHO Colorado staff. Program participation results in continuous medical education credit. PCP recruitment occurred through listserv emails sent to various Colorado-based medical organizations. Endocrinologists provided weekly hour-long sessions focused on 5 main topic domains: diabetes, obesity/lipids, thyroid disorders, reproductive and adrenal disorders, and bone/calcium disorders.
Results: Our endocrine ECHO program started in August 2020 and consisted of 30 weekly sessions (i.e. 9 diabetes, 8 obesity/lipids, 3 thyroid disorders, 5 reproductive and adrenal disorders, 4 bone/calcium disorders, and 1 pseudo-endocrine disorders). A total of 65 clinicians registered for the ECHO series. Sessions were designed by academic endocrinologists and fellows-in-training at the University of Colorado. During block 1 (diabetes block) there were 45 participants of which 12% practice in rural or frontier designated areas, 80% serve patients with Medicaid, and 42% primarily care for an underserved population. Matched pre/post-surveys asking about PCPs’ confidence with each ECHO session were obtained and final results are currently pending completion of the full series in March 2021. Survey data will inform future iterations of this program which is slated to run annually for at least 3 years.
Conclusion: Access to endocrinologists is often a scarce resource for rural communities and underserved populations. The ECHO model can serve as a means to provide longitudinal education and support for PCPs across a range of endocrine topics. Here we describe our initial experience with a 30-week endocrine ECHO program in Colorado and highlight future directions of this program.