bluuebunny/crossref_metadata_2025 huggingface dataset:
Sodium Glucose Co-Transporter2 (SGLT2) Inhibition for Refractory Hypomagnesemia in Monogenic Diabetes Type 5 (MODY 5)
Authors: Paul Anju A , Korytkowski Mary T
Published: May 2021

Background: MODY 5 is an infrequently reported form of monogenic diabetes attributed to deletions of chromosome 17q12 with impaired expression of HNF1β (Hepatocyte Nuclear Factor 1 Beta). We report a patient who presented with hyperglycemia and hypomagnesemia with an eventual diagnosis of MODY5 that responded to treatment with the SGLT2 inhibitor (SGLT2i), canagliflozin.

Clinical case: A 64-year-old male diagnosed with diabetes at age 60 and treated with glimepiride and metformin (HbA1c 6.1–6.2% without hypoglycemia) presented to establish care. He had a prior history of hypermagnesuric hypomagnesemia (serum Magnesium (Mg) 1.4 ± 0.3 mg/dl with Fractional Excretion of Mg (FEMg) 32 ± 3% [values >3–4% in the setting of normal renal function and hypomagnesemia indicates renal Mg loss]) that developed while taking Triamterene- HCTZ for hypertension, prompting discontinuation. Treatment with oral and intravenous (IV) Magnesium along with Amiloride failed to normalize serum Mg levels. Genetic evaluation revealed 17q12 deletion consistent with a diagnosis of MODY 5. Referral to nephrology resulted in discontinuation of glimepiride and addition of canagliflozin 100 mg titrated to 300 mg daily. Mg levels normalized (serum Mg level 1.9 ± 0.1 mg/dL) within 8 weeks of canagliflozin therapy, allowing discontinuation of IV Mg and patient reported improvement in physical stamina and quality of life. At his 1 year follow up visit, his serum Mg remains stable at 1.8mg/dl with a FEMg of 22 ± 2.5%. His current therapy includes Metformin 2 gm, Canagliflozin 300 mg, Amiloride 10 mg tid, and oral Mg.

Discussion: Prior to introduction of the SGLT2i, MODY 5 patients required oral and IV Mg repletion in combination with amiloride to achieve near normal Mg levels. Several clinical trials with SGLT2i demonstrated dose and agent dependent improvement in Mg levels in patients with type 2 diabetes. Proposed explanations include reductions in eGFR, changes in intraluminal electrical potential, and activation of renin angiotensin aldosterone system. Mg replacement results not only in symptomatic improvement, but has also been demonstrated to reduce risk of stroke and all-cause mortality.

In summary, SGLT2 inhibitors in patients with MODY 5 can be effective in restoring normal Mg levels, improving quality of life, and reducing all cause mortality.
Unfortunate Case of Hypoglycemia Induced Seizures Resulting in Anoxic Encephalopathy
Authors: Nallamothu Kavya , Douedi Steven , Hu Katherine , Ong Raquel , Cheng Jennifer
Published: May 2021

Background: Severe hypoglycemia in patient with diabetes mellitus can manifest as seizures and coma, most commonly occurring after excessive insulin administration.

Clinical Case: A 35-year-old woman with uncontrolled type 1 diabetes mellitus on basal-bolus insulin, complicated by gastroparesis, hypoglycemia unawareness, and frequent hypoglycemic episodes due to a tendency to give more than the recommended amount of insulin, who presented with seizures and diffuse brain edema as severe manifestations of profound hypoglycemia. Hemoglobin A1c was 7.3% but patient had wide variation in blood glucose (40- 300 mmol/L) on her glucometer. Patient had initially self-treated overnight hypoglycemic symptoms by drinking soda and then fell asleep without re-checking her blood sugar. She was then unresponsive in the morning. Patient’s husband reported that there was no glucagon at home since he used the last one and did not refill. On EMS arrival, patient had a blood glucose of 25, for which she received dextrose and glucagon with improvement of blood glucose but no change in mentation. En route to the hospital, patient developed tonic-clonic seizures and decerebrate posturing. She received Ativan and was intubated for airway protection. On exam, she had bilateral dilated sluggishly reactive pupils, eyes opened spontaneously but did not track, and limbs moved spontaneously but there was no purposeful movement. Initial CT head without contrast showed significant diffuse brain edema. Repeat MRI brain with and without contrast showed bilateral basal ganglia diffusion restriction with associated T2 and FLAIR hyperintense signal, suggestive of toxic-metabolic etiology including hypoglycemia. Video EEG showed findings consistent with anoxic encephalopathy. Patient received IV mannitol and IV dexamethasone for cerebral edema and Keppra for seizure prophylaxis, but was unable to be weaned from the ventilator and had to undergo tracheostomy and PEG tube placement, and was eventually discharged to inpatient rehabilitation. Conclusion: This case highlights the dangers of accidental overcorrection of high blood sugar with short-acting insulin and not appropriately treating hypoglycemia, which can lead to irreversible brain injury due to prolonged hypoglycemia. This unfortunate case highlights the importance of educating patients with diabetes mellitus on insulin how to appropriately manage low sugars to avoid such outcomes.
Current Utilization Trends of SGLT-2 Inhibitors in Type 2 Diabetics With Heart Failure
Authors: Dhillon Puneet , Grover Harshwant , Haq Shujaul , Patel Tirth , Sadiq Usama , Tariq Shafaq , Abideen Zain Ul , Rosenberg Daniel , Mallavarapu Vamshi
Published: May 2021

Background: Sodium glucose cotransporter-2 inhibitors (SGLT2 inhibitors) are a recent addition to the armamentarium for treating type 2 diabetes. Over the last couple of years, these agents have been studied in patients with cardiovascular disease, particularly heart failure. Results of the EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), CANVAS (Canagliflozin Cardiovascular Assessment Study) and DECLARE-TIMI (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction) have clearly shown SGLT2 inhibitors to be beneficial for patients with heart failure. FDA has approved Canagliflozin and Dapagliflozin for reduction of risk of adverse cardiovascular events in patients with Type 2 Diabetes with established Cardiovascular disease. This study was conducted to determine the current utilization trends of SGLT2 inhibitors in Type 2 Diabetics admitted with congestive heart failure exacerbation at Abington Memorial Hospital. Methods: The study was an observational retrospective chart review of 287 patients who were admitted to the telemetry floor with an admitting diagnosis of Congestive Heart Failure with a concomitant diagnosis of Type 2 Diabetes from 06/01/2019 to 11/30/2019. 186 patients met the inclusion criteria. Results: Mean age of the patient population was 69 years. Mean ejection fraction was 39%. Mean A1C was 7.7. Out of 186 patients who met the inclusion criteria, 2 patients were on SGLT2 inhibitor on admission and were discharged on it. 1 patient was started on a SGLT2 inhibitor during hospitalization and was discharged on it. Out of our patient population, only 1.6% of the patients were discharged on SGLT2 inhibitor. Conclusion: Even after FDA approval of SGLT-2 inhibitors in reducing heart failure hospitalizations in patients with known history of Type 2 diabetes and heart failure, the utilization of these drugs is very minimal. No other drug has been proven to improve mortality in patients of heart failure with preserved ejection fraction. Based on the results of this study, we propose that initiation of SGLT2 inhibitor should be one of the core measures during discharge of Type 2 Diabetics after a hospitalization with Heart Failure.
Predicting Major Adverse Cardiovascular Events in Asian Type 2 Diabetes Patients With Lasso-Cox Regression
Authors: Rui Lam Amanda Yun , Chan Min Min , Carmody David , Teh Ming Ming , Bee Yong Mong , Hsu Wynne , Lee Mong Li , Ng See Kiong , Ong Marcus Eng Hock
Published: May 2021

Background: South-East Asia has seen a dramatic increase in type 2 diabetes (T2D). Risk prediction models for Major adverse cardiovascular events (MACE) identify patients who may benefit most from intensive prevention strategies. Existing risk prediction models for T2D were developed mainly in Caucasian populations, limiting their generalizability to Asian populations. We developed a Lasso-Cox regression model to predict the 5-year risk of incident MACE in Asian patients with T2DM using data from the largest diabetes registry in Singapore. Methodology: The diabetes registry contained public healthcare data from 9 primary healthcare centers, 4 hospitals and 3 national specialty centers. Data from 120,131 T2D subjects without MACE at baseline, from 2008 to 2018, were used for model development and validation. Patients with less than 5 years of follow-up data were excluded. Lasso-Cox, a semi-parametric variant of the Cox Proportional Hazard Model with l1-regularization, was used to predict individual survival distribution of incident MACE. A total of 69 features within electronic health records, including demographic data, vital signs, laboratory tests, and prescriptions for blood pressure, lipid and glucose-lowering medication were supplied to the model. Regression shrinkage and selection via the lasso method was used to identify variables associated with incident MACE. Identified variables were used to generate individual survival probability curves. Incident MACE was defined as the first occurrence of nonfatal myocardial infarction, nonfatal stroke, and CV disease-related death. Results: A total of 12,535 (10.4%) subjects developed MACE between 2008 and 2018. Model performance was evaluated by time-dependent concordance index and Brier score at 1, 2 and 5 years. The results of 5-fold cross validation shows that the model displayed good discrimination, achieving time-dependent C-statistics of 0.746±0.005, 0.742±0.003 and 0.738±0.002 at 1, 2 and 5 years respectively. The model demonstrated low Brier scores of 0.0355±0.0004, 0.0601±0.0011, 0.104±0.004 at 1, 2 and 5 years respectively, indicating good calibration. Factors most predictive of MACE were age and a history of hypertension and hyperlipidemia. Conclusions: We have developed a risk prediction model for MACE in Asian T2D using a large Singaporean T2D cohort, which can be used to support clinical decision-making. The individual survival probability estimates achieve an average C-statistics of 0.742 and are well-calibrated at 1, 2 and 5 years.
Libre in Inpatient Covid Units
Authors: Pandya Reeni K , Sukkari Mohamad Anas , Olson Darin E
Published: May 2021

Continuous glucose monitors (CGM) have demonstrated accuracy in outpatients and were accurate with pilot data using blinded systems in inpatients. Libre CGMs were approved and donated to hospitalsfor use during the COVID-19 to minimize exposure and PPE use. We made a prospective plan to assess accuracy of the Libre on inpatients admitted to COVID units during an initial “validation phase”. Fingerstick blood glucose (FSBG) was checked for the first three days after placing the sensor and compared to Libre values within the next 1–15 minutes. Patients were instructed to scan the sensor after each FSBG, and at other times as clinically warranted. FSBG values were recorded from the medical record (CPRS) and compared to Libre values downloaded to LibreView. The mean absolute relative difference (MARD) between FSBG and Libre was calculated for each patient for one to three days. The average MARD across all patients was calculated. Accuracy was further assessed using the Bland-Altman Plot and error grid analysis using web-based tool. Of the 21 patients assessed in the validation phase, 19 had at least one day of data and 11 had at least three days. The mean MARD was 11.2% after one day, and 12.5% after three days. Four patients after one day and three patients after three days had a MARD of 15–20% where use of the Libre was continued with confirmatory FSBG. In 15/19 (78%) patients with one day of data and 8/11 (73%) of patients with 3 days of data had a MARD <15% and continued using the Libre without further FSBG. One patient had a MARD >20% that did not improve with changing the sensor, and Libre was discontinued. In 16 of 19 patients, the Libre values were lower than FSBG. No adverse events relating to Libre use were identified. Error grid analysis showed that most patients had no values outside the A and B ranges, and very few values outside of the clinically accurate range, occurring in 2 of the 19 patients (9% of values in the “slight risk” zone in 9% in one and 6% in the other). The Libre was well-accepted by patient and nursing staff, but did not have measurable effect on glycemic control, hypoglycemic events, or hospitalization measures. The libre was deemed a useful intervention in inpatients, but it can be inaccurate or only moderately accurate compared to FSBG in enough patients to require checking accuracy for at least 1–3 days. Inaccurate Libre values were mostly lower than FSBG requiring confirmatory measures of low Libre values with FSBG in our experience.
Publication Model, Ownership and Impact of the Top Endocrinology Journals
Authors: Shamsudeen Isabel , Jain Mehr , Ding Jeffrey , Khosa Faisal
Published: May 2021

Background: Subscription-based (SB) is the traditional publication model for peer-reviewed research; however, open-access (OA) models have been rising in popularity in recent years. Journals may be owned by commercial, professional society, university or government publishers. SCImago Journal Rank (SJR) indicator is a measure of the scientific influence of scholarly journals.

Objectives: The purpose of this study is to assess the publication model, ownership and SJR indicator of the top Endocrinology journals. This will help inform researchers’ decisions when selecting a journal to submit their work to.

Methods: The SCImagoJR website was used to obtain a database of active, peer-reviewed Endocrinology journals worldwide. Publishers were grouped by parent company and categorized as commercial, professional society, university or government. Journals were searched on the National Library of Medicine catalogue to determine whether they are indexed on MEDLINE. Data was analyzed using IBM Statistics version 25. Fischer’s exact test was performed to assess the distribution of publication model and indexing status. Kruskal-Wallis H test was used to assess the distribution of SJR.

Results: 207 Endocrinology journals were included; 134 SB (64.73%) and 73 OA (35.27%). 122 journals are indexed in MEDLINE. The top three publishers of Endocrinology journals are Elsevier, Springer Nature and Wiley, all of which are commercial entities. They collectively own 91/207 (43.96%) Endocrinology journals and 70/122 (57.38%) MEDLINE-indexed journals. The top three publishers own more SB than OA journals, though this difference was not statistically significant (p = 0.080). There was no significant difference in the distribution of indexing status across the top three publishers (p = 0.250) and the four publisher types (p = 0.928). There were significantly more SB than OA journals indexed in MEDLINE (p<0.001). There was no significant difference in the distribution of SJR indicator across the top three publishers (p = 0.283) and publisher types (p = 0.873) (see Table 1). SB journals had significantly higher SJR indicators compared to OA journals (all journals, p = 0.002; indexed journals only, p = 0.013).

CONCLUSIONS: Endocrinology journals are largely controlled by a few commercial entities and are primarily SB. Compared to OA, SB journals have significantly higher SJR indicators, meaning they are more influential. This is an important consideration for researchers when considering where to submit their work.
Identification of Sortilin Alternatively Spliced Variants in 3T3L1 Adipocytes
Authors: Lui Ashley , Patel Rekha , Patel Niketa A
Published: May 2021

Type 2 diabetes mellitus (T2DM) is a chronic and progressive metabolic disease with no cure. Adipocytes play a crucial role in glycemic regulation and take up circulating glucose in response to insulin signaling. In T2DM, translocation of major glucose transporter 4 (Glut4) from cytoplasmic locations to the plasma membrane is impaired. Sortilin is an important constituent of Glut4 storage vesicles and interacts with guiding proteins to determine location of Glut4 in the trans-Golgi network. Sortilin levels are shown to affect adipocyte function. Using mouse 3T3L1 adipocytes, we demonstrate that alternative splicing of sortilin pre-mRNA results in an inclusion of an exon (17b) between exons 17 and 18 in the 10CC motif of the VPS10p domain crucial for ligand interaction. Sort17b expression correlates to insulin resistance and over-expression of Sort17b decreases glucose uptake in adipocytes. Using co-immunoprecipitation assays, we demonstrate that Sort17b is a strong binding partner of Glut4. Using bioinformatic analysis, we show that this insertion results in a novel intrinsically disordered region and has potential sites of proteolytic cleavage. Our study is the first to describe sortilin’s alternatively spliced variants in adipocytes and their effects on glucose uptake. As a broader approach, the research demonstrates the impact of a post-transcriptional event on the metabolic fate of adipocytes in conditions of insulin resistance.
Young Adult LEW.1WR1 Rats Develop Dysregulated Islet Function and Impaired Liver Insulin Responses
Authors: Wilkerson-Vidal Quiana C , Collins Genoah L , Fowler Evann , Wimalarathne Madushika M , Mercado Luis D , Gibson Helen , Martin Sidney C , Love-Rutledge Sharifa Tahirah
Published: May 2021

Obesity in humans can lead to metabolic problems such as glucose intolerance and insulin resistance, which may result from pancreatic islet dysregulation and reduced insulin sensitivity in the liver. LEW.1WR1 (1WR1) rats became more glucose intolerant than LEW/SsNHsd (SsNHsd) rats after 12 weeks on a moderate sucrose diet.1 We hypothesize that the 1WR1 rats develop decreased insulin sensitivity due to impaired islet function and liver responses to insulin. To test this hypothesis we measured blood hormone levels and islet and liver gene expression. The terminal blood insulin (14988+/- 4024 vs. 22703+/-5101 pg/mL; p=0.0085; n=7,7) and glucagon (127.3+/-73.31 vs. 188.6+/-46.87 pg/mL; p=0.0537; n=7,7) were higher in the the 1WR1 rats. Using qRT-PCR, we determined the islets of 1WR1 rats had 3 fold increased insulin (p<0.0001; n=3,3) and glucagon (p<0.0001; n=3,2) relative gene expression. Yet, the β-cell area (22.05+/-6.408 vs. 2.276 +/-1.284mm2; p=0.0016; n=3,4) was significantly reduced in 1WR1 rats. Islet Plin5 expression was upregulated in 1WR1 rats (5.388+/-0.3806 F.C.; p<0.0001; n=3,3) indicating increased lipid droplet production, while Cyclin D (0.5726+/-0.08797 F.C.; p=0.0035; n=3,2) was downregulated indicating decreased cell cycle proliferation. These results indicate that the islets of the 1WR1 rats were insensitive to insulin signaling, which may have been caused by increased lipid droplets and a decrease in compensatory islet area. We also measured the relative expression of insulin-sensitive genes in the liver tissue to determine if there were alterations in liver insulin signaling. Downregulation of Irs-2 (0.5840+/-0.001045 F.C.; p<0.0001; n=7,7) expression was likely caused by the upregulated fat10 gene in 1WR1 rats.2 Fat10 (2315+/-0.01380 F.C.; p<0.0001; n=4,6) expression in the liver was significantly increased. Foxo1 (2.644+/- 0.001211 F.C.; p<0.0001; n=7,7) expression, which is normally reduced by insulin, was upregulated which indicates reduced insulin sensitivity. Upregulated expression of Fgf21 (2.260+/-0.002376 F.C.; p<0.0001; n=6,7), which improves glucose homeostasis, in the liver is why the fasting blood glucose of 1WR1 rats were not significantly different from the SsNHsd rats.1 In conclusion, 1WR1 rats show increasingly impaired metabolism over time. These rats have increased insulin and glucagon levels coupled with liver fat10 overexpression leading to impaired gene regulation of insulin-responsive genes in the liver. These changes synergistically increase susceptibility to pathological obesity and metabolic disease.

References: (1) Collins et al., Journal of the Endocrine Society. 2019 3(S1). (2) Ge, Q. et al., Frontiers in Physiology. 2018; 9(1051): 1–16.
Rates and Predictors of 30-Day Readmission in Adults with Type 1 Diabetes Hospitalized for Diabetic Ketoacidosis in the US: A Nationwide Study
Authors: Shaka Hafeez , Edigin Ehizogie , Akuna Emmanuel , Asemota Iriagbonse , Velazquez Genaro R , Asotibe Jennifer Chiagoziem , Achebe Ikechukwu
Published: May 2021

Introduction: Diabetic ketoacidosis (DKA) is an endocrinological emergency that may be associated with inpatient mortality. This hyperglycemic state is more common in type 1 diabetics (T1DM) as insulin deficiency promotes lipolysis and ketogenesis. Due to the difference in epidemiologic and comorbidity profiles between T1DM and other types of diabetes, it is important to investigate factors affecting this unique group. This study assessed the rate and predictors of readmission in adults with T1DM hospitalized for DKA.

Methods: The National Readmission Database for 2017 was searched for hospitalizations involving persons 18 years or older with T1DM who were principally admitted for DKA from January 1 to November 30, 2017. Patients admitted electively or traumatic admissions were excluded from the analysis. Outcomes assessed were 30-day readmission rates, mortality, length of stay (LOS) and hospitalization charges (THC). Multivariate cox regression model was adapted to identify independent predictors of readmission.

Results: A total of 91,625 hospitalizations involved adult with T1DM for DKA with 91,401 discharged alive. Of the patients discharged alive, the rate of 30-day readmission was 20.2%, involving 18,553 patients. A majority of patients had a principal readmission for DKA. Compared to the index admission, a 30-day readmission was associated with over two times the mortality rate (Risk ratio 2.06, 95% CI: 1.74 - 2.43, p<0.001). Readmission was associated with increased mean LOS in days (1.0, 95% CI: 0.9 - 1.2, p<0.001) and THC in USD (8217, 95% CI: 6940 - 9492, p<0.001). Independent predictors of readmission included female sex (Hazard Ratio [HR]: 1.14, 95% CI: 1.74 - 1.20, p<0.001), discharge against medical advice (HR: 1.54, 95% CI: 1.43 - 1.66, p<0.001), hypertension (HR: 1.28, 95% CI: 1.20 - 1.35, p<0.001), chronic kidney disease (HR: 1.13, 95% CI: 1.04 - 1.22, p<0.001) and anemia (HR: 1.42, 95% CI: 1.34 - 1.51, p<0.001). However, obesity (HR: 0.70, 95% CI: 0.62 - 0.79, p<0.001) and hyperlipidemia (HR: 0.92, 95% CI: 0.87 - 0.98, p=0.007) were associated with lower rate of readmission for DKA.

Conclusion: About a fifth of T1DM patients hospitalized for DKA are readmitted within 30 days of discharge. A 30-day readmission following hospitalization for DKA is associated with higher inpatient mortality in this group. Hypertension, chronic kidney disease, and anemia are amongst the predictors of readmission in patients with DKA. However, comorbid obesity and hyperlipidemia were associated with lower rates of readmissions. Healthcare utilization costs are significantly higher in readmitted patients compared to index admissions for DKA. Efforts should be channeled towards identifying these predictors in hospitalized patients as well as proper discharge planning to decrease the burden of readmissions.
Clinical Utility of 30-Min Postload Plasma Glucose in Paediatric Obesity
Authors: Poon Sarah Wing-yiu , Tung Joanna Yuet-ling
Published: May 2021

Introduction: Intermediary glucose measurements at other time points in a standard 2-hour oral glucose tolerance test (OGTT) is increasingly being investigated, and a number of studies have demonstated strong predictive value of 1-hour plasma glucose (PG) in identifying subjects with high risk of future diabetes and vascular complications. The association between 30-minute PG and incidence of diabetes is less extensively studied and all the suggested 30-minute PG cutoff values in current literature are derived from adult population. Our study aimed to evaluate the optimal cutoff value of 30-minute PG in predicting abnormal OGTT (prediabetes/diabetes) in a cohort of paediatric subjects with overweight or obesity. Since 30-minute PG could be easily performed even in a busy clinic setting, such cutoff allows clinicians identify high risk subjects who should proceed to a 2-hour OGTT.

Methods: Record of 332 paediatric subjects with overweight/obesity who had OGTT done in a tertiary unit from January 2012 to December 2018 was reviewed. Standard OGTT was performed and blood samples for PG and insulin were obtained at 0 minute, 30 minutes and 120 minutes. Subjects with prediabetic and diabetic response were considered together as a group (abnormal OGTT group) for statistical analysis. 30-min PG and insulinogenic index (IGI) were compared, and 30-min PG cutoff which predicts abnormal OGTT response was derived.

Results: Our cohort consists of 97.3% Chinese with mean age of 15.4 ± 2.3 years and mean BMI z-score of 2.7 ± 0.6. Sixty subjects (18.1%) had abnormal OGTT – out of which 47 (14.2%) and 13 (3.9%) had prediabetes and diabetes range of glycaemic response respectively. 30-minute PG was statistically higher in the abnormal OGTT group compared to the normal OGTT group (9.6 vs 7.9 mmol/L, p=0.001). IGI was statistically lower in the abnormal OGTT group compared to the normal group (262.1 vs 377.2, p=0003). 30-min PG ≥ 9.2 mmol/L predicts abnormal OGTT with best combination of sensitivity and specficity (AUC 0.77, sensitivty 62.1%, specificity 83.7%).

Conclusion: Children with abnormal OGTT reseponse showed impaired first phase insulin secretion suggestive of beta-cell loss. Instead of performing a 2-hour OGTT in every child referred for obesity, 30-min PG, with a cutoff value of 9.2mmol/L, could be used as a stratification tool in identifying high risk subjects who should return for a 2-hour OGTT in another visit.
HOMA-IR Levels in US Youth Ages 12–18 Years From 1999–2018
Authors: Thaker Vidhu V , Deng Shuliang , Zhou Chuhan , West Brady , Si Yajuan , Fennoy Ilene
Published: May 2021

Introduction: The Homeostasis Model Assessment of insulin resistance (HOMA-IR) is a validated surrogate measure of insulin sensitivity and beta-cell function for epidemiological studies. Insulin resistance is closely associated with obesity and shares dysmetabolic state with other cardiometabolic risk factors. The aim of this study was to analyze the change in HOMA-IR levels in US youth from 1999 to 2018.

Methods: Serial cross-sectional data of fasting insulin and glucose levels measured in youth aged 12 to 18 years enrolled in National Health and Nutrition Examination Surveys representative of US population from 1999 to 2018 were used. Two-year survey cycles were combined to derive 4-year survey periods, and NHANES recommended adjustments were made for glucose and insulin levels for forward conversion to 2017–18 instrument levels. Median HOMA-IR was compared across the survey periods in subgroups by age, gender, race/ethnicity and levels of obesity. Association of HOMA-IR with selected cardiometabolic risk factors was assessed. Change of HOMA-IR levels were analyzed using design adjusted multivariable regression models, association of HOMA-IR with cardiometabolic risk factors was assessed and percentiles were derived.

Results: In an analysis of 5,541 youth, the unadjusted median HOMA-IR increased from 1.83 (95% CI 1.77–1.89) in 1999-02 to 2.41 (95% CI 2.29–2.54) in 2007–10 and has remained in this range till 2015–18. Youth with obesity (Body mass index > 95th percentile or waist circumference > 90th percentile), female gender, those of Hispanic and Black origin, and those aged 12–16 years had higher levels of HOMA-IR (p <.001). While adjusting for age category, sex, race/ethnicity, obesity represented by waist circumference z-score with its quadratic term and interaction with gender, HOMA-IR increased by 26% (95% CI 15–37) in 2015–18 as compared to 1999-02. For waist-circumference z-score (WCZ) > 1, the HOMA-IR levels were higher in boys compared to girls. The addition of total body fat from DXA scans in the model, when available, explained the variance related to gender, but not the interaction between gender and WCZ. No change was observed in the higher levels of HOMA-IR by ethnicity when high sensitivity CRP level as a measure of inflammation was added to the model. There was a positive association of HOMA-IR with triglycerides (29 %/unit, 95% CI 25–33), non-HDL cholesterol (8 %/unit, 95% CI 6–10), systolic blood pressure (2% /unit, 95% CI 1–2) and alanine transferase (11 %/unit, 95% CI 8–14) while controlling for age, sex, race/ethnicity, obesity and survey period. In youth with BMI between 5-85th percentile, HOMA-IR decreased with increase in age from 12 to 18 years.

Conclusions: HOMA-IR levels in US youth have increased since 1999-02 and may herald future cardiometabolic risks.
Reconsidering the Basal Proportion of Insulin Dose: Glycemic and Microvascular Outcomes in Type 1 Diabetes Mellitus
Authors: Pozos-Varela Francisco Javier , Mena-Ureta Tania Sofía , Lam-Chung César Ernesto , Ibarra-Salce Raúl , Martínez-Zavala Néstor , Janka-Zires Marcela , Almeda-Valdes Paloma
Published: May 2021

Optimal glycemic control is required to lower the risk of complications in type 1 diabetes mellitus (T1DM). This can be achieved with multiple daily insulin injections (MDI) or with continuous subcutaneous insulin infusion (CSII). Most diabetes guidelines recommend a proportion of basal insulin (basal proportion of total insulin dose; %B/T) around 50% of the total daily dose (TDD), although there is scarce evidence that suggests that a lower %B/T is associated with lower HbA1c levels. Our objective was to evaluate the association of the %B/T with glycemic and microvascular outcomes. We included 132 T1DM adults of the Diabetes Clinic in a tertiary care center, 117 (88.6%) using MDI and 15 (11.4%) using CSII. Data from the medical records and insulin pumps software during outpatient visits were retrospectively collected. Individuals with end-stage renal disease, solid-organ transplant, pregnancy, and glucocorticoid use were excluded. A positive correlation between %B/T and HbA1c levels was found, r=0.26 (p=0.002). Three groups were analyzed according to the %B/T: ≤40%, 41–59% and ≥60%, observing differences in HbA1c concentrations: 7.1% (6.7–8.0%), 7.8% (7.2–9.1%) and 8.7% (7.6–10.2%), respectively (p=0.003). Regarding microvascular complications, the cases of nephropathy were 0 (0%), 23 (30.7%) and 18 (40%) across those groups (p=0.029) even though there was no difference in T1DM duration across groups. There were also no differences in body mass index, TDD, TDD/weight (units/kg/day), nor in the rates of retinopathy or neuropathy. Multiple regression analysis identified %B/T as an independent predictor of the HbA1c concentration. A difference in the rates of hypoglycemic episodes per month was found among individuals with a %B/T ≤50%: 2 (1–5) versus 6 (2.5–12) episodes per month in those having a higher %BT (p=0.002). There are limitations in our study, including the retrospective nature of the analysis, no data about meal content and a low usage of CGM (thus relying on variable self-monitoring of blood glucose). Therefore, we cannot asseverate that lowering the %B/T would improve glycemic and microvascular outcomes. Nevertheless, our findings indicate that the %B/T correlates with HbA1c levels and are consistent with those previously described. It also suggests a relationship with hypoglycemia and to the best of our knowledge, it is the first time that an association between %B/T and nephropathy has been noted.
Should Target Glucose Values Be Increased to Avoid Severe Hypoglycemia? Real-World Data Say “No.”
Authors: Welsh John , Dowd Robert , Price David A
Published: May 2021

Early studies such as the Diabetes Control and Complications Trial showed a strong inverse relationship between A1C and the risk of severe hypoglycemia in type 1 diabetes. This risk has historically limited insulin therapy intensification efforts, and some treatment guidelines (e.g., Rosenzweig et al., J Clin Endocrinol Metab 105:969, 2020) suggest that A1C values <7% confer an increased risk of hypoglycemia. Nowadays, real-time continuous glucose monitoring (CGM) systems can flatten and attenuate the relationship between overall glucose control and hypoglycemia (Oliver et al., Diabetes Care 43:53, 2020). The glucose management indicator (GMI) is an estimate of A1C derived from the CGM system’s mean estimated glucose value (EGV) (Bergenstal et al., Diabetes Care 41:2275, 2018). We analyzed real-world evidence of the relationship between the GMI and exposure to hypoglycemia. Data were from an anonymized convenience sample of US-based users of the G6 CGM system (Dexcom, Inc., San Diego, CA) who used a mobile device to upload EGVs in the third quarter of 2020. Only data from people who had uploaded ≥80% of possible values were included. Each person’s GMI was calculated as GMI = 3.31 + (0.02392 × mean EGV [mg/dL]). Each person’s exposure to hypoglycemia was estimated as the percentage of EGVs <70 mg/dL or <54 mg/dL (%<70 and %<54, respectively). Patients were grouped into 6 categories according to GMI values <6.5%, 6.5 to 6.9%, 7.0 to 7.4%, 7.5 to 7.9%, 8.0 to 8.4%, and ≥8.5%. Mean %<70 mg/dL and %<54 mg/dL were both inversely correlated with GMI, decreasing monotonically as the GMI category increased. GMI category, %<70, and %<54 are as follows: (<6.5%: 5.27%, 1.13%); (6.5 to 6.9%: 2.84%, 0.59%); (7.0 to 7.4%: 1.95%, 0.41%); (7.5 to 7.9%: 1.46%, 0.31%); (8.0 to 8.4%: 1.14%, 0.25%); (≥8.5%: 0.69%, 0.17%). However, in all GMI categories except for the “<6.5%” category, the extent of hypoglycemic exposure was below the consensus targets proposed by Battelino et al. (Diabetes Care 42:1593, 2019) of <4% for EGVs <70 mg/dL and <1% for EGVs <54 mg/dL. The approach of elevating A1C targets to reduce hypoglycemia risk is not supported by real-world evidence for CGM users who have GMI or A1C values ≥6.5%. CGM users can safely strive for A1C values <7.0%.
Response to Twin Enabled Precision Treatment for Reversing Diabetes: An Initial Analysis at 4 Weeks of the Ongoing Randomised Controlled Trial
Authors: Shamanna Paramesh , Dharmalingam Mala , Vadavi Arun , Mohammed Jahangir , Poon Terrence , Thajudeen Mohamed , Keshavamurthy Ashok , Bhonsley Suchitra
Published: May 2021

Introduction: Technology enabled precision nutrition, a combination of macro, micro and biota nutrients, along with Continuous Glucose Monitoring (CGM) have been demonstrated to be a key for reversal of diabetes.

Methods: We conducted an initial analysis (n=23) of the ongoing randomized controlled trial of Twin Precision Treatment (TPT): a novel whole-body digital twin enabled precision treatment for reversing diabetes. The clinical and the biochemical parameters were evaluated as the longitudinal follow up at the first follow up visit at 4 weeks. The target sample size is 300 with an estimated duration of 5 years. Descriptive statistics were used

Results: 8/23 (35%) patients achieved the intended outcome of reversal of HbA1c and off any anti-diabetic medications. There was a statistically significant improvement in HbA1c % (8.5 ± 1.6 to 6.8 ± 0.66; p<0.0001), Fasting Blood Glucose mg/dL (FBS) (151 ± 44 to 98 ± 18; p<0.0001), HOMA2-IR (1.7 ± 0.64 to 1 ± 0.45; p=0.0001), HOMA2-Beta (53 ± 28 to 86 ± 38; p=0.0013), Systolic BP (129 ± 11 to 120 ± 11; p=0.008) and serum albumin g/dL (4.5 ± 0.21 to 4.2 ± 0.31; p=0.0042). The baseline values for the other parameters including body weight, waist circumference, Diastolic BP, Alanine transaminase (ALT), Gamma-glutamyl transferase (GGT), eGFR, WBC, Platelet, Globulin, ESR, demonstrated a clinically relevant, superior change

Discussion: The initial analysis for the prospectively designed trial reveals a remarkable improvement in the clinical and the biochemical parameters that would determine the complete and the prolonged remission of diabetes. The initial results are an early indicator for the translation of the scientific rationale for the technological intervention, through digital twin technology, powered by Internet of Things (IoT) and Artificial Intelligence (AI), as a modality to enable reversal of diabetes into an achievable outcome that would be durable. The impactful glycemic control appears to have positive meaningful metabolic health consequences

Trial Registration: The trial has been prospectively registered in Clinical Trial Registry – India: Reference no. CTRI/2020/08/027072 on August 10, 2020
Artemisinin and the Derivatives Play Novel Role in Treatment for Graves’ Orbitopathy as Conventional Antimalarials
Authors: Guo Yan , Li Yanbing
Published: May 2021

Context: Graves’ orbitopathy (GO) an autoimmune disease in orbit, characterized with proptosis due to excessive proliferation, adipogenesis, fibrosis and hyaluronan secretion of orbital fibroblasts (OFs). OFs is potential to be a target for proptosis. But there are few effective therapies. Objectives: Our present purpose was to evaluate the effects of artemisinin (ARS) and the derivatives dihydroartemisinin (DHA), artesunate (ART) on OFs from GO patients in vitro. Design/Setting/Participants: OFs isolated from patients with GO (n = 10) were allowed to proliferate in the proliferation medium (PM); differentiate into adipocytes in the differentiation medium (DM) or differentiate into myofibroblast stimulated by TGF-β (10ng/ml); or produce hyaluronan stimulated by IL-1β (5ng/ml). Different dosages of ARS and the derivatives were administered in the above conditions. Main Outcome Measures: CCK-8 was used to assessed cell viability of OFs, EdU incorporation and flow cytometry were conducted to assess cellular proliferation. Adipogenesis was determined by Western blot and Oil Red O staining. Hyaluronan was quantified by ELISA. Fibrosis was assessed using Western blot. Results: ARS in concentrations lower than 100 μM, DHA < 20 μM and ART < 10 μM are nontoxic for OFs. Cellular proliferation of GO-OFs was halted by ARS and its derivatives at the maximum nontoxic dosage. ARS and its derivatives exerted an inhibitory action on adipogenesis of OFs in a concentration-dependent manner.

Moreover, hyaluronan secretion was obviously decreased by ARS and its derivatives. Intriguingly, fibrosis markers were also decreased by the antimalarias in a dosage-dependent way. Conclusions: We elucidated the efficacies of ARS and its derivatives on proliferation, adipogenesis, fibrosis and hyaluronan production of OFs, supporting that ARS-based antimalarials play potential role as a novel therapy for GO from a perspective of in-vitro study.
Bisphenol A and S, but Not F, Alter Oxidative Stress Levels in Spermatozoa
Authors: Nguyen Mimi , Sabry Reem , St. John ., Elizabeth J , Favetta Laura A
Published: May 2021

Exposures to endocrine disrupting compounds (EDCs) have been linked to male reproductive dysfunction. The increase in prevalence of male infertility to date has been correlated with the widespread use of bisphenols, particularly bisphenol A and its analogs. Current literature suggests that exposure to EDCs is associated with abnormalities in spermatogenesis, as well as reduced sperm motility and morphology. At this time, the mechanism for bisphenols’ action in spermatozoa is still unknown, though it has been proposed that bisphenols alter sperm parameters by affecting their oxidative stress pathways. The aim of this project is to elucidate whether BPA and its analogs affect oxidative stress levels inducing decreased sperm quality and fertilization capability. An in vitro bovine model was used as the most appropriate translational model to humans. Motile spermatozoa were separated using Percoll gradient centrifugation of frozen-thawed sperm and a pilot experiment was conducted in a time-dependent manner to establish the ideal incubation time of 4 hours. Sperm was then incubated in five treatment groups: control, vehicle (0.01% ethanol), BPA, BPS, and BPF, at the physiological relevant dose of 0.05 mg/ml in 0.01% ethanol. Key reactive oxygen species (ROS) scavenger genes (superoxide mutase 1 [SOD1], superoxide mutase 2 [SOD2], catalase [CAT], glutathione peroxidase 1 [GPX1], glutathione peroxidase 4 [GPX4]) were quantified at the RNA level using qPCR. Of the five genes examined: BPA, BPS, and BPF exposure significantly decreased GPX4 expression (p<0.05) compared to control and vehicle groups. BPA and BPS exposure significantly increased SOD1 expression compared to BPF, control, and vehicle (p<0.05). No significant differences were found in GPX1 after bisphenols’ exposure. SOD2 and CAT expression was not detectable in all five groups suggesting a lack of expression in bovine sperm. Future investigations will involve experiments at the protein level and quantifying total ROS levels. Additionally, sperm morphology was evaluated using Spermac stain. Preliminary results indicate an increased number of abnormal spermatozoa with notably tail defects after 4 hours of bisphenols exposure. These initial findings support BPA and BPS’s ability to alter oxidative stress pathways in sperm via changes in antioxidant enzymes but suggest that BPF likely acts through different mechanisms. Overall, this research aims to understand the effects of bisphenols on male fertility to improve male factors during assisted reproductive biotechnologies.
Hyperthermia as a Steroidogenic Inhibitor of Adrenodortical Cells, an Adrenal Sparing Treatment for Primary Aldosteronism?
Authors: Donlon Padraig T , Mullen Nathan , Warde Kate , O’Shea Paula M , O’Halloran Martin , Prakash Punit , Dennedy Michael Conall
Published: May 2021

Introduction: Primary Aldosteronism (PA) is the commonest secondary cause of hypertension. Mainstay therapy, adrenalectomy resects both hypersecreting and adjacent normal tissue. It is therefore only suitable for patients with unilateral disease (40% cases), whom are surgical candidates. Thermal therapy presents a plausible minimally invasive therapeutic, to target and disrupt hypersecreting adrenal nodules in primary aldosteronism, while also preserving adjacent normal adrenal cortex.

Methodology: Adrenocortical cell lines (H295R and HAC15) were treated with hyperthermia using a water bath at temperatures between 37-650C for 15 minutes. Cell death and apoptosis were analysed immediately, 24 hours, and 48 hours post hyperthermia using Annexin V / Propidium Iodide (PI) (flow cytometry), and Calcein / PI imaging techniques. Steroidogenic potential was also analysed post hyperthermia by (i) measuring cytosolic calcium flux in response to angiotensin II (ANGII) using Flou-4 staining (flow cytometry); (ii) measurement of steroidogenic enzyme expression (RT-PCR); (iii) by measurement of cortisol and aldosterone in cell supernatants (chemiluminescent assays). Cells were also stimulated with forskolin for steroid enzyme and output assays.

Results: Hyperthermia induced mainly necrotic cell death not apoptotic. Percentage cell death was significantly increased from 500C-65 0C (95.41+/- 5.74% versus control 9.17+/- 3.01%, p<0.0001). Cytosolic calcium changes in response to ANGII were lowered from 550C-650C in H295R (-36.33+/-7.06 Ca+ Response versus control 10.67+/- 1.76 Ca+ Response, p<0.001) and from 450C-650C in HAC15 (-43.33+/-12.36 Ca+ Response versus control 4.43+/-1.57 Ca+ Response, p<0.002), intracellular stored calcium was also diminished with increased hyperthermia exposures in both cell lines. CYP11B1 (-31.6+/-2.8 ααCt versus control, p<0.0001), CYP11B2 (-11.3+/-4.9 ααCt versus control, p<0.0001), and HSD3B2 (-42+/-9.8 ααCt versus control, p<0.0001) enzyme gene expression was decreased following 450C for 15 minutes in HAC15 cells while only CYP11B2 (-9.3+/-2.5 ααCt versus control, p<0.0001), and HSD3B2 (-15+/-1.3 ααCt versus control, p<0.0001) enzyme gene expression was decreased in H295R cells. Steroid output was also shown to be impaired at 450C for 15 minutes (22.35+/- 4.49 nmol/L versus control 117.7+/- 25 nmol/L, p<0.0001).

Conclusion: Hyperthermic therapy delivered at sublethal temperatures and exposure times inhibits steroidogenesis. Inhibiting steroidogenesis by applying targeted thermal therapy to functional adrenocortical nodules represents a novel adrenal sparing approach to definitive management of primary aldosteronism.
Monte Carlo Test for Stochastic Trend in Space State Models for the Location-Scale Family
Authors: Silva Ivair Ramos , Ernesto Dulcidia , Oliveira Fernando , Marques Reinaldo , Oliveira Anderson
Published: May 2021

In space state models for time series, a key point is the decision between modeling the trend of non-stationary processes through a deterministic or a stochastic term. The present paper introduces a Monte Carlo hypothesis test procedure to guide in such a decision. The method works for any time series distribution belonging to the location-scale family. The proposed method provides an alpha-level test for any time series of length greater than 3 and it does not demand assumptions on the distribution of the trend term when it is actually stochastic.
Do extended school day programs affect performance in college admission tests?
Authors: Araujo Daniel , Bayma Guilherme , Melo Carolina , Mendonça Milena , Sampaio Luciano
Published: May 2021

We assess the effects of a Brazilian extended high school day program on college admission test scores. The program entails an increase in Math/Science and Language class time, and the introduction of extra-class activity time. We exploit variation in program implementation timing to apply a difference-in-differences strategy and an event-study approach. Results show positive large effects on test scores and suggest that these effects are likely driven by increased class and extra-class activity hours. Moreover, the program affects not only scores in subjects for which it contemplates increased class time, but also in Humanities. Finally, we are able to show that increased time dedicated to academic-related extra-class activities works as a multiplier of program effects. In fact, these additional hours spent in complementary activities make the magnitude of program effects double from 0.092-0.150 to 0.180-0.317 standard deviation.