Nephroprotective Effects of Dapagliflozin in Patients with Type 2 Diabetes.

Objective This study analyzed changes in the estimated glomerular filtration rate calculated using cystatin C (eGFRcys) and sodium excretion in the urine after administering dapagliflozin as an add-on therapy to conventional treatment for diabetes. Methods This was a single-center, single-group, prospective interventional study. Dapagliflozin was administered to improve the plasma glucose control in 30 subjects with type 2 diabetes mellitus (age 53±8 years old; 66.6% men). Blood and urine tests were performed before and 6 and 12 months after dapagliflozin administration. The daily sodium excretion was estimated with the Kawasaki formula using second-morning urine samples. Results The eGFRcys did not markedly differ before and 6 months after the dapagliflozin administration but was significantly increased after 12 months (p<0.001), and the estimated daily sodium excretion was also significantly increased (p<0.001 at 6 months and p=0.002 at 12 months). The systolic and diastolic blood pressures tended to decrease after administration. The HbA1c level after the administration of dapagliflozin tended to be lower in the T3 group, showing the smallest increase in changes in the estimated daily sodium excretion from baseline to 6 months (28.2-107.5 mEq/day), than in the combined groups of T1 (219.5-110.1 mEq/day) and T2 (101.4-28.9 mEq/day). In contrast, the eGFRcys was significantly higher in the combined groups of T1 and T2 than that in the T3 group at both 6 and 12 months (p=0.031 and p=0.007, respectively). Conclusions Add-on therapy with dapagliflozin increased the urinary sodium excretion and decreased the blood pressure even in the early phase of this therapy. Our results suggest that dapagliflozin add-on therapy may exert nephroprotective effects in subjects with type 2 diabetes mellitus.

Hematocrit elevation after SGLT2 inhibitor administration may be associated with the degree of proximal tubular damage.

The renal protective effects of SGLT2 inhibitors are known to be due to the elimination of glomerular hypertension and improvement of hypoxia and oxidative stress in the proximal tubule. Therefore, this increased hematocrit (ΔHct) level has been hypothesized to indicate restored tubular function and improved renal prognosis. To analyze the relationship between ΔHct and decreased estimated glomerular filtration rate (eGFR) after SGLT2 inhibitor administration backward from medical record data. Data from 206 patients who continued SGLT2 inhibitors for >3 years were analyzed. The decreased eGFR after administration of SGLT2 inhibitors was defined as Slope B. Factors statistically significantly associated with Slope B in multiple regression analysis were systolic blood pressure (sBP) (ß -.211, P = .03), short-term decreased eGFR after SGLT2 inhibitor administration (initial dip) (ß -.235, P = .003), ΔHct (ß -.185, P = .026), and urine protein (ß -.204, P = .015). These findings were the opposite of our hypothesis. ΔHct was not a marker indicating improved renal prognosis and may reflect the extent of the proximal tubular disorder before administering SGLT2 inhibitors.

Machine learning approach to predict subtypes of primary aldosteronism is helpful to estimate indication of adrenal vein sampling.

INTRODUCTION: Primary aldosteronism (PA) is a common disease. Especially in unilateral PA (UPA), the risk of cardiovascular disease is high and proper localization is important. Adrenal vein sampling (AVS) is commonly used to localize PA, but its availability is limited. Therefore, it is important to predict the unilateral or bilateral PA and to choose the appropriate cases for AVS or watchful observation. AIM: The purpose of this study is to develop a model using machine learning to predict bilateral or unilateral PA to extract cases for AVS or watchful observation. METHODS: We retrospectively analyzed 154 patients diagnosed with PA and who underwent AVS at our hospital between January 2010 and June 2021. Based on machine learning, we determined predictors of PA subtypes diagnosis from the results of blood and loading tests. RESULTS: The accuracy of the machine learning was 88% and the top predictors of the UPA were plasma aldosterone concentration after the saline infusion test, aldosterone to renin ratio after the captopril challenge test, serum potassium and aldosterone-to-renin ratio. By using these factors, the accuracy, sensitivity, specificity and the area under the curve (AUC) were 91%, 70%, 99% and 0.91, respectively. Furthermore, we examined the surgical outcomes of UPA and found that the group diagnosed as unilateral by the predictors showed improvement in clinical findings, while the group diagnosed as bilateral by the predictors showed no improvement. CONCLUSION: Our predictive model based on machine learning can support to choose the performance of adrenal vein sampling or watchful observation.

Impact of gender differences on lifestyle and glycemic control in Japanese patients with diabetes during COVID-19 lockdowns.

AIMS: The COVID-19 pandemic has drastically changed global lifestyles. Some reports about lifestyle changes during this pandemic have been published. However, these studies have not assessed gender differences. Thus, we analyzed three lifestyle changes to determine gender differences. METHODS: We analyzed physical activity, snacking habits, and drinking habits in 323 patients with diabetes. Gender differences in lifestyle habits were analyzed using the ꭓ2 test, and comparisons of HbA1c between 2019 and 2020 were analyzed using the paired t-test. The factors that influenced the deterioration of HbA1c were determined using multivariate logistic regression analyses. RESULTS: Of the 323 patients, 212 were male and 111 were female. When examined by quarter, the HbA1c values increased significantly in 2020 compared with that in 2019 in the July-September period. In terms of gender differences in the changes of lifestyle habits, decreased physical activity was higher in women. The factors that affected deterioration in HbA1c were snacking habits for the overall and the male populations. CONCLUSIONS: The lifestyle changes differed between the genders during the pandemic. A balanced diet is important for all patients with diabetes. Additionally, more attention should be paid to physical inactivity in women.

A cross-sectional study of the correlation between diabetic therapy and serum zinc concentrations.

AIM: Zinc, an essential trace element, has various functions in humans. Zinc deficiency is associated with the elderly, patients with diabetes, and patients with frailty, a common geriatric syndrome. As few studies have reported the effects of anti-diabetic medication on zinc levels, we examined serum zinc concentrations in patients with diabetes and their correlation with anti-diabetic medications, especially in the elderly and patients with frailty, in Japan. METHODS: This cross-sectional study was conducted in 2014 and included 1033 patients with diabetes. Blood samples were taken, and a survey for the 8-item Short Form Health Survey of the Medical Outcomes Study was conducted. RESULTS: Because of renal dysfunction (with an estimated glomerular filtration rate of < 60 mL/min/1.73 m2), 337 patients out of 1033 were excluded. Hypozincemia was observed in 43.8% of the patients with diabetes. In 177 elderly patients with a low physical component summary score, multivariable logistic regression analysis revealed two anti-diabetic medications associated with hypozincemia: GLP-1RA (multivariable-adjusted odds ratio [OR] 0.08, 95% confidence interval [CI] 0.010-0.657, p = 0.019) and metformin (OR 0.415, 95% CI 0.222-0.774, p = 0.006). In addition, metformin had a dose-dependent correlation with zinc levels (R = 0.3067, p < 0.0001). CONCLUSIONS: Oral administration of metformin in the elderly with diabetes and non-progressive renal dysfunction was not associated with hypozincemia, even at high doses. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00521-6.

A case of diabetic ketoacidosis in a patient with COVID-19 and newly diagnosed type 1 diabetes.

To improve severe ketoacidosis with COVID-19, insulin treatment, invasive mechanical ventilation therapy, and continuous hemodiafiltration with sodium bicarbonate infusion were effective.

Critical review of IgG4-related hypophysitis.

PURPOSE: IgG4-related hypophysitis is a rare disease, with only 34 cases published in English (2015). Available short reviews may not present complete details of IgG4-related hypophysitis. We aimed to survey case reports of IgG4-related hypophysitis, including abstracts of scientific meetings, in English and Japanese. METHODS: We searched for information about IgG4-related hypophysitis in PubMed and Igakuchuozasshi (Japan Medical Abstracts Society). Among 104 case reports found, we reviewed 84 fulfilling Leporati's diagnostic criteria. RESULTS: The mean ±  SD age of onset was 64.2  ±  13.9, 67.5  ±  9.8, and 56.4  ±  18.6 years for all subjects, men, and women, respectively. Men:women was 2.4:1. On magnetic resonance imaging, pituitary, stalk, and pituitary-stalk mass were observed at frequencies of 14.3, 21.4, and 64.3%, respectively. Manifestations were anterior hypopituitarism in 26.2% (22 cases), central diabetes insipidus in 17.9% (15 cases), and panhypopituitarism in 52.4% (44 cases). The median level of serum IgG4 was 264.5 mg/dL for all subjects, 405 mg/dL for men, and 226 mg/dL for women. The mean number of IgG4-related systemic diseases was 2.7  ±  1.5 in all subjects, 3.0  ±  1.5 in men, and 1.8  ±  1.1 in women. Among the IgG4-related diseases, retroperitoneal fibrosis was the most frequent (26.2%), followed by salivary gland diseases (25%). Glucocorticoid therapy was generally effective, except for two cases that received replacement doses. There were significant differences between sexes in terms of age, serum IgG4 levels, and number of IgG4-related diseases. CONCLUSION: IgG4-related hypophysitis may have different clinical characteristics between genders. This survey may lack some information because the Japanese abstracts did not contain certain details.

Correction: Correlation between Serum Levels of 3,3',5'-Triiodothyronine and Thyroid Hormones Measured by Liquid Chromatography-Tandem Mass Spectrometry and Immunoassay.

[This corrects the article DOI: 10.1371/journal.pone.0138864.].

Correlation between Serum Levels of 3,3',5'-Triiodothyronine and Thyroid Hormones Measured by Liquid Chromatography-Tandem Mass Spectrometry and Immunoassay.

OBJECTIVE: For measuring serum 3,3',5'-triiodothyronine (rT3) levels, radioimmunoassay (RIA) has traditionally been used owing to the lack of other reliable methods; however, it has recently become difficult to perform. Meanwhile, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has recently been attracting attention as a novel alternative method in clinical chemistry. To the best of our knowledge, there are no studies to date comparing results of the quantification of human serum rT3 between LC-MS/MS and RIA. We therefore examined the feasibility of LC-MS/MS as a novel alternative method for measuring serum rT3, thyroxine (T4), and 3,5,3'-triiodothyronine (T3) levels. METHODS: Assay validation was performed by LC-MS/MS using quality control samples of rT3, T4, and T3 at 4 various concentrations which were prepared from reference compounds. Serum samples of 50 outpatients in our department were quantified both by LC-MS/MS and conventional immunoassay for rT3, T4, and T3. Correlation coefficients between the 2 measurement methods were statistically analyzed respectively. RESULTS: Matrix effects were not observed with our method. Intra-day and inter-day precisions were less than 10.8% and 9.6% for each analyte at each quality control level, respectively. Intra-day and inter-day accuracies were between 96.2% and 110%, and between 98.3% and 108.6%, respectively. The lower limit of quantification was 0.05 ng/mL. Strong correlations were observed between the 2 measurement methods (correlation coefficient, T4: 0.976, p < 0.001; T3: 0.912, p < 0.001; rT3: 0.928, p < 0.001). CONCLUSIONS: Our LC-MS/MS system requires no manual cleanup operation, and the process after application of a sample is fully automated; furthermore, it was found to be highly sensitive, and superior in both precision and accuracy. The correlation between the 2 methods over a wide range of concentrations was strong. LC-MS/MS is therefore expected to become a useful tool for clinical diagnosis and research.

Positional cloning of "Lisch-Like", a candidate modifier of susceptibility to type 2 diabetes in mice.

In 404 Lep(ob/ob) F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lep(ob). The phenotypes of B6.DBA congenic mice include reduced beta-cell replication rates accompanied by reduced beta-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated "Lisch-like" (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646-amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes.

Continuous carbachol infusion promotes peripheral cell proliferation and mimics vagus hyperactivity in a rat model of hypothalamic obesity.

Lesions of the ventromedial hypothalamus (VMH) result in obesity and enhanced cellular proliferation in various organs, including the pancreas, gastrointestinal tract, and liver. Previous studies have suggested that vagal hyperactivity, rather than overeating, induces the peripheral cell proliferation in VMH-lesioned rats. The goal of the present study was to investigate the mechanism of peripheral cell proliferation in VMH-lesion-induced obesity by infusing rats with the acetylcholine agonist, carbachol, and then measuring cellular proliferation in the pancreas and duodenum using immunohistochemistry. The ventromedial hypothalamus was bilaterally lesioned in five rats. In other rats, the bilateral vagus nerves were ligated (vagotomized), and saline or carbachol was continuously administered by an osmotic minipump (n = 5 in each group). Three days later, rats were killed, and cell proliferation was assessed in the pancreas and the duodenum using immunohistochemistry for proliferating cell nuclear antigen (PCNA). Additionally, cellular proliferation in the duodenum was more precisely examined by assessing incorporation of 5-bromo-2'-deoxyuridine (BrdU). Cellular proliferation was higher in rats that received carbachol infusions and in rats with VMH-lesions when compared with control rats (P < 0.05, respectively). The pancreatic PCNA-expressing cells were predominantly identified as the B-cells of the islets of Langerhans. These data demonstrate that carbachol infusion can induce pancreatic and duodenal cell proliferation to a degree that was comparable to that in vagal hyperactivity induced by VMH lesions.

Effects of a high-sucrose diet on body weight, plasma triglycerides, and stress tolerance.

We examine the effects of feeding a high-sucrose diet on body weight gain, plasma triglycerides, and stress tolerance in rats. Feeding a high-sucrose (60%) diet for 2 weeks did not induce a greater body weight gain compared with that of standard diet when caloric intake was similar in ventromedial hypothalamic-lesioned obese and sham-operated lean animals. The high-sucrose diet elevated plasma triglycerides by increasing the triglyceride secretion rate and decreasing the fractional catabolic rate in both groups. In response to stress, feeding a high-sucrose diet for one week induced enhanced gene expressions of heat shock proteins (HSP 70 and 27) and suppressed NOx production in the brain, whereas the standard diet did not. Results suggest that feeding a high-sucrose diet does not induce obesity in lean rats or enhance weight gain in obese rats, if caloric intake is appropriate. The diet does elevate plasma triglyerides in lean and obese rats, but it may have the potential to improve stress tolerance.