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.

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.

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.

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.