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AimThe purpose of the study was to investigate seasonal variations in HbA1c, GA and LDL-C and to examine the effects of the COVID-19 pandemic on these variations and on glycemic and lipid control themselves in patients with type 2 diabetes.Patients and methodsThe subjects were outpatients with type 2 diabetes who had received standard treatment for glycemic control for more than 3 years. Data for patients who visited our hospital from January 2021 to March 2021 were retrospectively investigated based on electronic medical records.ResultsHbA1c showed seasonal variation (high in winter–spring and low in summer–autumn), and this was similar during the COVID-19 pandemic. However, the mean HbA1c over 1 year was significantly elevated during the COVID-19 pandemic (7.53 ± 1.02% in 2020) compared with the previous 2 years: (7.34 ± 0.91 in 2018, 7.39 ± 0.93 in 2019; 2020 vs. 2018; 0.19%, P < 0.001; 2020 vs. 2019; 0.14%, P = 0.0013) and the difference was larger in winter. GA showed no apparent seasonal variation, but mean GA during the COVID-19 pandemic was elevated compared with earlier years (2020 vs. 2018, P < 0.001; 2020 vs. 2019, P < 0.001). LDL-C did not show apparent seasonal variation and was unaffected by COVID-19 pandemic.ConclusionThe COVID-19 pandemic influenced mean HbA1c and GA levels over 1 year, but did not affect seasonal variations, while LDL-C was not affected by COVID-19. Observation of these levels over a longer period is warranted to determine the longer-term influence of the COVID-19 pandemic.

To investigate the effect of androgens and estrogens on surtuin 1 (SIRT1) expression in human aortic endothelial cells (HAECs). Real-time polymerase chain reaction analysis of SIRT-1 expression over 48 hours (h) was performed in HAECs treated with various concentrations of dehydroepiandrostendione (DHEA), androstenedione and testosterone (androgens), estrone (E1), estradiol (E2), and estriol (E3) (estrogens) to investigate the dose-dependency of time courses. The influence of high glucose on SIRT1 expression induced by the androgens and estrogens was also examined. Dehydroepiandrostendione, androstenedione, and testosterone remarkedly produced a dose-dependent increase in SIRT1 expression in the range of 10 to 20 μg/ml. High glucose (40mM) medium had significantly inhibitory effects on 10 μg/ml DHEA-induced SIRT1 expression (p=0.024). Estrone and E2, but not E3, caused a marked dose-dependent increase in SIRT1 expression from 10 to 20 μg/ml. Treatment with 20 mM or 40 mM glucose medium did not significantly inhibit E1- and E3-induced SIRT1 expression in control medium; however, both high glucose mediums significantly emphasized E2-induced SIRT1 expression in control medium (p=0.007, p=0.005). These results suggest that DHEA, androstenedione, testosterone, E1, and E2 definitely activate SIRT1 expression in HAECs. A high glucose medium is potent to inhibit the basal gene expression; however, it could not reduce powerful androgen- and estrogen-induced SIRT1 expression in HAECs.

Enough is enough Appetite is regulated — at least in part — in the hypothalamus, the brain region that links the nervous and endocrine systems. A screen for appetite-regulating molecules has now identified a fragment of the protein nucleobindin 2, dubbed nesfatin-1, as a satiety molecule produced in the hypothalamus. When nesfatin-1 is injected into the brain, rats eat less and lose weight. When nesfatin-1 is blocked, animals eat more. Nesfatin-1 is therefore a possible target for antiobesity drugs. A secreted protein, nesfatin-1, is expressed in the hypothalamus and induces the feeling of being full. In rats, its injection into the brain decreases food intake, but blocking its action stimulates appetite. The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour 1 , 2 , 3 . Here we show that nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of α-melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor. We identify nesfatin-1 as a satiety molecule that is associated with melanocortin signalling in the hypothalamus.

The main purpose of the current study was to investigate the effect of season change and the influence of the COVID-19 pandemic on the ratio of glycoalbumin to hemoglobin A1c (GA/HbA1c) in patients with type 2 diabetes. A total of 267 patients in whom both HbA1c and GA were measured at baseline were included in this retrospective study. GA/HbA1c was investigated for three years, 2018, 2019, and 2020 (COVID-19 pandemic period). The mean values for GA/HbA1c per year in 2018, 2019, and 2020 were 2.64±0.35, 2.61±0.35, 2.64±0.39, respectively. There were no significant differences in GA/HbA1c during these years. There was a tendency toward seasonal variation in GA/HbA1c (i.e., higher in summer or autumn and lower in spring or winter). In patients with type 2 diabetes, GA/HbA1c tended to show seasonal variation, which was not influenced by the COVID-19 pandemic.

Renal anemia is generally caused by a decrease in the production of erythropoietin in kidney due to renal dysfunction, and this may be associated with the increase in mortality and cardiovascular events in addition to subjective symptoms such as fatigue and wobbliness. We report a case of an 87-year-old man with type 2 diabetes, hypertension, and dyslipidemia who had received roxadustat (a hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitor) for renal anemia due to diabetic nephropathy and in whom roxadustat was switched to daprodustat (another HIF-PH inhibitor) due to the onset of central hypothyroidism. About three weeks after this change, the patient developed acute asymptomatic cerebral infarction with an elevation of hemoglobin (Hb). It is unclear if the change to daprodustat was involved in the onset of cerebral infarction. However, this case suggests that particular caution should be paid to unexpected acute elevation of Hb after a change from one HIF-PH inhibitor to another, especially in a patient at high risk for cardiovascular events.

Objective This study was performed to evaluate the association of the serum level of angiopoietin-like protein 2 (ANGPTL2) with circulating inflammatory markers and oxidized and modified low-density lipoprotein (LDL) cholesterol as evaluated by lectin-like oxidized LDL receptor 1 ligand containing apolipoprotein B (LAB) in patients with type 2 diabetes. Methods The study included 70 patients with type 2 diabetes hospitalized for glycemic control and 9 control subjects. Results The serum level of ANGPTL2 was significantly higher in the patients with type 2 diabetes than in the healthy controls. There was a significant positive correlation between ANGPTL2 and the high-sensitivity C-reactive protein, fibrinogen, and LAB levels and a significant negative correlation between ANGPTL2 and the estimated glomerular filtration rate (eGFR). Conclusions These results suggest that the serum ANGPTL2 level has a close positive association with inflammatory markers, especially fibrinogen and oxidized and modified LDL as evaluated by LAB. The data also suggest that the serum ANGPTL2 level is influenced by renal function as reflected by the eGFR.

Previous studies have shown that dipeptidyl peptidase (DPP)-4, is released from adipocytes in a differentiation-dependent manner and a marker for insulin resistance in obese individuals who have particularly high circulating DPP-4/soluble CD26 (sCD26) concentrations. In this study, we have evaluated the effects of short-term hospitalization with calorie restriction on body composition and circulating DPP-4/sCD26 concentrations in patients with type 2 diabetes. A total of 47 Japanese adults with type 2 diabetes were recruited to the study (age; 56.6 ± 13.0 years, body mass index (BMI); 27.3 ± 5.6 kg/m2). Body composition, circulating DPP-4/sCD26 concentrations and metabolic parameters were assessed upon admission and at discharge from hospital (average of the period: 13.0 ± 2.5 days). Visceral fat area (VFA) was also assessed by dual impedance method. During hospitalization, there was a significant reduction in body weight, BMI, lean body mass, VFA and circulating DPP-4/sCD26 concentrations, but not in body fat mass. Fasting circulating DPP-4/sCD26 concentrations were significantly correlated with fasting insulin, aspartate aminotransferase, γ-glutamyltransferase (γ-GTP) levels, and HOMA-IR (r = 0.477, 0.423, 0.415, 0.548, respectively), but not with VFA (r = − 0.056) by liner regression analyses at base line. It was also observed a positive correlation between changes in circulating DPP-4/sCD26 concentrations and γ-GTP level, HOMA-IR, and a negative correlation between the changes in circulating DPP-4/sCD26 concentrations and VFA significantly (r = 0.300, 0.633, − 0.343, respectively). In conclusion, our observations suggest that liver enzymes as well as VFA might be associated with the response of DPP-4/sCD26 concentrations.

Objectives: The main purpose of the study was to study the association between circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels and various markers, including inflammatory markers such as high-sensitivity C-reactive protein and fibrinogen, serum lipids, and renal function, in patients with poorly controlled type 2 diabetes. Methods: The subjects were 70 patients (men 45, women 25) who were hospitalized for treatment of poor glycemic control. Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 levels were assayed using a sandwich chemiluminescence enzyme immunoassay. Results: Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 was significantly positively correlated with lectin-like oxidized low-density lipoprotein-1 ligands containing apolipoprotein B, reflecting modified low-density lipoprotein, and with inflammatory markers such as high-sensitivity C-reactive protein and fibrinogen. In addition, there was a significant positive correlation between soluble lectin-like oxidized low-density lipoprotein receptor-1 and urinary albumin excretion. Conclusions: Soluble lectin-like oxidized low-density lipoprotein receptor-1 may serve as a marker reflecting the degrees of inflammation and albuminuria in patients with poorly controlled type 2 diabetes.

Thyrotropin-releasing hormone (TRH) is a major stimulator of thyrotropin-stimulating hormone (TSH) synthesis in the anterior pituitary, though precisely how TRH stimulates the TSHβ gene remains unclear. Analysis of TRH-deficient mice differing in thyroid hormone status demonstrated that TRH was critical for the basal activity and responsiveness to thyroid hormone of the TSHβ gene. cDNA microarray and K-means cluster analyses with pituitaries from wild-type mice, TRH-deficient mice and TRH-deficient mice with thyroid hormone replacement revealed that the largest and most consistent decrease in expression in the absence of TRH and on supplementation with thyroid hormone was shown by the TSHβ gene, and the NR4A1 gene belonged to the same cluster as and showed a similar expression profile to the TSHβ gene. Immunohistochemical analysis demonstrated that NR4A1 was expressed not only in ACTH- and FSH- producing cells but also in thyrotrophs and the expression was remarkably reduced in TRH-deficient pituitary. Furthermore, experiments in vitro demonstrated that incubation with TRH in GH4C1 cells increased the endogenous NR4A1 mRNA level by approximately 50-fold within one hour, and this stimulation was inhibited by inhibitors for PKC and ERK1/2. Western blot analysis confirmed that TRH increased NR4A1 expression within 2 h. A series of deletions of the promoter demonstrated that the region between bp -138 and +37 of the TSHβ gene was responsible for the TRH-induced stimulation, and Chip analysis revealed that NR4A1 was recruited to this region. Conversely, knockdown of NR4A1 by siRNA led to a significant reduction in TRH-induced TSHβ promoter activity. Furthermore, TRH stimulated NR4A1 promoter activity through the TRH receptor. These findings demonstrated that 1) TRH is a highly specific regulator of the TSHβ gene, and 2) TRH mediated induction of the TSHβ gene, at least in part by sequential stimulation of the NR4A1-TSHβ genes through a PKC and ERK1/2 pathway.

The insulin responsive Glut4 transport vesicles contain the v-SNARE protein Vamp2 that associate with the plasma membrane t-SNARE protein Syntaxin 4 to drive insulin-stimulated Glut4 translocation in skeletal muscle and adipocytes. The syntaxin 4 interacting protein (Synip) binds to syntaxin 4 in the basal state and dissociates in the insulin-stimulated state allowing for the subsequent binding of Vamp2 containing Glut4 vesicles and fusion with the plasma membrane. In this study, we have found that Synip binds phosphatidylinositol 3,4,5-triphosphate (PIP3), but not phosphatidylinositol 3 phosphate (PIP) or phosphatidylinositol 3,4-biphosphate (PIP2) through the Synip WW domain as deletion of this domain (Synip ΔWW) failed to bind PIP3. Over-expressed Synip ΔWW in 3T3L1 adipocytes reduced the basal levels of Glut4 at the plasma membrane with no effect on the binding to syntaxin 4 in vitro. Subcellular fractionation demonstrated that the amount of Synip ΔWW at the PM was decreased in response to insulin in 3T3L1 adipocytes whereas the amount of Synip WT increased. These data suggest that in the presence of insulin, the dissociated Synip remains anchored to the plasma membrane by binding to PIP3.