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Aims/Introduction: The benefits of once‐daily insulin degludec/aspart (IDegAsp) compared with basal insulin in type 2 diabetes patients have not been established. Materials and Methods: This was a retrospective observational study. From a basal insulin cohort from three referral hospitals, patients were enrolled who initiated once‐daily IDegAsp. A control group maintaining basal insulin was selected by propensity score matching. Glycated hemoglobin (HbA1c) changes over a period of 6 months and associated clinical factors were evaluated. Results: The IDegAsp group and the control group comprised of 87 patients, respectively. Baseline HbA1c was comparable between the two groups (8.7 ± 0.9 vs 8.6 ± 0.9%, mean and standard deviation). After 6 months with matched insulin doses, HbA1c in the IDegAsp group was lower than that in the control group (8.1 ± 1.0 vs 8.4 ± 1.1%, P = 0.029). Among baseline variables, fasting plasma glucose (FPG) and fasting C‐peptide in the IDegAsp were lower than that in the control (FPG 124.2 ± 38.4 vs 148.0 ± 50.6 mg/dL, P < 0.001). Considering that the lower FPG despite the comparable HbA1c could be related with the efficacy of IDegAsp, subgroup analysis was carried out according to a ratio of FPG‐to‐estimated average glucose, which is calculated from HbA1c. When compared with each control group, the superiority of IDegAsp in the reduction of HbA1c was significant only in the patients with a lower FPG‐to‐estimated average glucose ratio (0.49 ± 0.09), but not in those with a higher FPG‐to‐estimated average glucose ratio (0.79 ± 0.20). Conclusions: We observed that IDegAsp was more effective than basal insulin in patients with an FPG lower than predicted by HbA1c, which might be related with insulin deficiency and postprandial hyperglycemia in patients on basal insulin therapy. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated the efficacy of a smartphone-based, patient-centered diabetes care system (mDiabetes) for type 2 diabetes that contains comprehensive modules for glucose monitoring, diet, physical activity, and a clinical decision support system.Research Design and Methods: We conducted a 24-week, multicenter, randomized controlled trial with adult patients with inadequately controlled type 2 diabetes. The patients were randomly assigned to the mDiabetes group or the paper logbook (pLogbook) group. The primary end point was the difference of the change in HbA1c from baseline between the two groups.Results: HbA1c reduction from baseline was greater in the mDiabetes group (-0.40 ± 0.09%, n = 90) than in the pLogbook group (-0.06 ± 0.10%, n = 82). The difference of adjusted mean changes was 0.35% (95% CI 0.14-0.55, P = 0.001). The proportion of patients whose HbA1c fell below 7.0% (53 mmol/mol) was 41.1% for the mDiabetes group and 20.7% for the pLogbook group (odds ratio [OR] 2.01, 95% CI 1.24-3.25, P = 0.003). The percentage of patients who attained HbA1c levels below 7.0% (53 mmol/mol) without hypoglycemia was 31.1% in the mDiabetes group and 17.1% in the pLogbook group (OR 1.82, 95% CI 1.03-3.21, P = 0.024). There was no difference in the event numbers of severe hyperglycemia and hypoglycemia between the two groups.Conclusions: The implementation of the mDiabetes for patients with inadequately controlled type 2 diabetes resulted in a significant reduction in HbA1c levels, with tolerable safety profiles. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 (GLP-1) can increase pancreatic β-cells, and α-cells could be a source for new β-cell generation. We investigated whether GLP-1 increases β-cells through α-cell transdifferentiation. New β-cells originating from non-β-cells were significantly increased in recombinant adenovirus expressing GLP-1 (rAd-GLP-1)-treated RIP-CreER;R26-YFP mice. Proliferating α-cells were increased in islets of rAd-GLP-1-treated mice and αTC1 clone 9 (αTC1-9) cells treated with exendin-4, a GLP-1 receptor agonist. Insulin+glucagon+ cells were significantly increased by rAd-GLP-1 or exendin-4 treatment in vivo and in vitro. Lineage tracing to label the glucagon-producing α-cells showed a higher proportion of regenerated β-cells from α-cells in rAd-GLP-1-treated Glucagon-rtTA;Tet-O-Cre;R26-YFP mice than rAd producing β-galactosidase-treated mice. In addition, exendin-4 increased the expression and secretion of fibroblast growth factor 21 (FGF21) in αTC1-9 cells and β-cell-ablated islets. FGF21 treatment of β-cell-ablated islets increased the expression of pancreatic and duodenal homeobox-1 and neurogenin-3 and significantly increased insulin+glucagon+ cells. Generation of insulin+glucagon+ cells by exendin-4 was significantly reduced in islets transfected with FGF21 small interfering RNA or islets of FGF21 knockout mice. Generation of insulin+ cells by rAd-GLP-1 treatment was significantly reduced in FGF21 knockout mice compared with wild-type mice. We suggest that GLP-1 has an important role in α-cell transdifferentiation to generate new β-cells, which might be mediated, in part, by FGF21 induction. [ABSTRACT FROM AUTHOR]

Aim: To study the effects of angiotensin receptor blockers (ARBs) on insulin secretion in hypertensive patients with type 2 diabetes. Materials and methods: A total of 41 patients were enrolled in this open‐label, active comparator‐controlled, crossover study. After a 2‐week run‐in period with amlodipine, the participants were assigned to receive either fimasartan (60–120 mg daily) or amlodipine (5–10 mg daily) for 16 weeks. Thereafter, they were treated with the other drug for another 16 weeks. Physical examinations and laboratory tests were performed before and after each treatment. Results: Blood pressure, glycated haemoglobin and oral glucose tolerance test (OGTT) values were similar with each treatment. Fimasartan treatment significantly increased median (range) homeostatic assessment of β‐cell function values (49.9 [22.5–174.4] vs 46.9 [15.6–148.0]), area under the curve of insulin during OGTT (27 284 [9501–94 525] vs 26 818 [8112–76 704] pmol/L × min), insulinogenic index at 60 minutes (19.7 [3.0–131.2] vs 15.0 [2.4–103.8] pmol/mmol) and at 120 minutes (19.1 [1.9–85.5] vs 12.6 [−4.3–178.8] pmol/mmol) compared with those with amlodipine (all P < .05); however, acute insulin response and insulin resistance indices were similar for both agents. Conclusions: Compared with amlodipine, fimasartan increased late‐phase glucose‐stimulated insulin secretion in patients with type 2 diabetes and hypertension. This finding suggests that ARBs would be more beneficial in such patients compared with other classes of anti‐hypertensives. [ABSTRACT FROM AUTHOR]

Aims/Introduction Dipeptidyl peptidase-4 inhibitors might have pleiotropic protective effects on cardiovascular disease ( CVD), in contrast to sulfonylureas. Therefore, we compared various CVD risk factors between vildagliptin and glimepiride. Materials and Methods We carried out a randomized, prospective and crossover trial. A total of 16 patients with type 2 diabetes whose glycated hemoglobin was >7% were randomized to add vildagliptin or glimepiride. After 12-week treatment, each drug was replaced with the other for another 12 weeks. Before and after each treatment, glucose homeostasis and CVD risk factors were assessed, and the continuous glucose monitoring system was applied to calculate glycemic variability. Results The mean age of the participants was 60 years, 31% were men, body mass index 25.5 kg/m2 and HbA1c 8.41%. Both vildagliptin and glimepiride significantly decreased glycated hemoglobin and glycemic variability indices. Despite the improved glucose homeostasis, favorable change of CVD markers was not prominent in both the arms, along with significant weight gain. Only plasma stromal cell-derived factor ( SDF)-1α decreased by 30% in the vildagliptin arm. According to regression analyses, the reduction of SDF-1α was independently associated with vildagliptin usage and serum interleukin-6 changes, but white blood cells were not related with the SDF-1α changes. Conclusion Compared with glimepiride, vildagliptin arrestingly decreased plasma SDF-1α, and its clinical implications should be further investigated. [ABSTRACT FROM AUTHOR]

Aims/Introduction Glycemic variability is known to induce oxidative stress. We investigated the relationships between glycemic variability and serum bilirubin levels, an endogenous anti-oxidant, in patients with diabetes. Materials and Methods A cross-sectional study was carried out with 77 patients with type 2 diabetes who had been recruited to two clinical studies from 2008 to 2014. There were no participants with diseases of the pancreas, liver, biliary tract and chronic renal insufficiency. Glycemic variation was calculated by a continuous glucose monitoring system, and correlation analyses were carried out to evaluate their association with bilirubin levels. Multiple linear regression was carried out to identify independent factors influencing bilirubin levels and glycemic variation. Results Among the participants, 42.3% were men. The mean (standard deviation) age was 61.5 years (10.4 years), body mass index was 24.2 kg/m2 (2.8 kg/m2), diabetes duration was 17.7 years (9.5 years), hemoglobin A1c was 60.7 mmol/mol (7.1 mmol/mol; 7.7 [0.7]%) and bilirubin was 11.8 μmol/L (4.10 μmol/L). Serum bilirubin levels were not different according to age, body mass index and hemoglobin A1c. However, the mean amplitude of glucose excursion was positively associated with bilirubin levels in women ( r = 0.588, P < 0.001). After adjustment with duration of diabetes, serum albumin, liver enzymes, and mean glucose, the correlation between bilirubin and mean amplitude of glucose excursion remained significant ( r = 0.566, P < 0.001). Multiple linear regression analyses showed that bilirubin was an independent determinant for the mean amplitude of glucose excursion in women. 1,5-Anhydroglucitol was also associated with bilirubin levels in women. Conclusions Bilirubin level within the physiological range might be an independent predictor for glycemic variability in women with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is caused by both insulin resistance and relative insulin deficiency. To investigate age-related changes in glucose metabolism and development of type 2 diabetes, we compared glucose homeostasis in different groups of C57BL/6J mice ranging in age from 4 months to 20 months (4, 8, 12, 16 and 20 months). Interestingly, we observed that non-fasting glucose levels were not significantly changed, but glucose tolerance gradually increased by 20 months of age, whereas insulin sensitivity declined with age. We found that the size of islets and glucose-stimulated insulin secretion increased with aging. However, mRNA expression of pancreatic and duodenal homeobox 1 and granuphilin was decreased in islets of older mice compared with that of 4-month-old mice. Serum calcium (Ca2+) levels were significantly decreased at 12, 20 and 28 months of age compared with 4 months and calcium sensing receptor (CaSR) mRNA expression in the islets significantly increased with age. An extracellular calcium depletion agent upregulated CaSR mRNA expression and consequently enhanced insulin secretion in INS-1 cells and mouse islets. In conclusion, we suggest that decreased Ca2+ levels and increased CaSR expression might be involved in increased insulin secretion to compensate for insulin resistance in aged mice. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article on the developmental regulation of proteolytic cleavage of the Flowering Locus T (FT) protein in Arabidopsis.

Abnormally high levels of circulating free fatty acids can lead to pancreatic islet β-cell dysfunction and apoptosis, contributing to β-cell failure in Type 2 diabetes. The NAD+-dependent protein deacetylase Sirtuin-3 (SIRT3) has been implicated in Type 2 diabetes. In this study, we tested whether SIRT3 overexpression affects palmitate-induced β-cell dysfunction in cells of line NIT1, which are derived from mouse pancreatic β-cells. Two different lengths of SIRT3 were overexpressed: full length SIRT3 (SIRT3LF), which was preferentially targeted to mitochondria and partially to the nucleus, and its N-terminal truncated form (SIRT3SF), which was located in the nucleus and cytoplasm. Overexpression of SIRT3LF and SIRT3SF using an adenoviral system alleviated palmitate-induced lipotoxicity such as reduction of cell viability and mitogen-activated protein kinase (MAPK) activation. Chronic exposure to low concentrations of palmitate suppressed glucose-stimulated insulin secretion, but the suppression was effectively reversed by overexpression of SIRT3LF or SIRT3SF. The mRNA levels of the endoplasmic reticulum (ER) stress responsive genes ATF4, GRP94 and FKBP11 were increased by palmitate treatment, but the increases were completely inhibited by SIRT3LF overexpression and less effectively inhibited by SIRT3SF overexpression. This result suggests that overexpression of SIRT3 inhibits induction of ER stress by palmitate. Collectively, we conclude that overexpression of SIRT3 alleviates palmitate-induced β-cell dysfunction. [ABSTRACT FROM AUTHOR]

Highlights: [&#x2022;] Repeated restraint stress gives rise to susceptible and resilient responses. [&#x2022;] Different stress susceptibility is associated with different anxiety behavior. [&#x2022;] Basal level of corticosterone is strongly correlated with stress susceptibility. [ABSTRACT FROM AUTHOR]