Molecular Evolution and Protein Structure Variation of Dkk Family.

Dkks have inhibitory effects on the Wnt signaling pathway, which is involved in the development of skin and its appendages and the regulation of hair growth. The nucleotide sequences were compared and analyzed to further investigate the relationship between the structure and function of the Dkk gene family and vertebrate epidermal hair. The analysis of the molecular evolution of the Dkk family revealed that the evolution rate of the genes changed significantly after speciation, with the Aves and Reptilia branches showing accelerated evolution. Additionally, positive selection was observed at specific sites. The tertiary structure of the protein was also predicted. The analysis of the functional divergence of the Dkk family revealed that the functional divergence coefficient of each gene was greater than 0, with most of the functional divergence sites were located in the Cys-2 domain and a few in the Cys-1 domain. This suggests that the amino acid and functional divergence sites may play a role in regulating the binding of the Dkk family to LRP5/6, and thus affect the inhibition of Wnt signaling, leading to different functions of Dkk1, Dkk2, and Dkk4 in the development of skin hair follicles. In addition, the Dkk families of Aves and Reptilia may have undergone adaptive evolution and functional divergence.

Effect of Baseline Characteristics on Hypoglycaemia Risk with Insulin Glargine 100 U/mL: Post Hoc Analysis of the BEYOND 7 Study.

INTRODUCTION: BEYOND 7 demonstrated that a higher starting dose (0.3 U/kg) of insulin glargine 100 U/mL (Gla-100) is as safe as the standard starting dose (0.2 U/kg) in Chinese individuals with type 2 diabetes who had uncontrolled hyperglycaemia despite receiving oral antihyperglycaemic drugs. This post hoc analysis determined the effect of baseline characteristics on hypoglycaemia risk in these individuals. METHODS: Participants from BEYOND 7 were assessed based on their age at baseline (< 60 vs. ≥ 60 years), duration of diabetes (< 10 vs. ≥ 10 years), glycated haemoglobin (HbA1c; < 9 vs. ≥ 9%) and fasting plasma glucose level (FPG; < 11 vs. ≥ 11 mmol/L). Endpoints included the proportion of participants with overall confirmed (≤ 3.9 mmol/L) and symptomatic hypoglycaemia, as well as the proportion of participants who achieved an HbA1c < 7% without hypoglycaemia, the time to first achievement of fasting blood glucose (FBG) < 7 mmol/L and the change in HbA1c from baseline between the two treatment arms in each of these subgroups. RESULTS: The proportion of participants with overall confirmed (6.1-16.7%) or symptomatic hypoglycaemia (5.7-18.4%) or the proportion who achieved HbA1c < 7.0% without hypoglycaemia (23.6-47.4%) was similar between the two treatment arms in all subgroups, with the exception of participants with a baseline duration of diabetes ≥ 10 years who experienced more symptomatic hypoglycaemia if initiating Gla-100 at a dose of 0.3 versus 0.2 U/kg. Participants aged < 60 years with an HbA1c < 9% or ≥ 9% or a duration of diabetes of 2-10 years achieved an FBG < 7.0 mmol/L in a significantly shorter time with Gla-100 starting dose of 0.3 U/kg versus 0.2 U/kg (all p < 0.001). No significant differences were seen among the subgroups in terms of change from baseline in HbA1c. CONCLUSIONS: Baseline age, duration of diabetes, HbA1c level and FPG level do not affect the risk of hypoglycaemia with a higher starting dose of Gla-100 versus its standard starting dose. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02836704.

Down-regulation of miR-340-5p promoted osteogenic differentiation through regulation of runt-related transcription factor-2 (RUNX2) in MC3T3-E1 cells.

Diabetic osteoporosis (DOP) is a chronic complication of diabetes in the skeletal system. High level of miR-340-5p may be harmful to the bone formation. In this study, the DOP model of rats was successfully established via streptozotocin (STZ) and ovariectomy (OVX) treatment. It was manifested by reduced body weight, insulin level, alkaline phosphatase (ALP) activity, and osteocalcin (OCN) and collagen-I expressions, as well as increased concentration of fasting blood glucose. Moreover, we found that miR-340-5p expression was increased while runt-related transcription factor-2 (RUNX2) was decreased in femurs. Furthermore, the effects of miR-340-5p on osteogenic differentiation (OD) in high glucose (HG)-treated MC3T3-E1 cells were explored. Exposure to OD and HG contributed to elevated miR-340-5p level. Inhibition of miR-340-5p enhanced ALP level, calcium deposition, and OCN, collagen-I and RUNX2 levels. On the contrary, miR-340-5p overexpression reversed these promotional effects. Luciferase assay indicated that RUNX2 may be a target gene of miR-340-5p. Moreover, RUNX2 deficiency decreased miR-340-5p inhibition-induced ALP activity, calcium accumulation and OCN, collagen-I, RUNX2 levels. In short, the above findings revealed that inhibition of miR-340-5p facilitated osteogenic differentiation through regulating RUNX2 in MC3TC-E1 cells, which provided targeted therapeutic strategies for the treatment of DOP.

Higher versus standard starting dose of insulin glargine 100 U/mL in overweight or obese Chinese patients with type 2 diabetes: Results of a multicentre, open-label, randomized controlled trial (BEYOND VII).

AIM: To determine the safety of a higher starting dose of basal insulin in overweight/obese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This 16-week, randomized, multicentre, open-label trial enrolled adults with T2D (body mass index 25-40 kg/m2 ) and suboptimal glycaemic control (glycated haemoglobin [HbA1c] 7.5-11.0% [58-97 mmol/mol] and fasting plasma glucose [FPG] >9.0 mmol/L) with two to three oral anti-hyperglycaemic drugs at 51 centres in China. Patients were randomized (1:1) to a higher (0.3 U/kg) or standard (0.2 U/kg) starting dose of insulin glargine 100 U/mL, which was then titrated to achieve a self-monitored fasting blood glucose (FBG) of 4.4 to 5.6 mmol/L. The primary endpoint was the percentage of patients with ≥1 episode of overall confirmed hypoglycaemia (≤3.9 mmol/L or severe). RESULTS: At the end of study (n = 866), 11.0% patients treated with the 0.3 U/kg starting insulin dose experienced overall confirmed hypoglycaemia versus 8.6% of patients treated with 0.2 U/kg (estimated difference 2.1%, 95% confidence interval - 1.68, 5.89). The proportions of patients with symptomatic (9.8% vs 7.0%; P = 0.128) and nocturnal hypoglycaemia (2.7% vs 1.2%; P = 0.102) were similar in the two groups. There were no events of severe hypoglycaemia or FBG <3.0 mmol/L during the 16-week treatment, and achievement of HbA1c <7.0% (53 mmol/mol) (37.1% vs 37.1%) or FPG <5.6 mmol/L (15.9% vs 16.3%), <6.1 mmol/L (27.6% vs 26.1%), or < 7.0 mmol/L (48.8% vs 48.3%) without hypoglycaemia were comparable in the two groups. Moreover, the mean time was shorter (4.53, 3.95 and 2.74 weeks vs 5.51, 5.21 and 3.64 weeks) and number of titrations was lower (3.5, 3.0 and 2.0 vs 4.3, 4.0 and 2.8) to achieve self-monitored FBG targets of <5.6, <6.1 and <7.0 mmol/L in the higher versus the standard insulin dose group (all P < 0.01). CONCLUSIONS: Among overweight/obese patients with T2D, a higher insulin starting dose was as safe as the standard starting dose, and self-monitored FBG targets were achieved earlier with the higher versus the standard dose.

Liraglutide exerts a bone-protective effect in ovariectomized rats with streptozotocin-induced diabetes by inhibiting osteoclastogenesis.

Liraglutide, a glucagon-like peptide-1 receptor agonist, is an anti-diabetic medicine associated with a reduced risk of fracture in diabetic patients. In the present study, rats with streptozotocin (STZ)-induced diabetes and/or bilateral ovariectomy (OVX) were treated with liraglutide for eight weeks. Liraglutide treatment increased insulin secretion and managed blood glucose levels in the rats following STZ-induced diabetes. In addition, STZ- and OVX-induced reduction of femoral bone mineral density and destruction of bone microarchitecture were alleviated by liraglutide. STZ decreased, whereas OVX increased, serum osteocalcin (OC) level (a bone formation marker) and osteoblast counts in the trabecular bone. OVX, however not STZ, markedly increased the level of serum c-terminal telopeptide of type 1 collagen (CTX-1, a bone resorption marker) and osteoclast counts in the trabecular area. Liraglutide treatment significantly increased serum OC levels in all three osteoporotic models, however had minimal effects on osteoblast counts. Furthermore, liraglutide significantly decreased serum CTX-1 level and osteoclast numbers in OVX and STZ+OVX rats. Furthermore, the present study examined the mRNA expression and serum concentrations of osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL), and liraglutide significantly decreased the RANKL/OPG ratio compared with the untreated rats, indicating that osteoclastogenesis was inhibited by liraglutide. In summary, the results suggested that liraglutide ameliorates STZ+OVX-induced bone deterioration in the rat model, primarily through the inhibition of osteoclastogenesis. These preliminary findings propose a potentially beneficial effect of liraglutide on the bone health of postmenopausal diabetic patients.

[A clinical study on gestational transient thyrotoxicosis].

OBJECTIVE: To investigate the prevalence of gestational transient thyrotoxicosis (GTT) and analyze the cause of thyrotoxicosis encountered in this period. METHODS: An epidemiologic survey in ten hospitals in Shenyang was performed and 534 pregnant women during the first trimester of pregnancy filled questionnaire, received physical examination and had serum thyroid-stimulating hormone (TSH), free T(4) (FT(4)), free T(3) (FT(3)), thyroid peroxidase antibody (TPOAb), thyrotrophin receptor antibody (TRAb), and human chorionic gonadotrophin (hCG) tests. RESULTS: (1) The total prevalence of thyrotoxicosis was 9.75% (52/534) in the first trimester and the prevalence of GTT was 7.86%, which accounted for 80.77% of the thyrotoxicosis encountered in this period. A total of 88.89% of the overt GTT showed only elevated FT(3) level. (2) The level of serum hCG increased gradually in the first trimester. The medians of hCG were 25 300, 85 220 and 81 780 IU/L 6, 8 - 10 and 12 weeks after gestation, respectively (P = 0.000). The medians of serum TSH were 1.45, 1.10 and 0.84 mIU/L 6, 8 - 10 and 12 weeks after gestation, respectively (P < 0.01). (3) When serum hCG was more than 50 000 IU/L, the prevalence of GTT increased obviously. When serum hCG was between 80 000 IU/L and 110 000 IU/L, subclinical GTT increased significantly. When serum hCG was more than 110 000 IU/L, overt GTT increased significantly. Correlation analysis showed that serum hCG was related negatively with TSH (r = -0.402, P = 0.000) and positively with FT(3) (r = 0.165, P = 0.000), but not related with FT(4). CONCLUSIONS: The prevalence of GTT is 7.86% in the first trimester and it is the main cause of thyrotoxicosis found in the first trimester, accounting for 80.77% of all the causes. The serological characteristic of overt GTT is mainly the elevation of serum FT(3) level. Serum hCG level is related with the severity of GTT.