Efficiency and Safety of Dextran-PAMAM/siMMP-9 Complexes for Decreasing Matrix Metalloproteinase-9 Expression and Promoting Wound Healing in Diabetic Rats.

Difficult healing of diabetic foot ulcers is associated with overexpression of matrix metalloproteinase 9 (MMP-9) in the local wound. Therefore, strategies aimed at downregulation of MMP-9 levels in ulcer sites may promote tissue regeneration and accelerate healing of diabetic foot ulcers (DFU). To fulfill this aim, we exploited dextran conjugated with poly(amidoamine) (Dextran-PAMAM) as a gene carrier to deliver MMP-9 targeted siRNA (siMMP-9). The prepared complexes could be efficiently endocytosed with low cytotoxicity to HaCat cells. Dextran-PAMAM could efficiently deliver siMMP-9 and significantly inhibit MMP-9 expression in vitro. Diabetic rats wound models showed that topical application of the Dextran-PAMAM/siMMP-9 complex effectively knocked down MMP-9 expression in skin wound tissue, thus accelerating wound healing. Taken together, this study demonstrates that the Dextran-PAMAM/siMMP-9 complex possesses high potential for wound healing and could serve as a promising regenerative platform for improving DFU healing.

Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome.

CONTEXT: Weight loss remains one of the most important arms in obese patients with polycystic ovary syndrome (PCOS). Further studies are needed to identify the best treatment. OBJECTIVE: To evaluate the effects of exenatide (EXE) on reproductive and metabolic function in overweight/obese (OW/OB) PCOS. DESIGN: This is a 24-week open-label prospective, randomized, clinical study. PATIENTS AND MEASUREMENTS: This study randomized 176 OW/OB women diagnosed with PCOS to receive either EXE 10 µg BID (n = 88) or metformin (MET) 1000 mg BID (n = 88) for the first 12 weeks. Then all patients were treated with MET alone during the second 12 weeks. We observed metabolic parameters at 0 and 12 weeks, and then tracked the rate of pregnancy during the second 12 weeks. RESULTS: After the first 12 weeks of intervention, compared with MET, subjects who received EXE had significantly decreased weight (4.29 ± 1.29 kg vs 2.28 ± 0.55 kg, P < .001) and total fat% (4.67 ± 0.09% vs 1.11 ± 0.32%, P < .001), improved the homeostasis model of assessment for insulin resistance (1.30 ± 0.58 vs 0.59 ± 0.12, P < .001) and increased the menstrual frequency ratio (0.62 ± 0.12 vs 0.37 ± 0.01, P < .001). During the second 12 weeks, the rate of natural pregnancy of EXE-treated patients was significantly higher than MET-treated patients (43.60% vs 18.70%, P < .05). CONCLUSIONS: Short-term EXE therapy was linked to significant weight loss and central adiposity reduction, which may further explain the improvements in insulin resistance, inflammatory marker and menstrual cycle, which may contribute to increasing pregnancy rates in OW/OB women with PCOS.

Clinical study of treatment switching from premixed insulin to basal insulin combined with oral hypoglycemic drugs in patients with type 2 diabetes.

AIM: Premixed insulin regimens are commonly used for the treatment of patients with type-2 diabetes mellitus (T2DM). However, limited data are available regarding next-step therapy options in cases where premixed insulin fails to provide adequate glycemic control. This 20-week observational study of everyday clinical practice evaluated the efficacy, safety and treatment satisfaction of insulin glargine plus oral anti-diabetic drugs (OADs) in T2DM patients previously treated with premixed insulin. METHODS: In this open-label, single-arm, 20-week study, 70 subjects with T2DM inadequately controlled with premixed insulin were switched to insulin glargine plus OADs. Changes in glycaemic control, incidence of hypoglycaemia, treatment satisfaction using the Diabetes Treatment Satisfaction Questionnaire (DTSQ), serum superoxide dismutase (SOD), and serum 8-iso-prostaglandin (8-iso-PG) were evaluated at the start and the end of the study. RESULTS: Over the 20 week treatment period, mean (±SD) HbA1c levels decreased from 8.28 ± 1.24% to 6.83 ± 1.09%, mean (±SD) FBG levels decreased from 7.64 ± 1.36 mmol/L to 5.57 ± 1.21 mmol/L, and 2 h PBG levels decreased from 12.07 ± 1.17 mmol/L to 8.94 ± 1.56 mmol/L, all P < 0.001. A total of 3 symptomatic hypoglycemic episodes were reported. No significant reductions in body weight were observed. The mean daily dose of insulin decreased by 14 U between week 0 (30.20 ± 9.93 U) and week 20 (16.38 ± 5.15 U). The total treatment satisfaction score showed a significant increase from study baseline to end point. Significant increases in SOD(90.00 ± 16.62 to 108.81 ± 27.02 u/ml, P < 0.01) and reductions in 8-iso-PG(2.15 ± 0.61 to 1.64 ± 0.42 pg/ml, P < 0.05) were observed between the start and end of the observation period. There were significant differences in baseline HbA1c, duration of diabetes, and baseline postprandial C-peptide between the A1c ≤ 6.5% group and the A1c > 7.0% group [HbA1c: 7.25% ± 1.02% vs. 9.32% ± 1.23%; duration: 7.84 ± 1.02 vs. 13.96 ± 1.35 years; postprandial C-peptide: 4.83 ± 2.11 vs 2.54 ± 0.87 nmol/L, all P < 0.05]. CONCLUSIONS: The observational study shows that, in T2DM patients inadequately controlled with premixed insulin, switching therapy to glargine plus OADs is associated with significant improvements in glycaemic control and treatment satisfaction, and is with low incidence of hypoglycemia. Baseline postprandial C-peptide, HbA1c, and duration of diabetes are the key factors closely related to efficacy of this treatment regimen.