Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.

Acetyllevocarnitine Hydrochloride for the Treatment of Diabetic Peripheral Neuropathy: A Phase 3 Randomized Clinical Trial in China.

Diabetic peripheral neuropathy (DPN) is a highly prevalent chronic complication in type 2 diabetes (T2D) for which no effective treatment is available. In this multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial in China, patients with T2D with DPN received acetyllevocarnitine hydrochloride (ALC; 1,500 mg/day; n = 231) or placebo (n = 227) for 24 weeks, during which antidiabetic therapy was maintained. A significantly greater reduction in modified Toronto clinical neuropathy score (mTCNS) as the primary end point occurred in the ALC group (-6.9 ± 5.3 points) compared with the placebo group (-4.7 ± 5.2 points; P < 0.001). Effect sizes (ALC 1.31 and placebo 0.85) represented a 0.65-fold improvement in ALC treatment efficacy. The mTCNS values for pain did not differ significantly between the two groups (P = 0.066), whereas the remaining 10 components of mTCNS showed significant improvement in the ALC group compared with the placebo group (P < 0.05 for all). Overall results of electrophysiological measurements were inconclusive, with significant improvement in individual measurements limited primarily to the ulnar and median nerves. Incidence of treatment-emergent adverse events was 51.2% in the ALC group, among which urinary tract infection (5.9%) and hyperlipidemia (7.9%) were most frequent.

MiR-221-3p regulates the microvascular dysfunction in diabetic retinopathy by targeting TIMP3.

Diabetic retinopathy is one of the major complications of diabetes and the main cause to lead to blindness for diabetic patients. However, the exact mechanisms involved in the progression of diabetic retinopathy are not completely known. Herein, we demonstrated a novel role of miR-221-3p in the microvascular dysfunction in diabetic retinopathy. MiR-221-3p expression was found to be substantially upregulated in the retina samples of diabetic rats. Besides, ganglion cell layer, inner nuclear layer, outer nuclear layer, and retinal pigment epithelium layer of diabetic rats expressed higher miR-221-3p than the matched areas of normal rats. High glucose-treated retinal microvascular endothelial cells RF/6A and HRECs exhibited higher miR-221-3p than that in normal condition. MiR-221-3p inhibition could alleviate the retinal vascular leakage induced by diabetes in vivo as evaluated by Evans blue leakage assay, and reduce the proliferation, accelerate the apoptosis development, and inhibit the migration capacity of high glucose-treated RF/6A cells in vitro, while miR-221-3p overexpression partially enhanced the detrimental effects. By bioinformatics analysis and luciferase reporter assay, we identified that TIMP3 is the direct target of miR-221-3p. TIMP3 overexpression counteracted the effect of miR-221-3p on the vessel leakage and endothelial cell function. In conclusion, this study highlights the negative role of miR-221-3p in the microvascular dysfunction in diabetic retinopathy by targeting TIMP3, representing a potential therapeutic target for human diabetic retinopathy.

miR-15b-5p ameliorated high glucose-induced podocyte injury through repressing apoptosis, oxidative stress, and inflammatory responses by targeting Sema3A.

Podocyte damage is a hallmark of diabetic nephropathy (DN). Accumulating evidence indicates that microRNAs play important roles in the DN pathogenesis. This study aimed to explore the possible roles and underlying mechanisms of miR-15b-5p on high glucose (HG)-triggered podocyte injury. We observed that miR-15b-5p declined dramatically in a time-dependent manner in podocytes exposed to HG. In addition, miR-15b-5p restored cell proliferation in HG-induced podocytes. Meanwhile, forced expression of miR-15b-5p apparently restrained HG-triggered apoptosis of podocytes, concomitant with downregulated in the proapoptotic protein markers Bax and cleavage caspase-3, and upregulated the antiapoptotic protein Bcl-2. Simultaneously, introduction of miR-15b-5p repressed HG-induced oxidative stress damage in HG-treated podocytes, as evidenced by reduced MDA content, NOX4 expression, and enhanced activities of superoxide dismutase and catalase. Moreover, enforced expression of miR-15b-5p remarkably restrained the HG-stimulated inflammatory response, as reflected by attenuated the level of the cytokines IL-1ß, TNF-α, and IL-6. More important, we also identified Sema3A as a direct target of miR-15b-5p. Reverse transcription polymerase chain reaction and western blot subsequently confirmed that miR-15b-5p negatively modulated the level of Sema3A. Mechanically, overexpression of Sema3A impeded the beneficial effects of miR-15b-5p on HG-mediated apoptosis, oxidative stress, and inflammatory response. Altogether, these findings manifested that miR-15b-5p protectively antagonized HG-triggered podocyte damage through relieving HG-induced apoptosis, oxidative stress, and inflammatory process in podocytes by targeting Sema3A, suggesting that miR-15b-5p might be a new therapeutic agent to improve management of DN.

Increased TRPC6 expression is associated with tubular epithelial cell proliferation and inflammation in diabetic nephropathy.

Although TRPC6 expression is shown to be significantly elevated in a rat model diabetic nephropathy (DN), its expression and role in human DN are unclear. We thus explored the role of TRPC6 in the pathophysiology of tubular epithelial cell injury following DN. HK-2 cells were cultured in a high-glucose medium to induce a DN cell model. Ad-TRPC6 and TRP6 siRNA were transfected to overexpress and knock down TRPC6. We found that TRPC6 expression was significantly upregulated in DN tissues and cells. TRPC6 siRNA inhibited cell proliferation and promoted cell apoptosis in HK-2 cells treated with high glucose, whereas Ad-TRPC6 showed the opposite effect. Furthermore, Ad-TRPC6 significantly promoted release of IL-8 and IL-6. Subsequent experiments demonstrated that the signaling pathway of nuclear factor of activated T cells (NFAT) was activated by Ad-TRPC6 and deactivated by TRPC6 siRNA. The NFAT signaling inhibitor, FK-506, eliminated the effect of TRPC6 on HK-2 cells. These results suggest that TRPC6 was upregulated in DN and could promote cell proliferation and inflammation by inhibiting the NFAT signaling pathway in tubular epithelial cells.

C1qTNF-related protein 1 improve insulin resistance by reducing phosphorylation of serine 1101 in insulin receptor substrate 1.

C1qTNF-related protein 1 (CTRP1) is independently associated with type 2 diabetes. However, the relationship between CTRP1 and insulin resistance is still not established. This study aimed to explore the role of CTRP1 under the situation of insulin resistance in adipose tissue. Plasma CTRP1 level was investigated in type 2 diabetic subjects (n = 35) and non-diabetic subjects (n = 35). The relationship between CTRP1 and phosphorylation of multi insulin receptor substrate 1 (IRS-1) serine (Ser) sites was further explored. Our data showed that Plasma CTRP1 was higher and negative correlation with insulin resistance in diabetic subjects (r = -0.283, p = 0.018). Glucose utilisation test revealed that the glucose utilisation rate of mature adipocytes was improved by CTRP1 in the presence of insulin. CTRP1 was not only related to IRS-1 protein, but also negatively correlated with IRS-1 Ser1101 phosphorylation (r = -0.398, p = 0.031). Furthermore, Phosphorylation levels of IRS-1 Ser1101 were significantly lower after incubation with 40 ng/mL CTRP1 in mature adipocytes than those with no intervention (p < 0.05). There was no significant correlation between CTRP1 and other IRS-1 serine sites (Ser302, Ser307, Ser612, Ser636/639, and Ser789). Collectively, our results suggested that CTRP1 might improve insulin resistance by reducing the phosphorylation of IRS-1 Ser1101, induced in the situation of insulin resistance as a feedback adipokine.

Elevated circulating levels of CTRP1, a novel adipokine, in diabetic patients.

Complement C1q tumor necrosis factor-related protein 1 (CTRP1), an adipose tissue-derived adipokine has been shown to decrease blood glucose levels and to improve metabolism of glucose in mice. In addition, CTRP1 has exhibited significant association with BMI, adiponectin and TNF-α in diabetic animal models. However, there are no published studies addressing CTRP1 levels in type 2 diabetic patients. Therefore, it was of interest to evaluate plasma CTRP1 levels and associated clinical parameters and biomarkers in patients with type 2 diabetes. 135 subjects were recruited to this study, including 62 type 2 diabetic patients (DM group) and 73 healthy subjects (control group). We measured biochemical parameters, CTRP1, TNF-α and adiponectin using enzyme-linked immunosorbent assay (ELISA). Plasma CTRP1 levels showed a significant difference between the DM group and the control group (646.3 ± 154.4 ng/mL vs. 442.6 ± 165.4 ng/mL, p < 0.01). In addition, CTRP1 was strongly positively associated with BMI, glucose levels, HbA1c, HOMA-IR and TNF-α in diabetic patients. CTRP1 showed negative correlation with adiponectin. In Multivariate regression analysis, CTRP1 was strongly independently associated with diabetes when CTRP1 levels were analyzed by both as a continuous variable and quartile (OR: 1.009, 95% CI: 1.004-1.015, p < 0.05; OR: 2.443, 95% CI: 1.379-4.182, p < 0.01, respectively). Increased plasma CTRP1 was independently associated with type 2 diabetes. Profiling of plasma adipokines such as CTRP1 is particularly important to obtain a greater understanding of their contribution to the type 2 diabetic state.