Short-term continuous subcutaneous insulin infusion combined with insulin sensitizers rosiglitazone, metformin, or antioxidant α-lipoic acid in patients with newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Short-term continuous subcutaneous insulin infusion (CSII) in patients with newly diagnosed type 2 diabetes has been proved effective in improving metabolic control and ß-cell function, thus inducing long-term drug-free remission. A randomized controlled trial was conducted to investigate whether CSII in combination with rosiglitazone, metformin, or α-lipoic acid separately brings about extra benefits. PATIENTS AND METHODS: One hundred sixty patients with newly diagnosed type 2 diabetes were randomized to one of four treatment groups: CSII alone, CSII in combination with rosiglitazone or metformin for 3 months, or CSII with α-lipoic acid intravenous infusion for 2 weeks. Duration of CSII treatment was identical in the four groups. Glucose and lipid profiles, homeostasis model assessment (HOMA) indices, acute insulin response (AIR), intramyocellular lipid (IMCL) level, and malondialdehyde level were compared before and after intervention. RESULTS: The near-normoglycemia rate at the third month in CSII alone and that in combination with rosiglitazone, metformin, or α-lipoic acid was 72.5%, 87.5%, 90%, and 75%, respectively (metformin group vs. CSII alone, P=0.045). The metformin group achieved euglycemia in a shorter time (2.6 ± 1.3 vs. 3.7 ± 1.8 days, P=0.020) with less daily insulin dosage and was more powerful in lowering total cholesterol, increasing AIR and HOMA ß-cell function, whereas reduction of IMCL in the soleus was more obvious in the rosiglitazone group but not in the metformin group. The efficacy of combination with α-lipoic acid was similar to that of CSII alone. CONCLUSIONS: Short-term CSII in combination with rosiglitazone or metformin is superior to CSII alone, yet the efficacy of the two differs in some way, whereas that with α-lipoic acid might not have an additive effect.

Adverse effect of metformin therapy on serum vitamin B12 and folate: short-term treatment causes disadvantages?

Diabetes is a global public health challenge that imposes heavy burdens on communities and individuals. Metformin, the first-line medication for diabetes, has the superiority of reducing risk of macrovascular diseases, all-cause mortality and even possibly cancers. Recent observational studies, however, have demonstrated that long-term metformin therapy increases the probability of vitamin B12 and folate deficiency, and might contribute to the progression of diabetic peripheral neuropathy. Despite metformin is widely used and extensively studied, randomized controlled trials performed to explore the effects of metformin on vitamin B12 and folate are limited. Besides, whether short-term treatment causes vitamin deficiency is a pending issue. We postulate that even a few-month treatment with metformin results in the decrease of vitamin B12 and folate. However, supplementation of vitamin B12 rather than the combination of vitamin B12 and folate might be profitable based on the mechanism of metformin on vitamins in patients with type 2 diabetes. This viewpoint differs from those of majority that a combined supplementation of vitamin B12 and folate is inclined to be advised.

Down-regulation of miR-218-2 and its host gene SLIT3 cooperate to promote invasion and progression of thyroid cancer.

CONTEXT: The functional relationships between intronic microRNAs (miRNAs) and their host genes in thyroid cancer remain unclear. miR-218, a miRNA down-regulated in several kinds of cancers and associated with multiple cancer phenotypes, is transcribed from 2 loci located on chromosomes 4p15.31 (miR-218-1) and 5q35.1 (miR-218-2) within the introns of SLIT2 and SLIT3, respectively. OBJECTIVE: The aim of our work was to investigate the expression and the roles of miR-218-1 and miR-218-2, as well as their host genes SLIT2 and SLIT3 in thyroid carcinogenesis. DESIGN: The expression of miR-218-1 and miR-218-2, as well as their host genes SLIT2 and SLIT3, in a panel of normal and neoplastic human thyroid tissues was assessed by quantitative RT-PCR. We restored the expression of miR-218-2 and SLIT3 in thyroid cancer cells and evaluated their effects on cell invasion, migration, and proliferation. RESULTS: We found that miR-218-2 and its host gene SLIT3 were down-regulated concomitantly in thyroid cancer. Synergistic inhibitory effects of miR-218-2 with SLIT3 on thyroid cancer cell invasion, migration, and proliferation were observed. Moreover, the effects of miR-218-2 on thyroid cancer cells were due, at least partially, to targeting PDGFRA and PLCG1. CONCLUSIONS: These results implicate the involvement of miR-218-2 and its host gene SLIT3 in thyroid cancer cell invasion, migration, and proliferation. Our findings highlight the functional associations of intronic miRNAs and their host genes in thyroid carcinogenesis.

Impact of vitamin D on chronic kidney diseases in non-dialysis patients: a meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES: Recent studies have supported a role for both newer and more established vitamin D compounds in improving proteinuria, although systematic evaluation is lacking. Furthermore, concerns remain regarding the influence of vitamin D on the progression of renal function. We analyzed the efficacy and safety of vitamin D in non-dialysis patients and compared the use of newer versus established vitamin D compounds by performing a meta-analysis of randomized controlled trials. DESIGN: A literature search of PubMed (1975 to September, 2012), EMBASE.com (1966 to September, 2012) and Ovid EBM Reviews (through September, 2012) was conducted. RESULTS: Eighteen studies were eligible for final inclusion; of these, six explored the effects of vitamin D on proteinuria, twelve studied the effects of supplementation on renal function, and fifteen discussed the incidence of hypercalcemia. Compared to the placebo or no interference, both the newer and established vitamin D sterols reduced proteinuria to a similar extent (RR, 2.00; 95% CI, 1.42 to 2.81). No decrease in the glomerular filter rate was observed (SMD, -0.10; 95%CI, -0.24 to 0.03), and the risk for dialysis initiation was 1.48 (95% CI, 0.54 to 4.03) with vitamin D treatment. Additionally, there was an increased risk of hypercalcemia for patients treated with either newer or established vitamin D compounds as compared with the controls (RR, 4.78; 95% CI, 2.20 to 10.37). The head-to-head studies showed no differences in the effects of either newer or established compounds on proteinuria or the risk of hypercalcemia. No serious adverse events were associated with the administration of vitamin D. CONCLUSIONS: Vitamin D therapy appears to decrease proteinuria and have no negative influence on renal function in non-dialysis patients. But the occurrence of hypercalcemia should be evaluated when vitamin D is provided. No superiority for newer versus established vitamin D analogue is found.

Fasting plasma glucose after intensive insulin therapy predicted long-term glycemic control in newly diagnosed type 2 diabetic patients.

Short term intensive insulin therapy has been reported to induce long term euglycemia remission in patients with newly diagnosed type 2 diabetes mellitus, but the factors that are responsible for long-term remission or hyperglycemia relapse are unknown. Original data of 188 patients with newly diagnosed type 2 diabetes treated with short term intensive insulin therapy was reanalyzed. Patients who maintained glycemic control for 12 months with only life style intervention were defined as remission while those who failed to maintain glycemic control for 12 months as hyperglycemia relapse. Relationships of metabolic control, ß cell function and insulin sensitivity with remission time and hyperglycemia relapse were explored. Totally 93 patients achieved 12-month euglycemic remission. Substantial improvement in blood glucose, parameters of ß cell function and insulin sensitivity were obtained in both remission and relapse patients. The duration of remission was correlated with fasting plasma glucose measured after cessation of continuous subcutaneous insulin infusion (CSII) therapy (fasting plasma glucose (FPG) after CSII, r= -0.349, p<0.0001). Multivariate logistic regression show that FPG after CSII was independent predictor of hyperglycemic relapse (Odds ratio=1.585, p=0.001). All patients were stratified into three groups according FPG after CSII. As multivariate Cox proportional hazards regression demonstrated, compared with the patients with FPG<6.1mmol/L, risk for hyperglycemia relapse was increased 60% in those with 6.1 mmol/L≤FPG≤7.0 mmol/L (Hazard ratio=1.60, p=0.049), and 1.69 folds in those with FPG>7.0 mmol/L (Hazard ratio=2.69, p<0.0001). Our study demonstrated that fasting plasma glucose after intensive insulin therapy is a convenient and significant predictor for hyperglycemic relapse.

Fufang Xue Shuan Tong capsules inhibit renal oxidative stress markers and indices of nephropathy in diabetic rats.

Fufang Xue Shuan Tong (FXST) capsules, a traditional Chinese medicine, have been used to treat diabetic nephropathy for many years. FXST has been shown to attenuate elevated levels of oxidative stress in the retina of diabetic rats. However, whether FXST protects kidneys through the same mechanism(s) remains unclear. In this study, diabetes was induced in rats by administration of a high-fat diet and low-dose streptozotocin. Rats were administered low (450 mg/kg/day), middle (900 mg/kg/day) or high (1800 mg/kg/day) doses of FXST orally for 3 months. Another group was administered 50 mg/kg/day orally for the same period. The results indicated that all doses of FXST reduced urinary protein excretion and creatinine clearance and ameliorated the diabetic nephropathy-related mesangial matrix expansion. However, only middle and high doses of FXST prevented glomerular hypertrophy in diabetic rats, and the high dose showed the greatest inhibitory effect with regard to mesangial matrix expansion. Furthermore, superoxide dismutase activities were significantly elevated, whereas malondialdehyde levels were significantly reduced in the renal cortex following FXST treatment. The kidney-protective role of FXST is not inferior to that of captopril, one of the most commonly used drugs for the treatment of diabetic nephropathy. In conclusion, FXST retards the progression of diabetic nephropathy, while high-dose FXST shows the most prominent effect in counteracting the pathological changes of diabetic nephropathy. The renoprotective action of FXST is induced by the reduction of oxidative stress in diabetic nephropathy.

The Akt/FoxO1/p27 pathway mediates the proliferative action of liraglutide in ß cells.

Numerous studies have shown that liraglutide, a modified form of human glucagon-like peptide-1 (GLP-1), increases ß-cell mass. However, the underlying molecular mechanisms remain unclear. In the present study, we investigated the role of Akt/FoxO1/p27 signaling in liraglutide-induced ß-cell proliferation. INS-1 rat insulinoma cells were exposed to two different concentrations of liraglutide. MTT assay was performed to evaluate ß-cell proliferation. The expression of Akt/FoxO1/p27 was detected by quantitative real-time PCR and Western blotting. The results revealed that in comparison to the non-treatment group, stimulating INS-1 cells with 10 and 100 nM liraglutide caused ß-cell proliferation to be significantly enhanced. The mRNA levels of p27 in INS-1 cells declined upon treatment with liraglutide compared to the non-treatment group. Western blot analysis revealed that the phosphorylation of Akt and FoxO1 was markedly elevated following exposure to liraglutide. Moreover, LY294002, a phosphatidylinositol 3-kinase (PI-3K) inhibitor, significantly abrogated liraglutide-induced effects. Therefore, we conclude that liraglutide increased the ß-cell mass by upregulating ß-cell proliferation and that the proliferative action of liraglutide in ß cells was mediated by activation of PI-3K/Akt, which resulted in inactivation of FoxO1 and decreased p27.

Early intensive insulin therapy attenuates the p38 pathway in the renal cortex and indices of nephropathy in diabetic rats.

In this rodent study, we compared the effects of early versus late intensive insulin therapy on diabetic nephropathy and potential causal mechanisms. Diabetes was induced in rats by high-fat diet and low-dose streptozotocin. Intensive insulin therapy was initiated in the early intensive insulin therapy groups as soon as diabetes was confirmed and lasted for 8 (8wEI group) and 16 weeks (16wEI group). In the late insulin therapy group (LI group), intensive insulin treatment was initiated 8 weeks later and lasted for 8 weeks. Age-matched diabetic rats (8wDM group and 16wDM group) and non-diabetic rats (8wNC group and 16wNC group) served as controls. Histological analysis, real-time PCR, and western blot were performed in renal cortex specimens. Glomerular hypertrophy and mesangial matrix expansion were prominent in the 16wDM and LI groups while the EI groups remained normal and similar to the 16wNC group. Western blots revealed that p38 MAPK activities in the EI groups decreased significantly, whereas the level in the LI group was markedly higher than the 16wEI group, and not different from the DM groups. Activities of MKK3/6, CREB and MKP-1 proteins as well as CREB and MKP-1 mRNA showed a similar pattern. Therefore, we concluded that early intensive insulin treatment and attainment of good glycemic control counteracted some renal molecular pathways associated with epigenetic metabolic memory to minimize risk of diabetic nephropathy. However, late insulin therapy did not abrogate the increased renal cortical p38 MAPK pathway activation in diabetic rats and led to glomerular hypertrophy and extracellular matrix expansion.