Two types of fixed-ratio combinations of basal insulin and a glucagon-like peptide-1 receptor agonist (GLP-1RA) have been approved for use in type 2 diabetes. One is insulin degludec/liraglutide ...(iDergLira), and the other is insulin glargine/lixisenatide (iGlarLixi). Direct comparisons between these two combination is not available.
The retrospective study included 186 patients with type 2 diabetes mellitus (DM) with inadequate glycemic control on metformin and basal insulin (degludec, glargine 100, glargine 300) who were switched to fixed-ratio combination GLP-1 RA and basal insulin. Patients were divided into two groups based on the basal insulin before study: group I (n = 86) treated with degludec were switched to iDegLira and patients group II (n = 99), treated with glargine were switched to iGlarLixi. The aim of this study was to directly compare the effects between two fixed - ratio combination on glycemic parameters and non glycemic parameters. Follow up was 6 months.
Mean HbA1c decreased similarly (- 1.2% vs.-1.1%). Higher percentage patients in iDegLira group had reached the HbA1c < 7% after 6 months (22% vs. 18.2%, p < 0.05). The mean change in fasting plasma glucose (FPG) was comparable for the two groups, while mean decrease postprandial plasma glucose (PPG) level were lower in iGlarLixi group (2 vs 1.8 mmol/l, p > 0.05). Change in body weight was significant in iDegLira group (1.8 kg vs. 0.7 kg, p < 0.001). At the end of the study patients showed decrease in total cholesterol (TC) and low-density lipoprotein (LDL) for 0.2 mmol/L in iDegLira, 0.1 mmol/l in iGlarLixi, triglycerides decreased 0.3 mmol/l in both groups, high-density lipoprotein(HDL) increased 0.1 mm/l in iGlarLixi.
Our results showed that more patients with iDegLira had HbA1c less than 7% and these combination had better effect on weight loss. There was no difference observed in FPG and PPG, lipid profile and rate of hypoglycemia.
Several studies report the important role of an altered gut microbiota in the development of obesity, highlighting the potential use of probiotics in the treatment of obesity. The aim of this study ...is to investigate the effect of a novel probiotic approach on the expression of specific miRNAs and mRNAs associated with obesity in combination with the hypocholesterolemic octacosanol. Twenty overweight/obese women participated in a randomized, placebo-controlled, double-blind study and were randomly divided into two groups: the intervention group (daily one capsule containing Lactobacillus plantarum 299v (DSM9843), Saccharomyces cerevisiae var. boulardii, and 40 mg octacosanol; N = 12) and the placebo group (N = 8). Changes in lipid parameters and expression of miRNAs and mRNAs were assessed before (T0) and after the 12-week intervention (T1). After the intervention, the expression of miR-155-5p (9.38 ± 0.85 vs. 8.38 ± 1.06, p = 0.05) and miR-24-3p (3.42 ± 0.38 vs. 2.71 ± 0.97, p = 0.031) showed significant decreases in the intervention group when compared to the control group. At T1, the expression of miR-155-5p (8.69 ± 1.31 vs. 9.3 ± 0.85, p = 0.04), miR-125b-5p (5.41 ± 1.18 vs. 5.99 ± 1.36, p = 0.049), and TNF-α (10.24 ± 1.66 vs. 11.36 ± 1.12, p = 0.009) were significantly decreased in the intervention group. No changes in lipids and anthropometric parameters were observed. The novel probiotic approach had a positive effect on regulating the expression of certain miRNAs and mRNAs important for regulating inflammation and adipogenesis, which are essential for obesity onset and control.
The role of autophagy, a process in which the cell self-digests its own components, was investigated in glioma cell death induced by the hydroxymethylglutaryl-coenzyme A (HMG-CoA) ...reductase-inhibiting drug simvastatin. Induction of autophagy and activation of autophagy-regulating signalling pathways were analyzed by immunoblotting. Flow cytometry/fluorescent microscopy was used to assess autophagy-associated intracellular acidification and apoptotic markers (phosphatidylserine exposure, DNA fragmentation and caspase activation). Cell viability was determined by crystal violet, MTT or LDH release assay. Simvastatin treatment of U251 and C6 glioma cell lines caused the appearance of autophagolysosome-like intracytoplasmic acidic vesicles. The induction of autophagy in U251 cells was confirmed by the upregulation of autophagosome-associated LC3-II and pro-autophagic beclin-1, as well as by the downregulation of the selective autophagic target p62. Simvastatin induced the activation of AMP-activated protein kinase (AMPK) and its target Raptor, while simultaneously downregulating activation of Akt. Mammalian target of rapamycin (mTOR), a major AMPK/Akt downstream target and a major negative autophagy regulator, and its substrate p70 S6 kinase 1 were also inhibited by simvastatin. Mevalonate, the product of HMG-CoA reductase enzymatic activity, AMPK siRNA or pharmacological inactivation of AMPK with compound C suppressed, while the inhibitors of Akt (10-DEBC hydrochloride) and mTOR (rapamycin) mimicked autophagy induction by simvastatin. Inhibition of autophagy with bafilomycin A1, 3-methyladenine and LC3β shRNA, as well as AMPK inhibition with compound C or AMPK siRNA, markedly increased apoptotic death of simvastatin-treated U251 cells. These data suggest that inhibition of AMPK-dependent autophagic response might sensitize glioma cells to statin-induced apoptotic death.
Insulin resistance is believed to be an integral component of the polycystic ovary syndrome (PCOS). Beta (ß) cell dysfunction is also found in PCOS. In the study, we determined the influence of age, ...body mass index (BMI), and waist-to-hip ratio (WHR) on insulin response to oral glucose load (OGTT) and on insulin sensitivity (Si) and ß-cell function in young women with PCOS. One hundred fourteen patients with PCOS and 41 controls with normal basal plasma glucose were studied. A 75-g OGTT was performed to determine glucose tolerance and insulin response. Insulin sensitivity and ß-cell function were studied using a modified frequently sampled IV glucose tolerance test (FISGTT) to determine the acute insulin response (AIRG), as well as Si by minimal model analysis. Si was decreased in PCOS women (2.49 0.18 vs. 3.41 ± 0.36, p<0.05), but no difference in AIRG existed between the PCOS and control group (75.1 ± 4.6 vs. 63.4 ± 4.6, p<0.05). BMI and WHR correlated negatively with Si (r = −0.43; r = −0.289, p<0.001, respectively), but not with AIRG (r = 0.116; r = −0.02, p>0.05, respectively). Increasing age correlated negatively with AIRG (r = −0.285, p<0.001). There was a significant interaction between disease (PCOS), BMI, and WHR on Si as well as between age and PCOS on AIRG. Thus, patients below the age of 25 with PCOS showed enhanced AIRG (89.5 ± 7.1 vs. 65.1 ± 6.7, p<0.05) and decreased Si (2.43 ± 0.25 vs. 4.52 ± 0.62, p<0.05) compared to age-matched controls. In conclusion, these data suggest that not all patients with PCOS have basal and stimulated hyperinsulinemia, insulin resistance, and impaired glucose tolerance. Based on these data in young PCOS subjects, the development of insulin resistance and T2DM may be prevented with appropriate treatment strategies.
Autophagy, a process of controlled cellular self-digestion, could be involved in cyclic remodeling of the human endometrium. We investigated endometrial mRNA expression of 23 autophagy-related (ATG) ...genes and transcription factors in healthy controls (n = 12) and anovulatory polycystic ovary syndrome (PCOS) patients (n = 24), as well as in their subgroup (n = 12) before and after metformin treatment. The mRNA levels of transcription factor forkhead box protein O1 (FOXO1) and several molecules involved in autophagosome formation (ATG13, RB1-inducible coiled-coil 1), autophagosome nucleation (ATG14, beclin 1, SH3-domain GRB2-like endophilin B1), autophagosome elongation (ATG3, ATG5, γ-aminobutyric acid receptor-associated protein - GABARAP), and delivery of ubiquitinated proteins to autophagosomes (sequestosome 1), were significantly reduced in anovulatory PCOS compared to healthy endometrium. Free androgen index, but not free estrogen index, insulin levels, or body mass index, negatively correlated with the endometrial expression of ATG3, ATG14, and GABARAP in PCOS patients. Treatment of PCOS patients with metformin (2 g/day for 3 months) significantly increased the endometrial mRNA levels of FOXO1, ATG3, and UV radiation resistance-associated gene. These data suggest that increased androgen availability in PCOS is associated with metformin-sensitive transcriptional downregulation of endometrial autophagy.
•Endometrial expression of several autophagy-related genes is reduced in PCOS.•Free androgen index negatively correlates with autophagy gene expression in PCOS.•Metformin treatment partly restores autophagy gene expression in PCOS endometrium.
In vitro and in vivo anti-melanoma action of metformin Janjetovic, Kristina; Harhaji-Trajkovic, Ljubica; Misirkic-Marjanovic, Maja ...
European journal of pharmacology,
10/2011, Letnik:
668, Številka:
3
Journal Article
Recenzirano
The in vitro and in vivo anti-melanoma effect of antidiabetic drug metformin was investigated using B16 mouse melanoma cell line. Metformin caused a G
2/M cell cycle arrest associated with apoptotic ...death of melanoma cells, as confirmed by the flow cytometric analysis of cell cycle/DNA fragmentation, phosphatidylserine exposure and caspase activation. Metformin-mediated apoptosis of melanoma cells was preceded by induction of oxidative stress and mitochondrial membrane depolarization, measured by flow cytometry in cells stained with appropriate fluorescent reporter dyes. The expression of tumor suppressor protein p53 was increased, while the mRNA levels of anti-apoptotic Bcl-2 were reduced by metformin, as revealed by cell-based ELISA and real-time RT-PCR, respectively. Treatment with metformin did not stimulate expression of the cycle blocker p21, indicating that p21 was dispensable for the observed cell cycle arrest. The activation of AMP-activated protein kinase (AMPK) was not required for the anti-melanoma action of metformin, as AMPK inhibitor compound C completely failed to restore viability of metformin-treated B16 cells. Metformin induced autophagy in B16 cells, as demonstrated by flow cytometry-detected increase in intracellular acidification and immunoblot-confirmed upregulation of autophagosome-associated LC3-II. Autophagy inhibitors ammonium chloride and wortmannin partly restored the viability of metformin-treated melanoma cells. Finally, oral administration of metformin led to a significant reduction in tumor size in a B16 mouse melanoma model. These data suggest that anti-melanoma effects of metformin are mediated through p21- and AMPK-independent cell cycle arrest, apoptosis and autophagy associated with p53/Bcl-2 modulation, mitochondrial damage and oxidative stress.
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Abstract Background It has been documented that patients with metabolic syndrome (MS) and vascular complications have higher homocysteine levels. Hyperhomocysteinemia correlates with IR, increasing ...oxidative stress, which causes lesions of vascular endothelium leading to endothelial dysfunction, hypertension and atherosclerosis. Objective The objectives of the study were to examine homocysteine values, along with cardiovascular risk factors (lipid and apolipoprotein status, CRP, blood pressure), indicators of renal function (microalbuminuria/24 h, uric acid), glucose regulation (glucose and insulin level, HbA1c, HOMA-IR) and anthropometric parameters (BMI, WC, HC, WHR) in patients with and without MS as a correlation between homocysteine and MS factors. Methods The study included obese and overweight individuals, aged of 30-75 yrs. classified into two groups: with MS (n = 35) and without MS (n = 41). Results Patients with MS had increased WC, BMI, BP, glycaemia, HOMA-IR, TG, CRP, microalbuminuria, homocysteine and decreased HDL-C (p < 0.05). Statistically significant difference between groups was found for WC, BMI, sBP and dBP, TG, HDL-C (p < 0.01) and glycaemia, CRP, Apo B, HOMA-IR (p < 0.05). Significant positive correlations were found between homocysteine and sBP (p = 0.036), dBP (p = 0.04), Apo B (p = 0.038) and hyperlipoproteinemia (type IIa, type IIb and type IV) (p = 0.04). Conclusion Patients with MS had increased abdominal obesity, hypertension, hypertriglyceridemia, inflammation factors, IR, homocysteine and microalbuminuria as markers of endothelial dysfunction. A correlation between homocysteine and hypertension and hyperlipoproteinemia showed that homocysteine could be used as a potential marker for atherosclerosis progression.
Abstract We explored the effect of therapeutic glucoregulation on the blood levels of proinflammatory T helper (Th)17 cytokines interleukin (IL)-17 and IL-23, and Th1 cytokines interferon (IFN)-γ and ...IL-12 in newly diagnosed type 2 diabetes patients. The investigated group consisted of 23 subjects (17 men and 6 women, age 26–64). The cytokine serum levels, glycated hemoglobin (HbA1c) as a marker of glucoregulation, homeostasis model assessment index as a measure of insulin resistance (HOMA-IR), and body mass index (BMI) were determined before and after 12 weeks of therapy consisting of standard lifestyle modification and metformin (1000 mg b.i.d.). The levels of Th17 and Th1 cytokines before treatment did not correlate with age, BMI or HOMA-IR. The patients with poor glucoregulation (HbA1c > 7%, n = 12), compared to those with good glucoregulation (HbA1c ≤ 7%, n = 11), had higher serum levels of Th17 and Th1 cytokines, but only the differences in IL-17 (median 21.2 pg/ml vs. 4.8 pg/ml) and IFN-γ 5 (0.6 pg/ml vs. 27.7 pg/ml) reached statistical significance ( p = 0.003 and p = 0.012, respectively). The reduction of HbA1c values (from 8.6 to 5.9%, p = 0.000) observed upon treatment in patients with poor glucoregulation was associated with a significant decrease in the concentration of IL-17 (from 21.2 to 12.9 pg/ml, p = 0.020), but not IFN-γ (50.6 vs. 52.3, p = 0.349). These data indicate that therapeutic improvement of glucoregulation might contribute to a reduction of IL-17 levels in newly diagnosed type 2 diabetes patients.
