The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin–silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes.

Effect of Metformin on Testosterone Levels in Male Patients With Type 2 Diabetes Mellitus Treated With Insulin

AimTo explore the chronic effects of metformin on testosterone levels in men with type 2 diabetes mellitus (T2DM).MethodsThis is a secondary analysis of a real-world study evaluating the efficacy and safety of premixed insulin treatment in patients with T2DM via 3-month intermittent flash glucose monitoring. Male patients aged 18-60 who were using metformin during the 3-month study period were included as the metformin group. The control group included males without metformin therapy by propensity score matching analysis with age as a covariate. Testosterone levels were measured at baseline and after 3-month treatment.ResultsAfter 3-month treatment, the control group had higher levels of total testosterone, free and bioavailable testosterone than those at baseline (P<0.05). Compared with the control group, the change of total (-0.82 ± 0.59 vs. 0.99 ± 0.59 nmol/L) and bioavailable (-0.13 ± 0.16 vs. 0.36 ± 0.16 nmol/L) testosterone levels in the metformin group significantly decreased (P=0.036 and 0.029, respectively). In Glycated Albumin (GA) improved subgroup, the TT, FT, and Bio-T levels in the control subgroup were higher than their baseline levels (P < 0.05). Compared with the metformin subgroup, TT level in the control subgroup also increased significantly (P=0.044). In GA unimproved subgroup, the change of TT level in the metformin subgroup was significantly lower than that in the control subgroup (P=0.040).ConclusionIn men with T2DM, 3-month metformin therapy can reduce testosterone levels, and counteract the testosterone elevation that accompanied with the improvement of blood glucose.Clinical Trial Registrationhttps://www.clinicaltrials.gov/ct2/show/NCT04847219?term=04847219&draw=2&rank=1.

Oral Antidiabetics and Sleep Among Type 2 Diabetes Patients: Data From the UK Biobank

Previous small-scale studies have found that oral antidiabetic therapy is associated with sleep difficulties among patients with type 2 diabetes (T2D). Here, we used data from 11 806 T2D patients from the UK Biobank baseline investigation to examine the association of oral antidiabetic therapy with self-reported difficulty falling and staying asleep and daily sleep duration. As shown by logistic regression adjusted for, e.g., age, T2D duration, and HbA1c, patients on non-metformin therapy (N=815; 86% were treated with sulphonylureas) had a 1.24-fold higher odds ratio of reporting regular difficulty falling and staying asleep at night compared to those without antidiabetic medication use (N=5 366, P<0.05) or those on metformin monotherapy (N=5 625, P<0.05). Non-metformin patients reported about 8 to 10 minutes longer daily sleep duration than the other groups (P<0.05). We did not find significant differences in sleep outcomes between untreated and metformin patients. Our findings suggest that non-metformin therapy may result in sleep initiation and maintenance difficulties, accompanied by a small but significant sleep extension. The results of the present study must be replicated in future studies using objective measures of sleep duration and validated questionnaires for insomnia. Considering that most T2D patients utilize multiple therapies to manage their glycemic control in the long term, it may also be worth investigating possible interactions of antidiabetic drugs on sleep.

Effectiveness of Metformin and its Combination with Probiotic in Polycystic Ovarian Disease with Hyperprolactinemia: A Randomized Clinical Trial

Background: Polycystic ovarian syndrome (PCOS) is an endocrine disorder that predominantly affects women of the reproductive age. Anovulation and abnormal uterine bleeding are caused by hyperprolactinemia, which affects the hypothalamic-pituitary-ovarian axis. Aim: In this study, the efficacy of combined Probiotic and Metformin therapy on hyperprolactinemia levels in PCOS patients was compared to Metformin therapy alone. Methodology: 102 participants having hyperprolactinemia were enrolled via convenient sampling technique between January 2019 to August 2019. Out of them women having Polycystic Ovarian Syndrome (PCOS) and high serum prolactin levels were randomly assigned to one of two groups: group one received oral Metformin tablet 500 mg T.D. for three months, and group two received oral Metformin tablet 500 mg T.D and Probiotic capsule 180 mg O.D for three months. Serum prolactin levels in both groups were compared before and after treatment. Results: 54 (53%) of the 102 hyperprolactinemia women had PCOS. The Combination group showed improvement in reduction in hyperprolactinemia levels after 12 weeks of intervention. Conclusion: The addition of Probiotic to Metformin improved prolactin levels in women with polycystic ovarian syndrome with hyperprolactinemia more than Metformin alone.

Lipocalin-2 Level in Patients with Polycystic Ovary Syndrome: Association with Insulin Resistance and Metformin Therapy

Background PCOS appears to be associated with an increased risk of metabolic aberrations, including insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease throughout womens’ lifespan. Obesity is a state of chronic low-grade systemic inflammation. This chronic inflammation is characterized by abnormal cytokine production and activation of inflammatory signaling pathways in adipose tissues, which contributes to insulin resistance and its related diseases such as PCOS and metabolic syndrome. Objective To evaluate Lipocalin-2 level in a sample of Egyptian females with PCOS and study the effect of metformin therapy on Lipocalin-2 level in patients with PCOS. Methods This case control study was conducted on 52 females, collected from the outpatient obstetrics and gynaecology clinics of Ain Shams University Hospitals from June 2018 to March 2019, their age ranged between 17-43 years old. divided into 2 groups: Group (I) 32 women with polycystic ovary syndrome According to the Rotterdam diagnostic criteria of PCOS, and Group (II) 20 healthy women old with normal ovulatory cycle as a control group. All subjects were subjected to full medical history taking, thorough physical examination including BMI and waist circumference. Fasting plasma glucose, Fasting s.insulin, HOMA-IR, lipocalin-2 level were assessed. Results Serum lipocalin-2 levels did not differ between patients with PCOS and BMI-matched healthy controls (P-value 0.193), and there was no significant difference between the 2 studied groups as regard HOMA-IR (p = 0.375). Metformin therapy for 3 months in patients with PCOS in the present study, resulted in significant reduction in lipocalin-2 level (p-value<0.01), (mean 54.2±15.3ng/ml before metformin therapy vs 42.9±14.2 ng/ml after metformin therapy). Moreover, metformin therapy in PCOS group resulted in significant reduction in weight, BMI, waist circumference and HOMA-IR. Furthermore, linear regression analysis for the parameters affecting lipocalin level in our study, showed that BMI was the only significant confounder affecting lipocalin level. So, the reduction in lipocalin level following metformin therapy in PCOS group in our study may be due to weight reduction perse. Conclusion PCOS per se is not associated with elevated serum lipocalin-2 levels. Metformin therapy induces a significant reduction in serum lipocalin-2 levels, weight, BMI, waist circumference and HOMA-IR in patients with PCOS. Reduction of BMI was the only significant confounder affecting lipocalin level after metformin therapy. So the reduction in lipocalin level following metformin therapy in patients with PCOS in our study may be due to weight reduction perse.