Dose Of Metformin Research Articles

Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active?

Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients. Patients with advanced melanoma, renal cell carcinoma or lung cancer receiving nivolumab with concurrent diabetes treated with metformin were retrospectively collected. The primary endpoint was the safety of nivolumab plus metformin combination. We collected 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy in four Italian Hospitals. The concomitant use of nivolumab and metformin was well tolerated; adverse events (AEs) of any grade occurred in 75% of patients (mainly fatigue, pruritus, rash, and asthenia). Grade 3 AEs occurred only in 20% of cases; no grade 4 AEs were observed. A statistically significant correlation was found between higher doses of metformin (>1,000 mg daily) and longer progression-free survival (p=0.021), overall survival (p=0.037) and higher overall response rate. The combination of nivolumab and metformin was safe and might have an antitumor activity, supporting further investigations on the synergistic antitumor effect of this combination.

Low-dose metformin targets the lysosomal AMPK pathway through PEN2

Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1–4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase8, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.

Chronic Treatment with Metformin Has No Disrupting Effect on the Hepatic Circadian Clock in Mice.

Background and Objectives: The antidiabetic agent metformin is known to activate AMP-activated protein kinase (AMPK) in various tissues. Because AMPK can modulate intracellular circadian clocks through regulating the stability of clock components, a single dose of metformin has been reported to affect circadian clocks in the peripheral tissues. In this study, therefore, we investigated whether chronic treatment with metformin causes the impairment of circadian clocks, especially if given at an inappropriate time. Materials and Methods: Non-diabetic C57BL/6J mice were allowed access to food only during 4 h at the beginning of the dark period, and repeatedly i.p. injected with a nearly maximum non-toxic dose of metformin, once daily either at 4 h after the beginning of the dark period or at the beginning of the light period. Diabetic ob/ob mice were given free access to food and treated with metformin in drinking water. Results: Under the controlled feeding regimen, 8-day treatment with metformin did not alter the mRNA expression rhythms of clock genes in both liver and adipose tissue of C57BL/6J mice, regardless of dosing time. In addition, chronic treatment with metformin for 2 weeks affected hepatic AMPK activation rhythm but did not disrupt the circadian clocks in the liver and adipose tissues of the ob/ob mice. Conclusions: These results mitigate concerns that treatment with metformin impairs peripheral circadian clocks, although confirmation is needed in humans.

A Successful Rescue Case of Lactic Acidosis and Acute Renal Failure Caused by Excessive Dose of Metformin

A Successful Rescue Case of Lactic Acidosis and Acute Renal Failure Caused by Excessive Dose of Metformin

Efficacy and Safety of Empagliflozin as Add-On Therapy in Patients of Type-2 Diabetes Mellitus

OBJECTIVES: To assess efficacy of two doses i.e., 10 mg and 25 mg in lowering the glycated haemoglobin (HbA1C) and fasting blood glucose (FBG) in patients of type 2 diabetes mellitus (T2DM) having suboptimal glycaemic control on maximal doses of Metformin and Sitagliptin, and to see the frequency of its side-effects. METHODOLOGY: The study design was a randomized control trial. Fifty nine adult patients of T2DM who were already on 2000 mg of Metformin and 100 mg of Sitagliptin and were having suboptimal glycaemic control (HBA1C >7% and <12%) were randomized to two groups, one group receiving 10 mg (Group A) and the other group receiving 25 mg of empagliflozin (Group B) as an additional treatment. HbA1C and FBG were taken before and 12 weeks after addition of empagliflozin in both the groups. Side effects of empagliflozin such as urinary tract infections (UTI) and genital mycotic infections were also recorded in both the groups. RESULTS: Total patients in-group A were 31 and their mean age was 51.48±4.29 years. In-group B there were 28 patients and their mean age was 52.39±5.20 years. There was a statistically significant reduction of both HbA1C and FBG in both the groups after empagliflozin treatment; (p=0.000) for both HbA1C and FBG in both the groups. Although numerically UTI and genital mycotic infections were more than pre-treatment numbers, they were not statistically significant (p>0.05). CONCLUSION: Empagliflozin can be safely added to the oral anti-diabetic regimen of patients with type 2 diabetes mellitus who have suboptimal glycaemic control and results in significant improvement in HbA1C.

Safe Combination of Cisplatin and Metformin Reverts the Malignant Ascites in a Mouse Model to a Solid Tumor by Downregulation of ΔNp63 and Induces Tumor Dormancy via mTOR/ p21 Mechanism

Background: Currently, combination therapy has become the cornerstone of cancer treatment. The combination of different anti-cancer mechanisms can induce tumor cell quiescence. However, toxicity to normal tissue is the major limitation of existing combined drugs. Method: In this experimental study, Ehrlich ascites carcinoma inoculated into mice was targeted with just one dose of cisplatin and later doses of metformin, a safe anti-diabetic drug with an anti-cancer effect, to maintain Ehrlich ascites carcinoma (EAC) cells in the quiescent state and secure a longer survival time without tumor recurrence. Results: The group that underwent dual therapy developed a delayed solid tumor instead of a malignant ascites. The induction of chemo-quiescence in the EAC cells was proven by the downregulation of mechanistic target of rapamycin and the upregulation of cyclin-dependent kinase inhibitor 1 (p21) expressions. Intriguingly, the conversion of free neoplastic cells into a solid tumor was associated with a significant decrease in ΔNp63 immunostaining in EAC cells. Conclusion: Taken together, a single dose of cisplatin followed by metformin doses could overcome the aggressiveness of malignant ascites by the conversion into a solid tumor, induction of chemo-quiescence, and the extension of survival time.

Repression of Cell-to-Matrix Adhesion by Metformin Chloride Supports Its Anti-Metastatic Potential in an In Vitro Study on Metastatic and Non-Metastatic Cancer Cells.

Glucose metabolism has significant impact on cancer cell survival and proliferation. Our previous studies have shown that level of glucose in the medium affects the cell attachment to and detachment from the substratum. Control of glucose metabolism in cancer cells has potential to serve as an anti-cancer therapy. Different anti-diabetic drugs have been reported to inhibit glucose uptake at cellular level by glucose transporters. Metformin chloride is commonly used as antidiabetic drug. It is known that use of metformin reduces chances of developing cancer in diabetic patients. Here we have investigated the effect of metformin on cell adhesion proteins and other related factors in different cancer cells, both metastatic and non-metastatic. The object was to evaluate the effect of different doses of metformin on the onset of metastasis after these are detached from their primary site of origin and re-attached at the secondary site. For this purpose, we grew different cancer cells (MDA-MB231, MCF7, HCT116, and SF767) in culturing media containing different concentrations of metformin chloride. Quantitative real-time PCR was used to evaluate the expression profile of the genes involved in cell adhesion. It was observed that metformin treatment increased the expression of epithelial isoforms of cell adhesion molecules along with integrins responsible for cell-to-matrix adhesion and inducing specific morphological changes such as development of cytoskeletal structures in different cancer cell lines which normally lead to attainment of mesenchymal phenotype. The effect of metformin appeared to be different in different doses. The glioblastoma cells (SF767) were observed to be the most sensitive cells among all cancer cells under study. Our data supports the idea that the metformin prevents the cancer cells from acquiring mesenchymal phenotype and hence prevents onset of metastasis, and if the process has already started then it has potential to prevent cancer cell attachment to the secondary site.

Investigation of Effects of Metformin on Rats’ Urinary Bladder Contractions Effects of Metformin on Rats’ Bladder Contractions

Objective: The effects of different doses of metformin on the contractility of female Sprague-Dawley rat bladder strips were evaluated. Material and Methods: Rats were decapitated and the bladder strips measuring 2–4 × 6–12 mm prepared from the whole urinary bladder were suspended in isolated tissue organ baths. Tissues in the chambers were rinsed every 30 minutes for 60 minutes and allowed to equilibrate. Afterwards, 10-4 M acetylcholine was added to all isolated tissue baths. After one hour of rinsing, metformin (2 mM) was added and incubated 30 minutes. After 30 minutes, the same dose of acetylcholine was added without rinsing, and immediately after this protocol was performed with 10 mM and 20 mM metformin doses. Results: All of these doses led to increased contractions in a dose-dependent manner. The 2 mM dose did not induce any contraction in area (213.67 ± 33.10 %) compared to control, but there was a significant increase in peak-to-peak amplitude (127.65 ± 4.24 mg, p<0.01). In addition, the peak-to-peak amplitude was significantly increased at the 10 mM and 20 mM doses (163.86 ± 8.57 and 162.58 ± 6.76 mg, p<0.001, respectively) compared to the control and there was a statistically significant difference. In addition, the area value increased significantly compared to control at the 20 mM dose alone (3767.64 ± 733.70 %, p<0.001). Conclusions: Our present data show that the treatment of varied high doses of metformin may lead to the increase of contractions at ex vivo isolated tissue bath. Therefore, this effect can escalate some symptoms of diabetic bladder dysfunction.

CME/Answers: Metformin - Dos and Don'ts

CME/Answers: Metformin - Dos and Don'ts Abstract. CME/Answers: Metformin - Dos and Don'ts In the absence of contraindications metformin is still considered the initial medication in patients with diabetes mellitus type 2, although diabetes therapy is rapidly changing. Metformin is used both as monotherapy and in combination with any other diabetic medication. As a biguanide metformin improves glycemic control by inhibiting gluconeogenesis and increasing insulin-mediated glucose utilization in peripheral tissues. Metformin promotes modest weight reduction and provides several other advantages: no risk of hypoglycemia, excellent general tolerability, well-known long-term safety profile and low-cost. The most common gastrointestinal side effects are usually mild and transient, but vitamin B12 deficiency may develop. Metformin-associated lactic acidosis (MALA) is a rare, but relevant and life-threatening complication. The risk increases with renal impairment; therefore the metformin dose must be adjusted to the eGFR. The use of metformin is contraindicated with an eGFR <30 ml/min/1.73 m2. There are other contraindications: concurrent active or progressive severe liver disease, active alcohol abuse, unstable or acute heart failure, hypoperfusion and hemodynamic instability, as well as a past history of lactic acidosis. Since metformin remains a modern therapy, it is important to be aware of its indications and contraindications.

Effects of low‐dose metformin on pre‐frailty among middle‐aged and elderly pre‐diabetic people

AbstractBackgroundPre‐frailty has been identified as a clinically silent mechanism pre‐disposing people to frailty. The goal of this study is to investigate the impact of low‐dose metformin on pre‐diabetic pre‐frail patients (&gt;50 years) on skeletal muscle mass, speed of gait, handgrip power, and health‐related quality of life (HR‐QoL).MethodsWe did a retrospective cohort study of subjects aged 50 years and older who were diagnosed with pre‐frailty (one or two criteria present based on Fried Frailty Index) and pre‐diabetes (HbA1c 5.7% to 6.4%) from May 2018 to April 2020. Subjects taking low‐dose metformin were compared with non‐metformin participants through a review of the medical records. The results were analysed at baseline and 6–12 months post‐prescription with or without metformin. All data were accompanied by a 95% confidence interval.ResultsOne hundred and thirteen pre‐diabetic and pre‐frail subjects were recruited to metformin [the mean metformin administration was 750 (140) mg/day] (n = 58) or control group (n = 55). The average age was 66.3 (6.8) years old, with 52.2% of the population being female. The baseline demographic, nutritional, physical, and mental status data did not differ between groups. In comparison with the control group, an 8.9 (1.8) month low‐dose metformin intervention resulted in a higher skeletal muscle mass index of 1.26 (1.66) kg/m2 (P = 0.029), a faster gait speed of 0.15 (0.22) m/s (P = 0.011), and a greater handgrip strength of 2.1 (2.9) kg (P = 0.037). However, there was no difference in myostatin serum levels or HR‐QoL between groups.ConclusionsLow‐dose metformin was statistically and clinically meaningful to improve the original skeletal muscle mass index, gait speed, and grip strength as part of the sarcopenia dimension, but the Euro Quality of Life‐5 Dimensions index and myostatin serum levels did not change significantly.

Metformin and colorectal cancer

Colorectal cancer (CRC) is one of the main causes of cancer-related mortality in the developed world despite recent developments in detection and treatment. Several epidemiological studies indicate that metformin, a widely prescribed antidiabetic drug, exerts a protective effect on different cancers including CRC. Furthermore, a recent double-blind placebo-controlled, randomized trial showed that metformin significantly decreased colorectal adenoma recurrence. Studies exploring the mechanism of action of metformin in cells derived from different types of cancers reported many effects including respiratory chain complex 1 inhibition, Akt phosphorylation inhibition, ATP depletion, PKA activation and Wnt signaling inhibition. However, many of these results were obtained employing metformin at concentrations several fold higher than those achieved in target tissues in diabetic patients receiving therapeutic recommended doses of metformin. In contrast, recent studies obtained with metformin at concentrations compatible with those detected in human intestines revealed that metformin elicit responses that target β-catenin, PI3K/Akt, E-cadherin, p120-catenin and focal adhesion kinase which are key molecules and signaling pathways associated to colorectal cancer development. This brief review revisit several know aspects as well as novel ones on the effects of metformin on cancer cells.

Real-world Retrospective Assessment of Initiation and Effectiveness of Dual Combination Therapy with Metformin and Teneligliptin in Drug Naïve Indian Type 2 Diabetes Mellitus Patients (INITIATE)

Introduction: Diabetes Mellitus (DM) has become the leading health concern worldwide over the last few decades. But despite advances in both understanding of the pathophysiology of Type 2 Diabetes Mellitus (T2DM), and the development of new treatment strategies, current management of patients with T2DM remains suboptimal. Initial monotherapy is frequently inadequate in patients with high baseline Glycated Haemoglobin (HbA1c). Thus, initial combination therapy has emerged as an alternative approach. Aim: To assess INItiation and effecTiveness of dual combInation therapy with metformin And Teneligliptin in drug naïvE T2DM patients (INITIATE). Materials and Methods: In this retrospective, multicentre study, newly diagnosed drug naïve T2DM patients failed with diet and exercise prior to screening and initiated with dual therapy of metformin and teneligliptin were enrolled. Data of all the patients prescribed with any therapeutic dose of metformin (250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg) and teneligliptin (20 mg, 40 mg) was considered. The data was analysed to assess change in glycaemic parameters from baseline to 12 weeks. Paired t-test was applied for statistical results. Results: Data of 7857 patients were analysed. The mean change of Fasting Plasma Glucose (FPG) from baseline {202.29±52.2 mg/dL (11.23±2.89 mmol/L)} to 12 weeks {142.57±34.5 mg/dL (7.91±1.91 mmol/L)} was -59.72±17.7 mg/dL (-3.31±0.98 mmol/L) (p-value &lt;0.0001). The absolute change in mean Postprandial Plasma Glucose (PPG) from baseline {(286.26±80.43 mg/dL (15.89±4.46 mmol/L)} to 12 weeks {(198.30±42.24 mg/dL (11±2.34 mmol/L)} was -87.96±38.19 mg/dL (-4.88±2.12 mmol/L) (p-value &lt;0.0001). Mean HbA1c level was 8.11%±1% (65±10.9 mmol/mol) at baseline and decreased significantly to 7.15%±0.94% (55±10.3 mmol/mol) (p-value &lt;0.0001) with a mean change of -0.96±0.06 (-10.5±0.7 mmol/mol) at 12 weeks. Total 42.83% (n=3365) patients achieved target HbA1c (&lt;7%) at 12 weeks. Conclusion: Initiation of dual therapy with metformin and teneligliptin in drug naïve Indian T2DM patients significantly improved glycaemic control.

Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma.

ObjectiveTo explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate‐activated kinase (AMPK) activator, in ocular melanoma.MethodsCCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocular melanoma cells. A mouse orthotopic xenograft model was built to detect ocular tumor growth in vivo. Western blot, immunofluorescence, and electron microscopy were adopted to evaluate the autophagy levels of ocular melanoma cells, and high‐throughput proteomics and CUT & Tag assays were performed to analyze the candidate for autophagy alteration.ResultsHere, we revealed for the first time that a relatively low dose of metformin induced significant tumorspecific inhibition of the proliferation and migration of ocular melanoma cells both in vitro and in vivo. Intriguingly, we found that metformin significantly attenuated autophagic influx in ocular melanoma cells. Through high‐throughput proteomics analysis, we revealed that optineurin (OPTN), which is a key candidate for autophagosome formation and maturation, was significantly downregulated after metformin treatment. Moreover, excessive OPTN expression was associated with an unfavorable prognosis of patients. Most importantly, we found that a histone deacetylase, SIRT1, was significantly upregulated after AMPK activation, resulting in histone deacetylation in the OPTN promoter.ConclusionsOverall, we revealed for the first time that metformin significantly inhibited the progression of ocular melanoma, and verified that metformin acted as an autophagy inhibitor through histone deacetylation of OPTN. This study provides novel insights into metformin ‐ guided suppression of ocular melanoma and the potential mechanism underlying the dual role of metformin in autophagy regulation.

Efekat metformina na vijabilitet i mitohondrijalni status tumorske i netumorske ćelijske linije

Introduction: Metformin is a drug of choice in the therapy of type II Diabetes mellitus. There is a growing evidence of metformin's antitumor activity, but the suggested mechanisms of such activity are still not fully elucidated. Aim: To investigate the effect of therapeutic doses of metformin on viability and mitochondrial status of human non-small cell lung carcinoma (NCI-H460) and human immortalized lung fibroblasts (MRC-5) cell lines. Material and methods: Acid phosphatase and Crystal Violet assays were used for the determination of NCI-H460 and MRC-5 cell viability after the treatment with metformin (10-60 µM) for 1-7 days. Mitochondrial membrane potential, production of reactive oxygen species and superoxide anion, as well as mitochondrial mass were measured using flow cytometry after the treatment of the cells for 3, 24 and 120 h, followed by staining with appropriate fluorochromes: JC-1, DHR, DHE and Mitotracker Red. Results: Metformin did not change the viability of both NCI-H460 and MRC-5 cells in all investigated time-points and all used concentrations. Depolarization of mitochondrial membrane was observed 3 h post-treatment in MRC-5 cells. Prolonged treatment (120 h) increased superoxide anion production and mitochondrial mass in NCI-H460 cells. No significant changes in production of reactive oxygen species were observed in both cells lines after short or extended exposure to metformin. Conclusion: : Therapeutic concentrations of metformin do not influence the viability of NCI-H460 and MRC-5 cells, but induce mitochondrial depolarization after short-term exposure in lung fibroblasts and increase production of superoxide anion and mitochondrial mass in lung carcinoma cells after prolonged treatment.

Metformin Intolerance: A Proposal for Definition Using the GSRS

Metformin is a first line drug for the treatment of patients with type 2 diabetes mellitus (T2DM) and has been associated with metformin intolerance with disappointing patient adherence. Since there is no official definition for metformin intolerance, comparison of international study results on gastrointestinal complaints is almost impossible. In the present study with type 2 diabetes patients who are on a metformin immediate-release (MIR) and are visiting the outpatient’s department of internal medicine. To create a quantifiable and standardized definition of metformin intolerance, this study used the Gastro-intestinal Symptom Rating Scale (GSRS) to evaluate the gastrointestinal complaints. A total of 59 patients (mean age 62.56; +/- 12.08) completed the GSRS in an interview with a skilled investigator. The mean GSRS score for the study population was 34.56 (+/- 14.57). Subsequently two subpopulations were created using 50 as a cutoff point. This resulted in two populations with statistically significant different GSRS scores of 55.50 (+/- 7.88) for patients with a GSRS score of ≥ 50 versus 28.04 (+/- 8.86) for patients with a GSRS score of < 50. The total GSRS results for the various metformin dosages yielded comparable results (figure 1, p<0.05). The authors recommend the use of the GSRS in all studies on the topic of metformin intolerance to enable the comparison of results of international studies. In addition, the authors propose the use of a cutoff GSRS score of 50 as an international definition for metformin intolerance.

Evaluation of lowe dose Metformin response and Dyslipidemia levels in patients with Prediabetes

Evaluation of lowe dose Metformin response and Dyslipidemia levels in patients with Prediabetes

Investigating the protective role of metformin on lithium-induced hypothyroidism.

Induction of oxidative stress events has been shown to be associated with lithium (Li) hypothyroidism induction. Metformin (MET) is a commonly used antidiabetic drug with multiple properties including antiproliferative activity, antioxidant potency, and is usedin polycystic ovarian syndrome treatment. Here, in this study, we aimed to investigate the effect of different doses of MET on Li-induced hypothyroidism for elucidating its mechanism of action. The obtained results demonstrated the oxidative stress reduction in thyroid tissues upon MET treatment. Besides this, the biochemical analysis revealed a significant reduction in T3 and TSH levels (down to 2 ng/ml and 0.05 µU/ml, respectively) in coordination with an observable reduction in T4 level (up to 2.1 ng/ml). Also, a significant reduction in Li-related tissue damages including changes in the morphology and the size of follicles, rate of vascularity, detachment of follicular cells, inflammatory cells infiltration, and follicular cells hypertrophy and disruption was observed. Ultimately, regarding the significant improvement in thyroid tissues and valuable antioxidant activity determined in tissues treated with MET, it is concluded that MET co-administration with Li can significantly reduce the negative effects of Li and enhance the efficacy of Li therapy.

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N=220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. Treatment groups were well balanced at baseline (mean HbA1c=8.0%, BMI=30.9 kg/m2 , age=14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference=-0.49% (-0.90, -0.09), p=0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

Metformin Preserves Mitochondrial Integrity at Old Age in Male Rats.

Metformin is being deployed in clinical trials to ameliorate aging in older humans who do not have diabetes. In C. elegans, metformin treatment at old ages exacerbated mitochondrial dysfunction, led to respiratory failure, and shortened lifespan. Metformin is a commonly used, well-tolerated treatment for diabetes in older adults. Mitochondrial effects of metformin treatment in aged mammals has not been sufficiently investigated. We hypothesized that metformin treatment would not be toxic to older mammals. To define a therapeutic dose in aged hybrid rats, we evaluated two doses of metformin (0.1%, 0.75% of the diet) at 30-months of age. Body mass decreased at the 0.75% dose. Neither dose affected mortality between 30- and 34-months of age. We assessed mitochondrial quality, quantity, and function in aged rats treated with metformin at the 0.75% dose by measuring mitochondrial DNA copy number, deletion mutation frequency, and respirometry in skeletal muscle and heart. In skeletal muscle, we observed no effect of metformin on quadriceps mass, mtDNA copy number or deletion frequency. In the heart, metformin treated rats had higher mtDNA copy number, lower cardiac mass and no effect on deletion frequency. Metformin treatment resulted in lower mitochondrial complex I activity in both heart and quadriceps. Metformin did not compromise mitochondrial integrity, was well tolerated, and may have cardiac benefits to rats at old ages.

L6H21 protects against cognitive impairment and brain pathologies via toll-like receptor 4-myeloid differentiation factor 2 signalling in prediabetic rats.

Chronic high-fat diet (HFD) intake instigates prediabetes and brain pathologies, which include cognitive decline and neuroinflammation. The myeloid differentiation factor 2 (MD-2)/toll-like receptor 4 (TLR4) complex plays a pivotal role in neuroinflammation. The MD-2 inhibitor (L6H21) reduces systemic inflammation and metabolic disturbances in HFD-induced prediabetes. However, the potential role of L6H21, and its comparison with metformin, on brain pathologies in HFD-induced prediabetes has never been investigated. Male Wistar rats were given either a normal diet (ND) (n = 8) or a HFD (n = 104) for 16 weeks. At the 13th week, ND-fed rats were given a vehicle, whereas HFD-fed rats were randomly divided into 13 subgroups. Each subgroup was given vehicle, L6H21 (three doses) or metformin (300-mg·kg-1 ·day-1 ) for 1, 2 or 4 weeks. Metabolic parameters, cognitive function, brain mitochondrial function, brain TLR4-MD-2 signalling, microglial morphology, brain oxidative stress, brain cell death and dendritic spine density were investigated. HFD-fed rats developed prediabetes, neuroinflammation, brain pathologies and cognitive impairment. All doses of L6H21 and metformin given to HFD-fed rats at 2 and 4 weeks attenuated metabolic disturbance. In rats, L6H21 and metformin restored cognition and attenuated brain pathologies dose and time-dependently. These results indicate a neuroprotective role of MD-2 inhibitor in a model of prediabetes.