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Journal of Diabetes Research 2023This review summarizes the correlation between diabetes mellitus (DM) and gastric cancer (GC) from the perspectives of epidemiology, drug use, and potential mechanisms.... (Review)
Review
This review summarizes the correlation between diabetes mellitus (DM) and gastric cancer (GC) from the perspectives of epidemiology, drug use, and potential mechanisms. The association between DM and GC is inconclusive, and the positive direction of the association reported in most published meta-analyses suggests that DM may be an independent risk factor for GC. Many clinical investigations have shown that people with DM and GC who undergo gastrectomy may have better glycemic control. The potential link between DM and GC may involve the interaction of multiple common risk factors, such as obesity, hyperglycemia and hyperinsulinemia, infection, and the use of metformin. Although and data support that infection status and metformin can influence GC risk in DM patients, there are conflicting results. Patient survival outcomes are influenced by multiple factors, so further research is needed to identify the patients who may benefit.
Topics: Humans; Stomach Neoplasms; Diabetes Mellitus; Risk Factors; Hyperglycemia; Metformin; Helicobacter Infections
PubMed: 38020199
DOI: 10.1155/2023/4388437 -
Biochemical Pharmacology Sep 2023An intricate interplay between genetic and environmental factors contributes to the development of type 2 diabetes (T2D) and its complications. Therefore, it is not... (Review)
Review
An intricate interplay between genetic and environmental factors contributes to the development of type 2 diabetes (T2D) and its complications. Therefore, it is not surprising that the epigenome also plays a crucial role in the pathogenesis of T2D. Hyperglycemia can indeed trigger epigenetic modifications, thereby regulating different gene expression patterns. Such epigenetic changes can persist after normalizing serum glucose concentrations, suggesting the presence of a 'metabolic memory' of previous hyperglycemia which may also be epigenetically regulated. Metformin, a derivative of biguanide known to reduce serum glucose concentrations in patients with T2D, appears to exert additional pleiotropic effects that are mediated by multiple epigenetic modifications. Such modifications have been reported in various organs, tissues, and cellular compartments and appear to account for the effects of metformin on glycemic control as well as local and systemic inflammation, oxidant stress, and fibrosis. This review discusses the emerging evidence regarding the reported metformin-mediated epigenetic modifications, particularly on short and long non-coding RNAs, DNA methylation, and histone proteins post-translational modifications, their biological and clinical significance, potential therapeutic applications, and future research directions.
Topics: Humans; Diabetes Mellitus, Type 2; Metformin; Clinical Relevance; Epigenesis, Genetic; DNA Methylation; Hyperglycemia; Glucose
PubMed: 37541452
DOI: 10.1016/j.bcp.2023.115732 -
JCI Insight Aug 2023Age-associated sarcopenia, characterized by a progressive loss in muscle mass and strength, is the largest cause of frailty and disability in the elderly worldwide....
Age-associated sarcopenia, characterized by a progressive loss in muscle mass and strength, is the largest cause of frailty and disability in the elderly worldwide. Current treatments involve nonpharmacological guidelines that few subjects can abide by, highlighting the need for effective drugs. Preclinical models were employed to test the benefits of RJx-01, a combination drug composed of metformin and galantamine, on sarcopenia. In worms, RJx-01 treatment improved lifespan, locomotion, pharyngeal pumping, and muscle fiber organization. The synergistic effects of RJx-01 were recapitulated in a transgenic mouse model that displays an exacerbated aging phenotype (Opa1-/-). In these mice, RJx-01 ameliorated physical performance, muscle mass and force, neuromuscular junction stability, and systemic inflammation. RJx-01 also improved physical performance and muscle strength in 22-month-old WT mice and also improved skeletal muscle ultrastructure, mitochondrial morphology, autophagy, lysosomal function, and satellite cell content. Denervation and myofiber damage were decreased in RJx-01-treated animals compared with controls. RJx-01 improved muscle quality rather than quantity, indicating that the improvement in quality underlies the beneficial effects of the combination drug. The studies herein indicate synergistic beneficial effects of RJx-01 in the treatment of sarcopenia and support the pursuit of RJx-01 in a human clinical trial as a therapeutic intervention for sarcopenia.
Topics: Humans; Mice; Animals; Aged; Infant; Sarcopenia; Galantamine; Metformin; Aging; Muscle, Skeletal; Mice, Transgenic
PubMed: 37551712
DOI: 10.1172/jci.insight.168787 -
Current Problems in Cancer Aug 2023Metformin is an ancient drug for the treatment of type 2 diabetes, and many studies now suggested that metformin can be used as an adjuvant drug in the treatment of many... (Review)
Review
Metformin is an ancient drug for the treatment of type 2 diabetes, and many studies now suggested that metformin can be used as an adjuvant drug in the treatment of many types of tumors. The mechanism of action of metformin for tumor treatment mainly involves: 1. activation of AMPK signaling pathway 2. inhibition of DNA damage repair in tumor cells 3. downregulation of IGF-1 expression 4. inhibition of chemoresistance and enhancement of chemotherapy sensitivity in tumor cells 5. enhancement of antitumor immunity 6. inhibition of oxidative phosphorylation (OXPHOS). Metformin also plays an important role in the treatment of hematologic tumors, especially in leukemia, lymphoma, and multiple myeloma (MM). The combination of metformin and chemotherapy enhances the efficacy of chemotherapy, and metformin reduces the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. The purpose of this review is to summarize the anticancer mechanism of metformin and the role and mechanism of action of metformin in hematologic tumors. We mainly summarize the studies related to metformin in hematologic tumors, including cellular experiments and animal experiments, as well as controlled clinical studies and clinical trials. In addition, we also focus on the possible side effects of metformin. Although a large number of preclinical and clinical studies have been performed and the role of metformin in preventing the progression of MGUS to MM has been demonstrated, metformin has not been approved for the treatment of hematologic tumors, which is related to the adverse effects of its high-dose application. Low-dose metformin reduces adverse effects and has been shown to alter the tumor microenvironment and enhance antitumor immune response, which is one of the main directions for future research.
Topics: Animals; Humans; Metformin; Diabetes Mellitus, Type 2; Drug Repositioning; Multiple Myeloma; Hematologic Neoplasms; Tumor Microenvironment
PubMed: 37364455
DOI: 10.1016/j.currproblcancer.2023.100972 -
The Journal of Clinical Endocrinology... Apr 2024Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D.
METHODS
In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test.
RESULTS
At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI.
CONCLUSION
Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.
Topics: Female; Adolescent; Humans; Male; Metformin; Liraglutide; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Gluconeogenesis; Blood Glucose; Glucose
PubMed: 37967247
DOI: 10.1210/clinem/dgad669 -
Oncotarget Jul 2023
Topics: Humans; Metformin; Obesity Paradox; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Body Mass Index
PubMed: 37395790
DOI: 10.18632/oncotarget.28432 -
Current Osteoporosis Reports Dec 2023Metformin is an anti-glycemic agent, which is widely prescribed to diabetes patients. Although its alleged role on bone strength has been reported for some time, this... (Review)
Review
PURPOSE OF REVIEW
Metformin is an anti-glycemic agent, which is widely prescribed to diabetes patients. Although its alleged role on bone strength has been reported for some time, this review focuses primarily on the recent mechanistical insights of metformin on osteocytes, osteoblasts, and osteoclasts.
RECENT FINDINGS
Overall, metformin contributed to steering anabolic activity in osteocytes. It caused lower expression in osteocytes of the negative regulators of bone formation sclerostin and DKK1. Likewise, the osteoclastogenesis function of osteoblasts was also skewed towards lower RANKL and higher OPG expressions. Osteoblast lineage cells generally responded to metformin by activating bone formation parameters, such as alkaline phosphatase activity, higher expression of anabolic members of the Wnt pathway, transcription factor Runx2, bone matrix protein proteins, and subsequent mineralization. Metformin affected osteoclast formation and activity in a negative way, reducing the number of multinucleated cells in association with lower expression of typical osteoclast markers and with inhibited resorption. A common denominator studied in all three cell types is its beneficial effect on activating phosphorylated AMP kinase (AMPK) which is associated with the coordination of energy metabolism. Metformin differentially affects bone cells, shifting the balance to more bone formation. Although metformin is a drug prescribed for diabetic patients, the overall bone anabolic effects on osteocytes and osteoblasts and the anti-catabolic effect on osteoclast suggest that metformin could be seen as a promising drug in the bone field.
Topics: Humans; Osteoclasts; Osteocytes; Metformin; Osteoblasts; Bone and Bones; RANK Ligand; Cell Differentiation
PubMed: 37796390
DOI: 10.1007/s11914-023-00828-0 -
ELife Jul 2023Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures...
Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics, and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type 2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed-wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in the T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in the T2D mice in all injury models. In vitro analysis indicated that compromised proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from the T2D mice were rescued by metformin treatment when compared to WT controls. Furthermore, metformin could effectively rescue the impaired detrimental lineage commitment of BMSCs isolated from the T2D mice in vivo as assessed by subcutaneous ossicle formation of the BMSC implants in recipient T2D mice. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in the T2D mice receiving metformin treatment. The chondrocyte transcript factors SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from the T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, more specifically bone formation and chondrogenesis in T2D mouse models.
Topics: Mice; Animals; Metformin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Bony Callus; Osteogenesis; Fractures, Bone; Mesenchymal Stem Cells
PubMed: 37417730
DOI: 10.7554/eLife.88310 -
Journal of Cerebral Blood Flow and... Nov 2023Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments....
Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments. The white matter, which is essential for neuronal information processing and integration, is nourished by a network of capillaries and is vulnerable to chronic hypoperfusion. Here, we show that metformin, a widely used drug for the treatment of type 2 diabetes, alleviates the white matter damage and improves cognitive impairment in a mouse model of VCID established by bilateral carotid artery stenosis (BCAS)-induced chronic hypoperfusion. Mechanistically, metformin restores the dysfunctions of oligodendrocyte precursor cells (OPCs) under hypoxia. Metformin up-regulates prolyl hydroxylases 2 via activating the AMP-activated protein kinase pathway, leading to hypoxia-inducible factor-1α (HIF-1α) degradation in OPCs. These findings suggest that metformin may have a promising therapeutic role in alleviating cognitive abnormalities by ameliorating white matter damage of VCID.
Topics: Mice; Animals; White Matter; Metformin; Diabetes Mellitus, Type 2; Brain Ischemia; Cognitive Dysfunction; Dementia, Vascular; Carotid Stenosis; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37177813
DOI: 10.1177/0271678X231175189 -
Journal For Immunotherapy of Cancer Oct 2023Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We...
BACKGROUND
Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study.
METHODS
Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0-1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry.
RESULTS
A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50-67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475).
CONCLUSIONS
Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.
Topics: Humans; Female; Middle Aged; Male; Nivolumab; Programmed Cell Death 1 Receptor; Metformin; Colorectal Neoplasms; Microsatellite Repeats; Tumor Microenvironment
PubMed: 37852737
DOI: 10.1136/jitc-2023-007235