Metformin: A Potential Therapeutic Tool for Rheumatologists

Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes, acting via indirect activation of 5′ Adenosine Monophosphate-activated Protein Kinase (AMPK). Actually, evidence has accumulated of an intriguing anti-inflammatory activity, mainly mediated by AMPK through a variety of mechanisms such as the inhibition of cytokine-stimulated Nuclear Factor-κB (NF-κB) and the downregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathways. Moreover, AMPK plays an important role in the modulation of T lymphocytes and other pivotal cells of the innate immune system. The current understanding of these AMPK effects provides a strong rationale for metformin repurposing in the management of autoimmune and inflammatory conditions. Several studies demonstrated metformin’s beneficial effects on both animal and human rheumatologic diseases, especially on rheumatoid arthritis. Unfortunately, even though data are large and remarkable, they almost exclusively come from experimental investigations with only a few from clinical trials. The lack of support from prospective placebo-controlled trials does not allow metformin to enter the therapeutic repertoire of rheumatologists. However, a large proportion of rheumatologic patients can currently benefit from metformin, such as those with concomitant obesity and type 2 diabetes, two conditions strongly associated with rheumatoid arthritis, osteoarthritis, and gout, as well as those with diabetes secondary to steroid therapy.

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Central Administration of Resveratrol Improves Diet-Induced Diabetes

Endocrinology ◽

10.1210/en.2009-0528 ◽

2009 ◽

Vol 150 (12) ◽

pp. 5326-5333 ◽

Cited By ~ 84

Author(s):

Giorgio Ramadori ◽

Laurent Gautron ◽

Teppei Fujikawa ◽

Claudia R. Vianna ◽

Joel K. Elmquist ◽

...

Keyword(s):

Type 2 Diabetes ◽

Phosphoenolpyruvate Carboxykinase ◽

Nuclear Factor Κb ◽

Mrna Levels ◽

Nuclear Factor ◽

Central Administration ◽

Beneficial Effects ◽

Intracerebroventricular Infusion ◽

Iκb Kinase

Abstract Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in central nervous system (CNS) neurons known to control glucose and insulin homeostasis, we hypothesized that resveratrol antidiabetic effects are mediated by the brain. Here, we report that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in diet-induced obese and diabetic mice. It is noteworthy that these effects are independent of changes in body weight, food intake, and circulating leptin levels. In addition, CNS resveratrol delivery improves hypothalamic nuclear factor-κB inflammatory signaling by reducing acetylated-RelA/p65 and total RelA/p65 protein contents, and inhibitor of nuclear factor-κB α and IκB kinase β mRNA levels. Furthermore, this treatment leads to reduced hepatic phosphoenolpyruvate carboxykinase 1 mRNA and protein levels and ameliorates pyruvate-induced hyperglycemia in this mouse model of type 2 diabetes. Collectively, our results unveiled a previously unrecognized key role for the CNS in mediating the antidiabetic actions of resveratrol.

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Serum Complement C3 and Type 2 Diabetes in Rheumatoid Arthritis: A Case-Control Study

Reviews on Recent Clinical Trials ◽

10.2174/1574887113666180314092757 ◽

2018 ◽

Vol 13 (3) ◽

pp. 215-221 ◽

Cited By ~ 3

Author(s):

Francesco Ursini ◽

Salvatore D`Angelo ◽

Emilio Russo ◽

Giorgio Ammerata ◽

Ludovico Abenavoli ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Type 2 Diabetes ◽

Case Control Study ◽

Case Control ◽

Complement C3 ◽

Serum Complement ◽

Control Study

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Association of biological antirheumatic therapy with risk for type 2 diabetes: a retrospective cohort study in incident rheumatoid arthritis

BMJ Open ◽

10.1136/bmjopen-2020-042246 ◽

2021 ◽

Vol 11 (6) ◽

pp. e042246

Author(s):

Sanjoy K Paul ◽

Olga Montvida ◽

Jennie H Best ◽

Sara Gale ◽

Attila Pethö-Schramm ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Type 2 Diabetes ◽

T Cell ◽

Disease Modifying Antirheumatic Drugs ◽

Antirheumatic Therapy ◽

Treatment Groups ◽

Significant Difference ◽

Necrosis Factor

ObjectiveTo explore possible associations of treatment with biological disease-modifying antirheumatic drugs (bDMARDs), including T-cell-based and interleukin-6 inhibition (IL-6i)-based therapies, and the risk for type 2 diabetes mellitus (T2DM) in patients with rheumatoid arthritis (RA).Study design, setting and participantsFive treatment groups were selected from a United States Electronic Medical Records database of 283 756 patients with RA (mean follow-up, 5 years): never received bDMARD (No bDMARD, n=125 337), tumour necrosis factor inhibitors (TNFi, n=34 873), IL-6i (n=1884), T-cell inhibitors (n=5935) and IL-6i+T cell inhibitor abatacept (n=1213). Probability and risk for T2DM were estimated with adjustment for relevant confounders.ResultsIn the cohort of 169 242 patients with a mean 4.5 years of follow-up and a mean 641 200 person years of follow-up, the adjusted probability of developing T2DM was significantly lower in the IL-6i (probability, 1%; 95% CI 0.6 to 2.0), T-cell inhibitor (probability, 3%; 95% CI 2.3 to 3.3) and IL-6i+T cell inhibitor (probability, 2%; 95% CI 0.1 to 2.9) groups than in the No bDMARD (probability, 5%; 95% CI 4.6 to 4.9) and TNFi (probability, 4%; 95% CI 3.7 to 4.7) groups. Compared with No bDMARD, the IL-6i and IL-6i+T cell inhibitor groups had 37% (95% CI of HR 0.42 to 0.96) and 34% (95% CI of HR 0.46 to 0.93) significantly lower risk for T2DM, respectively; there was no significant difference in risk in the TNFi (HR 0.99; 95% CI 0.93 to 1.06) and T-cell inhibitor (HR 0.96; 95% CI 0.82 to 1.12) groups.ConclusionsTreatment with IL-6i, with or without T-cell inhibitors, was associated with reduced risk for T2DM compared with TNFi or No bDMARDs; a less pronounced association was observed for the T-cell inhibitor abatacept.

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FRI0052 INFLUENCE OF RHEUMATOID ARTHRITIS ON THE CLINICAL AND BIOLOGICAL PROFILE OF TYPE-2 DIABETES MELLITUS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5408 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 601.2-602

Author(s):

J. Avouac ◽

M. Elhai ◽

M. Forien ◽

J. Sellam ◽

F. Eymard ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Requirement ◽

Multivariate Logistic Regression ◽

Biological Profile ◽

Research Support ◽

Insulin Resistant ◽

Research Grant

Background:Type-2 diabetes and rheumatoid arthritis (RA) are two chronic diseases characterized by tissue inflammation and insulin resistance. To date, no data have evaluated the influence of RA-induced joint and systemic inflammation on the course of type-2 diabetes.Objectives:To study the impact of RA on type-2 diabetesMethods:Observational, multicenter, cross-sectional usual-care study, including 7 rheumatology centers. This study included over a 24-month period consecutive patients with type-2 diabetes and RA, fulfilling the 2010 ACR / EULAR criteria, and diabetic controls with osteoarthritis (OA). The following data were collected: demographics, disease activity and severity indices, current treatment for RA and diabetes, history and complications of diabetes. A systematic blood test was performed, assessing inflammatory (CRP levels) and metabolic (fasting glycemia and insulin levels, HbA1c) parameters. The HOMA2%B (insulin secretion) and HOMA2%S (tissue insulin sensitivity) indices (HOMA calculator, © Diabetes Trials Unit, University of Oxford) were used to assess insulin resistance. Ra and OA patients were compared using parametric tests after adjusting for age and BMI. A multivariate logistic regression was performed ti identify factors independently associated with insulin resistance.Results:We included 122 RA patients (74% women, mean age 64+/-11 years, mean disease duration 15+/-11 11 years, 75% with positive ACPA antibodies and 64% with erosive disease) and 54 controls with OA. 64% of RA patients were treated with oral corticosteroids <10 mg/day, 65% received methotrexate and 53% received targeted biological therapies.The characteristics of type-2 diabetes in the 54 OA patients corresponded to severe insulin-resistant diabetes: age> 65 years, high BMI> 30 kg/m2, mean HbA1c 7.3%+/-11 1.3%, 30% of insulin requirement, high frequency of other cardiovascular risk factors, macroangiopathy found in almost half of patients and biological criteria of insulin resistance (elevation of HOMA2%B and decrease of HOMA2%S).RA patients with type-2 diabetes had a younger age (64+/-11 years vs. 68+/-12 years, p=0.031) and lower BMI (27.7+/-11 5.5 vs. 31.5+/-11 6.3, p<0.001). These patients also had severe diabetes (HbA1c 7.0%+/-11 1.2%, 29% of insulin requirement, 43% of macroangiopathy) with an insulin resistance profile identical to OA controls. After adjusting for age and BMI, RA patients had a significantly increased insulin secretion compared to OA patients (HOMA2%B: 83.1+/-11 65.2 vs. 49.3+/-11 25.7, p=0.023) as well as a significant reduction of insulin sensitivity (HOMA2%S: 61.1+/-11 31.6 vs. 92.9+/-11 68.1, p=0.016). This insulin resistance was associated with the inflammatory activity of RA, with a negative correlation between the HOMA2%S and the DAS28 (r=-0.28, p=0.027). The multivariate logistic regression confirmed the independent association between the HOMA2%S index and DAS28 (OR: 3.93, 95% CI 1.02-15.06), as well as high blood pressure (OR: 1.29, 95% CI 0.33-1.99 CI).Conclusion:RA patients with type-2 diabetes displayed severe, poorly controlled diabetes, highlighting the burden of comorbidities associated with RA. The clinical-biological profile of diabetic RA patients was severe insulin-resistant diabetes, with a biological profile of insulin resistance linked to the inflammatory activity of the disease. These findings may have therapeutic implications, with the potential targeting of insulin resistance through the treatment of joint and systemic inflammation.Acknowledgments:Société Française de Rhumatologie (research grant)Bristol Myers Squibb (research grant)Disclosure of Interests:Jérôme Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Muriel ELHAI: None declared, Marine Forien: None declared, Jérémie SELLAM: None declared, Florent Eymard Consultant of: Regenlab, Anna Moltó Grant/research support from: Pfizer, UCB, Consultant of: Abbvie, BMS, MSD, Novartis, Pfizer, UCB, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB, Frédéric Banal: None declared, Joel Daminano: None declared, Philippe Dieudé: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

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Managing Osteoporosis and Joint Damage in Patients with Rheumatoid Arthritis: An Overview

Journal of Clinical Medicine ◽

10.3390/jcm10061241 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1241

Author(s):

Yoshiya Tanaka

Keyword(s):

Rheumatoid Arthritis ◽

Structural Damage ◽

Kinase Inhibitors ◽

Joint Destruction ◽

Joint Damage ◽

Nuclear Factor Κb ◽

Cartilage Destruction ◽

Janus Kinase ◽

Systemic Autoimmune Disease ◽

And Cartilage

In rheumatoid arthritis, a representative systemic autoimmune disease, immune abnormality and accompanying persistent synovitis cause bone and cartilage destruction and systemic osteoporosis. Biologics targeting tumor necrosis factor, which plays a central role in the inflammatory process, and Janus kinase inhibitors have been introduced in the treatment of rheumatoid arthritis, making clinical remission a realistic treatment goal. These drugs can prevent structural damage to bone and cartilage. In addition, osteoporosis, caused by factors such as menopause, aging, immobility, and glucocorticoid use, can be treated with bisphosphonates and the anti-receptor activator of the nuclear factor-κB ligand antibody. An imbalance in the immune system in rheumatoid arthritis induces an imbalance in bone metabolism. However, osteoporosis and bone and cartilage destruction occur through totally different mechanisms. Understanding the mechanisms underlying osteoporosis and joint destruction in rheumatoid arthritis leads to improved care and the development of new treatments.

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Beneficial effects of gliclazide modified release compared with glibenclamide on endothelial activation and low-grade inflammation in patients with type 2 diabetes

Diabetes Obesity and Metabolism ◽

10.1111/j.1463-1326.2006.00571.x ◽

2007 ◽

Vol 9 (1) ◽

pp. 127-129 ◽

Cited By ~ 20

Author(s):

A. Räkel ◽

G. Renier ◽

A. Roussin ◽

J. Buithieu ◽

J.-C. Mamputu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Endothelial Activation ◽

Low Grade ◽

Modified Release ◽

Beneficial Effects ◽

Low Grade Inflammation

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Beneficial Effects of Canagliflozin in Combination with Pioglitazone on Insulin Sensitivity in Rodent Models of Obese Type 2 Diabetes

PLoS ONE ◽

10.1371/journal.pone.0116851 ◽

2015 ◽

Vol 10 (1) ◽

pp. e0116851 ◽

Cited By ~ 21

Author(s):

Yoshinori Watanabe ◽

Keiko Nakayama ◽

Nobuhiko Taniuchi ◽

Yasushi Horai ◽

Chiaki Kuriyama ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Rodent Models ◽

Beneficial Effects

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A comparison of the effect of glitazones on serum sialic acid in patients with type 2 diabetes

Diabetes and Vascular Disease Research ◽

10.1177/1479164111428629 ◽

2011 ◽

Vol 9 (3) ◽

pp. 238-240 ◽

Cited By ~ 4

Author(s):

Inayat ur Rahman ◽

Muhammad Idrees ◽

Mohammad Salman ◽

Rooh Ullah Khan ◽

MI Khan ◽

...

Keyword(s):

Type 2 Diabetes ◽

Sialic Acid ◽

Treated Group ◽

Diabetes Therapy ◽

Beneficial Effects ◽

Hba1 C ◽

Serum Sialic Acid ◽

High Incidence ◽

Cv Disease

Although management of hyperglycaemia represents one of the principal treatment goals of diabetes therapy, the high incidence of cardiovascular (CV) complications in diabetes also needs effective management. Therefore, the present study was designed to determine and compare the effect of glitazones on serum sialic acid (SSA), a known risk marker for CV disease, along with fasting plasma glucose (FPG), glycohaemoglobin (HbA1-c) and blood lipids, in overweight, previously only diet-treated patients with type 2 diabetes ( n=60). The study was conducted for a period of 12 months. Significant improvement in FPG and HbA1-c were shown by both rosiglitazone ( p<0.003 and p<0.001, respectively) and pioglitazone ( p<0.005 and p<0.001, respectively), compared with baseline, and pioglitazone showed greater beneficial effects on other parameters monitored, significantly reducing total cholesterol (TC) ( p≤0.05). Both the drugs showed a decrease in SSA and no significant differences were observed between the groups. However, the decrease was significant only in the pioglitazone-treated group at month 12 ( p≤0.05), compared with baseline. A significant decrease in SSA by pioglitazone indicates its greater cardioprotective effect compared with rosiglitazone.

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