Review Open Access
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Mar 15, 2021; 12(3): 238-260
Published online Mar 15, 2021. doi: 10.4239/wjd.v12.i3.238
Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis
Chrong-Reen Wang, Hung-Wen Tsai
Chrong-Reen Wang, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
Hung-Wen Tsai, Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
ORCID number: Chrong-Reen Wang (0000-0001-9881-7024); Hung-Wen Tsai (0000-0001-9223-2535).
Author contributions: Wang CR designed the review and wrote the paper; Wang CR and Tsai HW collected and analyzed the clinical data.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Chrong-Reen Wang, MD, PhD, Professor, Department of Internal Medicine, National Cheng Kung University Hospital, No. 138 Sheng-Li Road, Tainan 70403, Taiwan.
Received: December 21, 2020
Peer-review started: December 21, 2020
First decision: January 7, 2021
Revised: January 7, 2021
Accepted: January 21, 2021
Article in press: January 21, 2021
Published online: March 15, 2021


In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to establishment of diabetes mellitus (DM) is the resistance of target cells to insulin, i.e. insulin resistance (IR), indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor, downstream to the substrates of insulin action. IR is a common feature of most metabolic disorders, particularly type II DM as well as some cases of type I DM. A variety of human inflammatory disorders with increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α- and non-TNF-α-targeted therapies on IR in patients with RA, PsA and AS. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phospho-diesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.

Key Words: Insulin resistance, Diabetes mellitus, Tumor necrosis factor-α-targeted therapy, Non-tumor necrosis factor-α-targeted therapy, Rheumatoid arthritis, Psoriatic arthritis

Core Tip: The crucial mechanism leading to development of diabetes mellitus is the resistance of target cells to insulin, i.e. insulin resistance (IR), indicating the ineffective strength of signaling transduction from the receptor, downstream to the final substrates of insulin action. Autoimmune-mediated arthritis including rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, with the involvement of proinflammatory cytokines like tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β as their central pathogenesis, has been demonstrated to be associated with IR. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phosphodiesterase type 4 blocker can reduce IR and improve diabetic hyperglycemia in autoimmune-mediated arthritis.


In addition to β-cell failure with inadequate insulin secretion, the central mechanism leading to the development of diabetes mellitus (DM) is the resistance of target cells to insulin, i.e., insulin resistance (IR)[1,2]. Such a pathological condition in the human body indicates resistance to the effects of insulin, with a requirement of beyond-normal insulin concentrations to maintain euglycemic status and ineffective strength of insulin signaling from the receptor, downstream to the final substrates of its action. The transmembrane insulin receptor consists of two extracellular a and two intracellular b subunits linked by disulphide bonds[3]. Binding of insulin to the α subunits can activate the tyrosine kinase in the β subunits. Upon activation, autophosphorylation of the β subunit amplifies the kinase activity, further recruiting the adaptor proteins, insulin receptor substrates (IRSs)[4]. This process creates a suitable binding site for an IRS, that is phosphorylated by different insulin-induced kinases, including protein kinase C, salt-inducible kinase 2, protein kinase B (PKB), p70-S6 kinase, mammalian target of rapamycin, extracellular signal-regulated kinase (ERK)1/2, and rho-associated, coiled-coil-containing protein kinase 1[5].

The phosphorylated IRS can act as a docking protein for various effector molecules possessing the src homology 2 (SH2) domain[2]. The intracellular SH2 domain protein binds to the phosphotyrosine residues of IRSs. These IRS partners include adaptors such as phosphoinositide 3-kinase (PI3K), growth factor receptor-bound protein 2, CT10 regulator of kinase and non-catalytic region of tyrosine kinase adaptor protein 1 (Nck), and enzymes comprised of Fyn, C-terminal Src kinase, SH2 domain-containing inositol polyphosphate 5'-phosphatase and SH2-containing protein tyrosine phosphatase 2[6,7]. The activated IRS triggers subsequent signals by binding to PI3K and activating it, to catalyze the conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate (PIP3)[8]. PIP3 is a potent inducer for activating various kinases, PKB in particular, to facilitate the entry of glucose into cells by translocating glucose transporter 4 (GLUT4) to the cell surface and to promote the synthesis of glycogen by suppressing the inhibitory glycogen synthase kinase-3β[9-12]. Most of the physiological effects of insulin are mediated by the signaling pathway involving the activated IRS and SH2 domain proteins[1-3], leading to activation of multiple downstream effectors to regulate cell differentiation, growth, survival, and metabolism via a variety of intracellular pathways.

IR is an impedance of human tissues to the action of insulin on glucose uptake, metabolism or storage[2], a common feature of most metabolic disorders, including atherosclerosis and hypertension, non-alcoholic fatty liver disorder, hyperlipidemia, metabolic syndrome, obesity and type II DM as well as some cases in type I DM[13,14]. In hepatocytes, IR increases the circulating levels of glucose due to a reduction of glycogen synthesis, further compounded by the inability of skeletal muscle cells and adipocytes to take up glucose[2,14]. Although the exact pathogenic mechanisms of IR remains to be elucidated, any defects in expression or function of any enzymes and modulatory proteins involved in the insulin signal transduction may impair normal insulin signaling, leading to IR in peripheral tissues[14,15]. Notably, non-transmembrane protein-tyrosine phosphatase 1B (PTP1B) is a dominant-negative regulator of insulin signaling, which functions by reversing the phosphorylation on IRS-1 tyrosine residues to reduce the insulin signal transduction[16]. Transgenic mice overexpressing human PTP1B selectively in muscle displayed IR with an impairment in insulin-induced glucose transport into skeletal muscle[17], whereas mice lacking the PTP1B gene had a reduced risk of IR with higher insulin sensitivity in peripheral tissues[18]. In human, overexpression of the PTP1B protein has been observed in an obesity-related IR status[19], implicating reduction of PTP1B levels as a therapeutic strategy for IR[20].

Miscellaneous inflammatory disorders in human with increased levels of proinflammatory cytokines, as measured by tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 depending on the study designs, have been reported to be associated with increased risk of developing IR[2,21]. There are commonly encountered autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS)[22]. Active disease activities in these inflammatory arthritis conditions have been demonstrated to be associated with IR[23-25]. Recently, there has been an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α and non-TNF-α-targeted therapies on IR in RA, PsA and AS patients.


Upon binding of TNF-α to its receptor, sphingomyelinases can be activated to trigger further interactions with the insulin signaling pathway[26,27]. Via the action of sphingomyelinases, serine phosphorylation of IRS-1 and reduced tyrosine phosphorylation of the insulin receptor and IRS-1 are induced. The serine-phosphorylated IRS-1 acts in a negative feedback loop to inhibit tyrosine kinase activity of the insulin receptor. An inhibitory kB kinase (IKK)-β has been identified as the cellular kinase responsible for the serine phosphorylation of IRS-1 in response to TNF-α stimulation[28]. Insulin-targeted cells lacking endogenous IRS-1 were found to be resistant to TNF-α-mediated inhibition of insulin receptor signaling, while transfecting IRS-1 into these cells enhanced the sensitivity to such an effect of TNF-α[29].

Other mechanisms responsible for TNF-α-induced IR have been elucidated, including down-regulated expression levels of IRS-1, GLUT4, CCAAT enhancer-binding protein α, peroxisome proliferator-activated receptor (PPAR)-γ, perilipin, and adipocyte complement-related protein of 30 kDa (Acrp30)[27]. In addition to directly inducing lipolysis in adipose tissues, TNF-α can reduce the expression of Acrp30, also named as adiponectin, by suppressing its promoter activity to reduce the circulating concentrations, leading to a decrease in fatty acid oxidation in skeletal muscle and consequently a rise in free fatty acid (FFA) levels and induction of IR[27,30,31]. Notably, activation of nuclear factor-κB (NF-κB), a key mediator in most of the TNF-α responses, is associated with the repression of adipocyte-related genes involved in the uptake and storage of FFA and glucose essential for the function of adipocytes[32]. In particular, NF-κB-mediated suppressed synthesis of PPAR-γ, an essential gene for the induction and maintenance of adipocyte genes expression[33], is a critical determinant of insulin sensitivity in adipose tissues[34]. Notably, the expression of suppressor of cytokine signaling 3 (SOCS3), an inhibitor responsible for preventing the excessive cytokine signaling, can reduce insulin-induced tyrosine phosphorylation of IRS-1[35]. TNF-α has been shown to induce a sustained SOCS-3 expression in targeted tissues[36].

In human observations, elevated circulating concentrations of bioactive TNF-α have been observed in type II DM patients, as compared with the healthy individuals[37,38]. A single intravenous (i.v.) infusion of recombinant TNF-α has demonstrated an alteration of glucose metabolism by lowering basal insulin levels without impairing β-cell function or hepatic insulin sensitivity in non-diabetic healthy persons[39]. Moreover, a 4-d course of i.v. TNF-α infusion bought about IR, with increased homeostasis model assessment (HOMA)-IR levels, in healthy young volunteers[40]. An earlier study carried out in obese non-diabetic subjects failed to demonstrate positive effects on IR by i.v. administration of a recombinant soluble TNF-α receptor/immunoglobulin G (IgG)-Fc fusion proteins (rsTNFRFPs)[41]. Despite increased circulating levels of adiponectin, no beneficial effects on IR were observed in the study populations with metabolic syndrome receiving the subcutaneous injection of etanercept (ETA), a rsTNFRFP[42,43].

Effects on IR of targeting TNF-α in RA patients

TNF-α participates in the pathogenesis and disease progression of RA[44], and biologics antagonizing this cytokine display significant efficacy in inhibiting arthritis activities[45]. IR in RA is driven majorly by the activity-related inflammation[46], and elevated plasma levels of TNF-α have been demonstrated in such patients with increased IR[47]. Considerable case-control and cohort studies have shown increased risks of both type I and II DM prevalence among RA patients[48]. An association in type I DM is specific in a subgroup of RA with the presence of cyclic citrullinated peptide antibody[49], and both diseases share susceptibility genes, including HLA-DRB1, PTPN22, CTLA-4, TAGAP, and KIAA109-TENR-IL2-IL21[49-53]. In a cohort with 11158 RA patients followed-up from the period of 1986 to 2010, there was an increased incidence of type II DM, substantially ascribed to factors like obesity rather than disease activity[54]. A large prospective study of 114342 women showed no differences in the type II DM occurrence between individuals with and without RA[55]; whereas, in another investigation of 48718 RA patients, there was an increased risk of type II DM compared to a healthy population with 442033 persons[56]. Despite a weaker association between RA and type II DM, such patients also have other diabetic risks, including glucocorticoid use, lifestyle factors (like alcohol and smoking), obese status, and exposure to certain traditional disease-modifying anti-rheumatic drugs that may enhance the development of diabetes[24].

Two therapeutic modalities have been used to inactivate TNF-α in treating autoimmune-related arthritis, namely rsTNFRFP ETA and monoclonal antibodies (mAbs) comprising adalimumab (ADA), certolizumab, golimumab (GLO), and infliximab (IFX)[57]. These agents bind to TNF-α to reduce its effects on inflammatory processes; however, ETA has an additional capability to block lymphotoxin-α (LT-α)[58]. Interestingly, genetic studies have linked polymorphisms in genes encoding LT-α to patients with such IR-associated diseases as type II DM and metabolic syndrome[59,60]. In a cohort of 522 non-diabetic RA cases receiving the TNF-α inhibitors (TNFis) including ADA, ETA, GLO and IFX, there was a more than 50% reduction in the risk of DM development[61]. Nevertheless, another retrospective observational study with 2111 RA patients, not excluding DM, failed to demonstrate hypoglycemic effects at 6 mo following the initiation of TNFi therapy with ETA and four other mAbs[62]. Since hyperglycemia, a critical contributor to IR, can interfere with the effects of TNFi on insulin sensitivity, most published reports examined the studied population in non-diabetic RA patients. The mixed therapeutic effects with rsTNFRFP and different mAbs on IR have been demonstrated in RA patients[63-66]. Nevertheless, using individual blockade to examine the efficacy of TNF-α inhibition in improving insulin sensitivity would be a more appropriate approach due to distinct pharmacokinetic and pharmacodynamic actions in different TNFi under clinical administration[57].

Table 1 summarizes 15 published studies that examined the effects of anti-TNF therapies on IR in non-diabetic RA patients[63-77]. There were four with at least two TNFi (mixed therapeutic effects), eight with IFX alone, three with ADA alone, and two with ETA alone. Except for only one study with hyperinsulinemic euglycemic glucose clamp to measure IR[70], HOMA-IR levels were calculated in other investigations. All studies with IFX or ETA alone showed improvement in IR; however, two with ADA alone failed to demonstrate such an effect[71,76].

Table 1 Studies on effects of anti-tumor necrosis factor therapies on insulin resistance in non-diabetic rheumatoid arthritis patients.
No.SourceCharacterCases, n, drug (s)Clinical feature (s)DurationEffects on IRRef.
12004, AustriamAb2 IFXNon-diabetic4 or 8 moImproved HOMA-IR only in high-IR group[67]
22005, GreecemAb28 IFXNon-diabetic6 moImproved HOMA-IR only in high-IR group[68]
32006, SpainmAb27 IFXNon-diabetic2 h after infusionImproved HOMA-IR[69]
42007, NetherlandsmAb5 IFXNon-diabetic6 wkImproved insulin sensitivity1[70]
52007, DenmarkmAb9 ADANon-diabetic, high IR8 wkIneffective HOMA-IR[71]
62007, ChinamAb19 IFXNon-diabetic14 wkImproved HOMA-IR[72]
72007, TurkeymAb7 IFXNon-diabetic5-15 moImproved HOMA-IR[73]
82008, SpainmAb21 IFXNon-diabetic24 wkImproved HOMA-IR[74]
92008, ItalymAbs, sTNFRFP, Mixed20 ETA, 18 IFX, Total 38Non-diabetic24 wkImproved HOMA-IR[63]
102011, SpainmAbs, rsTNFRFP, Mixed8 ADA, 6 IFX, 2 ETA, Total 16Non-diabetic12 moIneffective HOMA-IR[64]
112012, United KingdommAbs, rsTNFRFP, Mixed49 IFX, 11 ADA, 1 ETA, Total 61Non-diabetic12 wkImproved HOMA-IR in high-IR group[65]
122012, GreecemAbs, rsTNFRFP, Mixed20 IFX, 11 ETA, 1 ADA, Total 32Non-diabetic6 moImproved HOMA-IR in high-IR, non-obese group[66]
132019, ItalymAbs, rsTNFRFP, Separated11 IFX, 12 ETA, 10 ADA, Total 33Non-diabetic, non-obese24 wkImproved HOMA-IR in individual group of all TNF blockers[75]
142020, NetherlandsmAb28 ADANon-diabetic6 moIneffective HOMA-IR, improved-β-cell function[76]
152020, TaiwanrsTNFRFP30 ETANon-diabetic, non-obese24 wkImproved HOMA-IR in high-IR group[77]

IL-6 is a multifunctional cytokine, largely produced by adipocytes and macrophages within adipose tissues as well as skeletal muscle and liver[78]. In vitro and in vivo studies have confirmed that the production of IL-6 can be regulated by insulin[79], and hyperinsulinemia can produce an increase in IL-6 expression in adipose tissues with raised systemic levels[80]. Circulating levels of IL-6 have been observed to be elevated in type II DM patients[81]. This cytokine is a risk factor for the development of such a disease[82]. Its plasma levels have been shown to be positively correlated with the percentage of body fat[83]. Activated IKK-β, a molecular target of IR[84], phosphorylates an inhibitor of NF-κB, IκBα, and promotes its degradation to free NF-κB and allows its entry into the nucleus[85]. This kinase can not only activate NF-κB to stimulate the production of IL-6 but it can also directly induce the serine phosphorylation of IRS-1[86]. Injection of neutralizing antibodies against IL-6 could reverse IKK-β-induced IR in mice[87]. Notably, IL-6 has a negative impact on insulin signaling by decreasing tyrosine phosphorylation of IRS-1, inhibiting activation of PKB[88], and inducing a rapid recruitment of IRS-1 to the IL-6 receptor complex to phosphorylate the inhibitory serine residue of IRS-1[89]. Particularly, an inhibitory mechanism of IL-6 on insulin action is to induce the expression of SOCS-3 in target cells to reduce auto-phosphorylation of insulin receptor-β, tyrosine phosphorylation of IRS-1, association of IRS-1 with PI3K, and activation of PKB and ERK1/2[90,91]. IL-6 has also been shown to reduce the expression of adiponectin, GLUT4, IRS-1, PPAR-γ and insulin receptor-β in adipocytes[91-93]. Furthermore, IL-6 was found to be constitutively expressed by human pancreatic α and β cells, with local islet IL-6 levels reduced in type I but elevated in type II DM patients[94,95]. In islet cells treated with high levels of glucose, IL-6 could protect α-cells from apoptosis, whereas there was enhanced apoptosis of β-cells in the presence of IL-6[96].

In contrast to the above-mentioned studies which illustrate that IL-6 is a negative regulator of insulin action, results from other investigations also suggest a beneficial role of IL-6 in insulin sensitivity. Increased circulating levels of IL-6 have been detected in individuals with obesity; however, it remains undetermined whether this cytokine has favorable or detrimental effects on the obese status[97]. IL-6 receptor signaling in target cells has been shown to have protective antiinflammatory effects, mediated by the skewing of macrophages towards a M2 phenotype and thus limiting the development of IR during obesity[98]. In vitro short-term treatment with IL-6 could enhance the glucose uptake in adipocytes[99]. Physical inactivity, an IR induction factor, has been demonstrated to be associated with reduced IL-6 secretion from skeletal muscle[100], while exercise can enhance the production of IL-6 by skeletal muscle, leading to an improvement in insulin sensitivity[101]. IL-6 treatment could increase the translocation of GLUT4 to plasma membrane via adenosine monophosphate (AMP)-activated protein kinase, to increase the insulin-mediated glucose uptake in myotube cells[102]. Exposure to IL-6 induces a rapid recruitment of IRS-1 to the IL-6 receptor complex and further activation of downstream PKB signaling, resulting in the improvement of insulin action in skeletal muscle[103]. In vitro addition of IL-6 in human islet cell culture could enhance the production of glucagon-like peptide-1, a hormone which induces β-cells to secret insulin and improves hyperglycemic status[104]. Interestingly, IL-6 treatment for 3 h increased glucose uptake in myocytes; on the contrary, treatment for 24 h decreased insulin-stimulated glucose uptake through impaired GLUT4 translocation and defects in IRS-1, indicating a dual role of IL-6 in regulating insulin action[105]. To sum up, the effects of IL-6 on insulin-targeted tissues are dependent on distinct factors which can regulate its signaling and affect its action in different experimental settings, including therapeutic concentrations, observation kinetics, metabolic stressors (glucose or FFA) and other mediators (cytokines or chemokines)[106].

In human trials, single i.v. infusion of recombinant IL-6 in healthy volunteers could increase glucose infusion rate and glucose oxidation, as determined by measuring with a hyperinsulinemic-euglycemic clamp, suggesting that acute IL-6 treatment can enhance insulin-stimulated in vivo glucose disposal in human[107]. Conversely, a similar IL-6 infusion protocol in type II DM patients failed to alter glucose infusion rates and appearance/disappearance rates during the clamp, indicating that an acute elevation of IL-6 concentrations would not affect insulin-mediated glucose uptake in the diabetic state[108]. In addition to TNFi, non-TNF-α-targeted therapy in RA includes an approved humanized IL-6R antibody tocilizumab (TCZ), which completely inhibits the IL-6 signaling through blocking the binding of this cytokine to both membrane-bound and soluble receptors[109]. In particular, TCZ has been shown to reduce hemoglobin A1c (HbA1C) levels and the use of antidiabetic drugs in type II diabetic patients with active RA after a 6-mo treatment period[110]. Notably, both pro- and anti-inflammatory roles have been identified for IL-6, distinguished by two specific signaling transduction cascades, i.e. classic and trans-signaling[111]. Increased evidence suggests that dual behavior of IL-6 in the development of IR and the improvement of insulin sensitivity could be related to whether it acts via a trans-signaling or classic signaling mechanism[106,111]. The trans-signaling is involved in the infiltration of macrophages into adipose tissues, resulting in a proinflammatory status with IR in obese subjects[112]. On the other hand, through classic signaling in pancreatic tissues, there is increased cellular proliferation as well as insulin secretion in islet cells, resulting in an anti-inflammatory state with improvement in glycemic state[113]. These findings suggest that specific inhibition of trans-signaling might produce a better outcome in improving insulin sensitivity compared with the global inhibition of IL-6. Nevertheless, intraperitoneal injection of soluble gp130Fc-an extracellular gp130 portion fused to the IgG-Fc region specifically blocking IL-6 trans- (without affecting classical) signaling[114]-failed to alter the blood glucose levels in the streptozotocin-induced mouse model[115], indicating the existence of complex mechanisms of pleiotropic IL-6 signaling in glucose metabolism.

Effects on IR of non-TNF-α targeted therapies in RA patients

Table 2 lists the published reports examining the effects on IR in RA patients receiving non-TNF-α targeted therapies. Besides anti-IL-6 therapy, other studies include abatacept (ABA) treatment alone and mixed effects with ABA and TCZ therapy[65,116-125]. In eight reports of patients receiving TCZ treatment alone, three not excluding DM cases demonstrated ineffectiveness of IR reduction in RA. ABA, a fusion protein with a CTLA-4 domain and IgG1-Fc portion interfering with T-cell co-stimulation/activation by binding to CD80/CD86 molecules, has been approved to treat RA patients[126]. The proposed mechanism for improving insulin sensitivity by this biologic agent is the reduction of adipose tissue inflammation by lessening effector T-cell infiltration and polarizing macrophages to the anti-inflammatory M2 phenotype[119,127]. In two studies with limited patient numbers[65,118], one failed to demonstrate the effects on IR reduction after ABA therapy for 12 wk, while another showed improved insulin sensitivity under a 6 mo treatment period. In addition, improved leptin/adiponectin ratios, an alternative marker of IR, was identified in RA patients treated with non-TNF-α targeted agents including ABA and TCZ as compared with those receiving TNFi therapy[124].

Table 2 Studies on effects of non-tumor necrosis factor-targeted therapies on insulin resistance in rheumatoid arthritis patients.
No.SourceDrugCases, nClinical featuresDurationEffects on IRRef.
12010, GermanyTCZ11Non-diabetic3 moImproved HOMA-IR[116]
22012, United KingdomABA7Non-diabetic, active disease12 wkIneffective HOMA-IR[65]
32013, United KingdomTCZ221Active disease24 wkImproved HOMA-IR[117]
42013, United KingdomTCZ62Active disease, JRA children6 wkImproved HOMA-IR in high-IR group[118]
52015, ItalyABA15Non-diabetic, active disease6 moImproved ISI, ineffective β-cell functions[119]
62015, TaiwanTCZ24Active disease24 wkImproved HOMA-IR[120]
72015, GreeceTCZ19Active disease6 moIneffective HOMA-IR[121]
82017, FranceTCZ15Active disease6 moIneffective HOMA-IR[122]
92019, SpainTCZ50Non-diabetic1 h after 1st infusionImproved HOMA-IR[123]
102019, FranceOther1, TNFi107, 96Active disease24 wkImproved leptin/adiponectin ratios in other group than TNFi group[124]
112020, FranceTCZ77Active disease12 moIneffective HOMA-IR[125]

The IL-1 family consists of IL-1α and IL-1β (the first identified cytokines with strong proinflammatory functions), and a naturally occurring anti-inflammatory mediator, IL-1 receptor antagonist (IL-1Ra)[128]. IL-1 can regulate T-cell function by polarizing such cells towards cell-mediated immunity by inducing the development of Th1 and Th17 cells, or production of antibodies via a Th2 bias. These cytokines, IL-1β in particular, participate in regulating inflammatory diseases, as observed in diabetic patients[129]. Elevated serum con-centrations of IL-1α and production levels of IL-1β from mononuclear cells were observed in patients at the onset of type I DM[130,131]. IL-1β has been proposed to mediate both dysfunction and destruction of pancreatic β-cells during the autoimmune process of insulin-dependent DM (IDDM)[132]. Antagonizing IL-1 with soluble receptor or IL-1Ra has been shown to reduce the incidences of type I DM in non-obese diabetic (NOD) mice and diabetic BB rats[133,134], indicating a modulatory role of IL-1 on the immune system and pancreatic β-cells[135]. Concentrations of IL-1β, together with IL-6, can predict the risk of type II DM in humans[136]. IL-1Ra-deficient mice with excessive IL-1 signaling had lower fasting insulin levels[137], and expression of IL-1Ra was diminished in pancreatic islets of type II diabetic patients[138].

It has been demonstrated that, in insulin-targeted cells, IL-1β reduces the IRS-1 expression through an ERK-dependent mechanism at the transcriptional level and an ERK-independent mechanism at the post-transcriptional level[139]. By targeting IRS-1 and activating the IKKβ/NF-κB pathway, IL-1β is capable of impairing insulin signaling and its action, thus participating in the development of IR[139,140]. In vitro exposure of human islets to high concentrations of glucose resulted in increased production of IL-1β from β-cells, followed by NF-κB activation and cellular apoptosis[141]. Although local IL-1β activity can govern inflammation of pancreatic islets and control the function of islet cells, this cytokine has been observed to exert bimodal effects on pancreatic β-cells. Short-time and lower concentration stimulation activates the β -cells to increase the release of insulin, whereas an exposure to higher concentrations can induce reduced secretion of insulin through activating NF-κB, mitogen-activated-protein-kinase and c-Jun N-terminal kinase signaling, leading to endoplasmic reticulum and mitochondrial stress and eventually activating the apoptotic machinery[24,142]. Interestingly, there is an emerging hypothetic pathogenesis for type II DM, in which an imbalance between the hyperactivity of IL-1β and the countering effect of IL-1Ra can determine the outcome of islet inflammation[143]. Collectively, these findings indicate that the IL-1 cytokine family may represent therapeutic targets to reverse the adverse metabolic consequences of DM[134,141,143].

Until now, three IL-1-targeted agents have been approved for managing inflammatory disorders, including anakinra (ANA), an IL-1Ra for treating RA and cryopyrin-associated periodic syndromes (CAPS), rilonacept (referred to as RIL), a decoy receptor consisting of extracellular IL-1R portion fused to IgG1-Fc for CAPS therapy, and canakinumab (CAN), an IL-1β mAb for autoinflammatory diseases and gouty arthritis[144]. In particular, after receiving 6 mo of ANA treatment for arthritis activity, 2 RA and 3 GA patients, whose cases were combined with non-insulin-dependent DM (NIDDM), showed reduced HbA1C and fasting glucose levels, which was followed by reduction in or removal from antidiabetic medications in 2 of the cases, implicating IL-1 as a therapeutic target in diabetic therapy[145,146].

Effects on DM by applying anti-TNF-α and other targeted agents used for rheumatology disorders

Table 3 demonstrates the published efficacy in DM of application of anti-TNF-α and other targeted agents to treat rheumatology disorders. For two reports using TNFi in type II diabetic patients, a short-term ETA trial for 4 wk, despite a marginally improved insulin response in i.v. glucose tolerance test, showed inefficacy in insulin sensitivity[147], while a 10-year observation with ETA and IFX therapy for RA and Crohn’s disease co-morbidities, respectively, demonstrated reduced HbA1C and fasting glucose levels[148]. Interestingly, rituximab (RTX), a chimeric mAb approved for RA therapy through targeting surface CD20 molecule to deplete β-cell[149], has been applied to treat IDDM and type B insulin resistance syndrome-associated NIDDM[150,151]. Although the immunopathogenic mechanism of β-cell destruction in type 1 DM is T-cell mediated autoimmunity, B-cells can be involved in the immune process by serving as antigen-presenting cells to present such autoantigens as cryptic peptides to which T-cells are not tolerant[150]. In NOD mice, the development of insulitis has been shown to be completely abrogated upon injection of an anti-μ chain polyclonal antibody, which depletes B lymphocytes[152].

Table 3 Studied effects on diabetes mellitus by applying anti-tumor necrosis factor- and non-tumor necrosis factor- targeted agents for treating patients with rheumatology disorders.
No.SourceDrugMechanismPNClinical feature(s)DurationEffect on IR or diabetic statusRef.
12005, United StatesETArSTNFRFP10Type II DM, obese4 wkIneffective IS[147]
22007, INCANAIL-1Ra34Type II DM13 wkReduced HbA1C and increased insulin secretion at 13 wk, reduced insulin doses at 39 wk[156]
32009, United StatesRTXCD20 mAb49Type I DM, recent1 yrReduced HbA1C/insulin doses and higher 2 h C-peptide AUC at 1 yr, no differences at 30 mo[150]
42011, United StatesABACTLA4-Ig73Type I DM, recent2 yrHigher 2 h C-peptide AUC[155]
52011, United StatesTNFiETA, IFX8Type II DM10 yrReduced HbA1C and fasting glucose levels[148]
62011, JapanTCZIL-6R mAb10Type II DM6 moReduced HbA1C and use of antidiabetic drugs[110]
72012, INCCANIL-1 mAb151Type II DM4 wkIncreased insulin secretion (ISR relative to glucose at 0 to 0.5 h)[157]
82012, INCCANIL-1 mAb372Type II DM4 moIneffective HbA1C, fasting glucose and insulin levels[158]
92012, INCGEVIL-1 mAb81Type II DM13 wkReduced HbA1C, increased IS and insulin secretion at single i.v. groups (0.03, 0.1 mg/kg)[159]
102013, INCANAIL-1 Ra25Type I DM, recent9 moIneffective 2 h C-peptide AUC[160]
112013, INCCANIL-1 mAb45Type I DM, recentI yrIneffective 2 h C-peptide AUC[160]
122014, INCCANIL-1 mAb14Type II DM24 wkReduced HbA1C at single i.v. 1.5 and 10 mg/kg groups[161]
132015, NetherlandsANAIL-1Ra14Type I DM1 wkReduced HbA1C, insulin doses and fasting glucose levels, increased IS[162]
142015, ItalyANAIL-1Ra2Type II DM6 moReduced HbA1C and fasting glucose levels, reduced or off antidiabetic therapeutics[145]
152015, ItalyANAIL-1Ra3Type II DM6 moReduced HbA1C and fasting glucose levels[146]
162015, GermanyBERIL-1 mAb7Type II DM60 dIncreased insulin secretion[163]
172016, SwitzerlandGEVIL-1 mAb15Type I DM1 yrIneffective 2-h C-peptide AUC[164]
182016, SwitzerlandCANIL-1 mAb6Type II DM24 wkReduced HbA1C[165]
192017, JapanRTXCD20 mAb3Type II DM, insulin RS6-16 moReduced HbA1C and insulin doses, disappearance of IR antibody[151]
202018, United StatesRILIL-1R-Ig13Type I DM, recent26 wkHigher 2 h C-peptide AUC[166]
212019, ItalyANAIL-1Ra17Type II DM6 moReduced HbA1C[167]
222019, ItalyANAIL-1Ra15Type II DM6 moIncreased IS, improved β-cell function, decreased glucagon levels[168]
232020, United StatesTOFJAKi634Type I, II DM9 moDM treatment (insulin/non-insulin) intensification lowest in using TOF[178]

In a clinical trial, at 1 year after the first infusion of RTX in newly diagnosed type I DM patients, there were cases showing reduced HbA1C and the required insulin doses with a higher 2 h C-peptide area under the curve (AUC)[150]. After a 30 mo follow-up, the AUC, HbA1C and insulin doses were similar between the RTX-treated and placebo groups[153], suggesting that β-cell depletion therapy does not fundamentally alter the underlying disease pathogenesis. In a subsequent observation in 3 cases with type B insulin resistance syndrome characterized by IR with refractory hyperglycemia and the presence of insulin receptor antibodies, RTX therapy reduced HbA1C levels and insulin requirement with undetectable anti-insulin receptor levels[151]. Blocking T-cell costimulatory signaling with a CTLA4-Ig fusion protein could prevent DM development in NOD mice by administration before the occurrence of frank diabetic status[154]. In addition to improving the insulin sensitivity in non-diabetic RA patients[119], continued administration of ABA over 2 years was shown to yield higher 2 h C-peptide AUC in recent-onset type I DM patients, implicating an ongoing T-cell activation at the time of the type I DM diagnosis[155].

Altogether there have been 16 published studies examining the effects of anti-IL-1 therapy on diabetic status, including 7 with ANA, 5 with CAN, and 1 with RIL, as well as 3 reports with the unapproved mAbs bermekimab (anti-IL-1α) and gevokizumab (anti-IL-1β)[145,146,156-168]. Except for one ineffective study recruiting newly diagnosed type I DM[160], six other investigations have shown beneficent effects of ANA therapy on type I and II DM patients. Although CAN treatment demonstrated the efficacy in four reports with type II DM, and such therapy showed ineffectiveness in a report with type I DM[157,158,160,161,165]. Similar to the observations from CAN therapy, there were effective results in type II but not in type I diabetic patients under gevokizumab treatment[159,164]. The study examining recent-onset type I diabetic cases receiving regular RIL injection revealed a higher 2-h C-peptide AUC[166]. Another investigation analyzing type II DM patients under the administration of bermekimab exhibited an increase in the secretion of insulin[163]. Although there was controversial efficacy in type I diabetes sufferers, these trials have supported the beneficial effects of anti-IL-1 therapy on type II DM patients.

The Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathways include JAK 1 to 3, tyrosine kinase 2 (TYK2) and STAT 1 to 6, regulating more than 50 cytokine or hormone receptors, many of which have pathogenic roles in a variety of autoimmune and inflammation diseases[169,170]. Upon activation by cytokines or hormones, JAK phosphotransferases can auto- and mutually phosphorylate tyrosine residues as well as the intracellular tail of receptor subunits, recruiting and docking of the downstream signaling molecules, STATs. These transcription factors can be phosphorylated by JAKs, leading to homo- or hetero-dimerization and further translocation into the nucleus to bind their associated promoters and regulate the transcription of target genes. Individual cytokine receptors can recruit their own combinations of JAKs/STATs to activate different processes in targeted cells, and antagonizing a specific JAK can impede more than one cytokine pathway, expanding the efficacy in using such antagonists[171]. Notably, rheumatology disorders are often characterized by activation of cytokine signaling pathways with distinct expression profiles, generating the rationale for using JAK inhibitors as cytokine-targeted therapy[172]. In particular, tofacitinib (TOF) is the first small molecule oral selective JAK1 and JAK3 inhibitor approved in 2017 by the Federal Food and Drug Administration (FDA) and in 2018 by the European Medicines Agency (EMA) for treating RA patients[173]. In addition, the identification of a link between JAKs/TYK2 gene polymorphisms and IDDM has brought about a therapeutic potential in targeting the JAK-STAT pathways in such patients[174].

Accumulated evidence from animal studies has suggested a substantial pathogenic role of the JAK/STAT pathways in the development of low-grade chronic inflammatory response contributing to obesity and type II DM[175-177]. Notably, in a type II diabetic rat model induced by fructose/streptozotocin administration, treating with TOF alone, despite more potent efficacy in combination with aspirin to inhibit the NF-κB signaling, could lower serum proinflammatory cytokine expressions and skeletal muscle SOCS-3 Levels, resulting in reduced IR with decreased blood glucose and HOMA-IR levels and improved β-cell function with increased serum insulin and HOMA-β levels[176]. Moreover, in a recent survey of more than 10000 RA patients with type I or II DM co-morbidity under a 9 mo follow-up, the diabetic treatment intensification was found to be lowest in those using TOF than others receiving TNFi and non-TNF-α-targeted therapies[178].

Effects of anti-TNF-α and non-TNF-α-targeted therapies on IR or diabetes in PsA and AS patients

The central role of TNF-α, a critical IR inducer[27], in inflammation morbidities like AS, PsA and psoriasis (PsO) has been demonstrated by the ability of biologic agents that impede the action of TNF-α to offer substantial and comparable therapeutic effects[179,180]. In a PsA cohort, there was a 16% prevalence of IR and an association of metabolic syndrome with more severe arthritis[181]. Levels of adipokine and HOMA-IR in PsA were shown to be higher than in PsO without arthritis, and adipokine concentrations in PsA were associated with active joint counts[182]. In comparison with healthy controls, PsA patients have an increase in HOMA-IR and a higher prevalence of DM[183]. Notably, the prevalence of IDDM in PsA is higher than that in the general population[25], and the diabetic risk appears to be increased for women and for active disease[184,185]. Elevated circulating levels of TNF-α and adipokines favor the development of IR, contributing to such an association. Since inflammation of both skin and joint combined has a greater influence on glucose metabolism than that of skin alone, there is a stronger relationship between PsA and DM than between PsO and DM[186,187]. In Table 4, three studies and three case reports are summarized that examined the effects of anti-TNF-α therapy on IR or DM status in patients with PsA/PsO[188-193]. ETA treatment could reduce fasting glucose, HbA1C and insulin levels, even with hypoglycemic episodes; however, a study with ADA therapy failed to improve fasting glucose levels[192].

Table 4 Studies and case reports on effects of anti-tumor necrosis factor and non-tumor necrosis factor-targeted therapies on insulin resistance or diabetes in ankylosing spondylitis and psoriatic arthritis/psoriasis patients.
No.SourceDrugCase, n diseaseClinical feature(s)DurationEffect on IR or DM statusRef.
12005, GreeceIFX17, ASNon-DM6 moReduced HOMA-IR in high-IR group[68]
22007, ItalyETA9, PsONon-DM24 wkReduced HbA1C and insulin levels[188]
32009, BrazilETA1, PsOType II DM7 hHypoglycemic episode[189]
42009, United StatesETA1, PsOType II DM20 moReduced HbA1C and fasting glucose levels, discontinuing insulin use[190]
52010, BrazilTNF blocker118, PsANon-DM6 moNo changes in fasting glucose levels[191]
62010, BrazilTNF blocker137, ASNon-DM6 moNo changes in fasting glucose levels[191]
62011, United StatesADA54, PsODM 13%, PsA 41%16 wkIneffective changes in fasting glucose levels in DM[192]
72012, SpainIFX30, ASNon-DM120 minReduced HOMA-IR[196]
82014, TurkeyIFX30, ASNon-DM12 wkIneffective HOMA-IR[197]
92017, United StatesETA1, PsAType II DM, obesity12 wkReduced HbA1C and fasting glucose levels, discontinuing insulin use[193]
102018, TaiwanUST93, PsOObesity 45%24 wkIncreased fasting glucose levels[207]
112018, United StatesIXE2328, PsODM 9%, PsA 24%12 wkNo changes in fasting glucose levels[202]
122019, GermanySEC828, PsODM 10%, PsA 19%52 wkNo changes in fasting glucose levels[204]
132019, INCAPR1089, PsA/ODM 9%52 wkReduced HbA1C, improvement highest in HbA1C no less than 6.5%[210]
142019, ItalyAPR1, PsOType II DM, obesity6 moReduced HbA1C and fasting glucose levels, discontinuing insulin use[211]
152020, ItalyAPR113, PsA/ODM, 25%52 wkReduced fasting glucose levels[212]
162020, INCTOF474, PsAMetS, 42%6 moNo increased blood glucose levels, hyperglycemic event and diabetic occurrence[217]
172021, TaiwanTOF5, PsANon-DM, non-obese, high-IR12 wkReduced HOMA-IRPS

Despite less evidence than has been published for RA patients, increased prevalence of IR and altered glucose metabolism have been documented in AS patients[194,195]. In four studies using TNFi treatment in AS patients, two with IFX demonstrated reduced HOMA-IR, especially in the high-IR group[68,191,196,197].

Increased circulating Th17 numbers and elevated IL-17 Levels have been identified in type II diabetic patients[198,199]. In addition, IL-17 has been observed to be involved in the pathogenesis of a mouse model of angiotensin II type 1 receptor-induced IR by administrating IL-17 neutralizing antibody to reduce IR by lowering circulating TNF-α levels[200]. Nevertheless, a large-scale study with 2328 PsA/PsO patients receiving the infusion of ixekizumab, a humanized mAb against IL-17A[201], showed no effects in lowering fasting glucose levels[202]. An investigation of PsA/PsO patients treated with another IL-17A mAb, secukinumab[203], also showed no efficacy in improving glucose metabolism[204].

The inflammatory cytokine IL-23 was found to be elevated in diabetic pancreatic islets, thereby inducing β-cell oxidative and endoplasmic reticulum stress; moreover, neutralizing IL-23 in the high-fat diet-induced obesity mouse model reduced β-cell stress and reversed the hyperglycemic state[205]. One study evaluating the glucose homeostasis in PsA patients receiving ustekinumab, a mAb binding the common p40 subunit of IL-12 and IL-23[206], showed more elevated fasting glucose levels after a 24-wk treatment period[207].

Apremilast (APR), an oral small molecule approved for PsA and PsO therapy, inhibits phosphodiesterase 4 (PDE4), an enzyme regulating intracellular levels of cyclic AMP to influence the synthesis of cytokines[208]. PDE4C and PDE4D, expressed in pancreatic β-cells, play a critical role in controlling the secretion of insulin[209]. In a large-scale study with 1089 PsA/PsO patients under APR therapy for 52 wk, there were reduced HbA1C levels found, with the highest improvement occurring in those with baseline HbA1C levels no less than 6.5%[210]. In addition, reduced HbA1C and fasting glucose levels with discontinuing insulin use was observed in a case with PsO and type II DM after taking APR therapy for 6 mo[211]. Another investigation treating PsA/PsO patients with APR for 52 wk also demonstrated reduced fasting blood glucose levels[212].

Oral small molecule JAK inhibitors have emerged as a novel class of medications for PsA, and among three JAK antagonists approved for use in autoimmune disorders, only TOF has obtained approval from the FDA and EMA for PsA therapy[213]. This JAK inhibitor acts on the JAK-STAT pathway to mediate intracellular signaling and downregulate multiple cytokines involved in the PsA pathogenesis, including IL-2, IL-6, IL-17, IL-22, and IL-23[213,214]. Recently, emerging data from animal and human studies have showed that the JAK/STAT signaling is required for homeostasis of euglycemia, and when dysregulated, contributes to the development of IR[215]. Notably, in addition to the involvement in cytokine signaling activation, the JAKs/STATs pathway has been shown to regulate the function and survival of pancreatic β-cells[215,216]. Notably, animal studies have implicated targeting such a pathway in reducing IR and treating type II diabetes[175-177]. In human trials, the diabetic treatment intensification in RA combined with DM comorbidity was lowest in patients under the 9 mo TOF treatment[178]. There were no increased blood glucose levels, hyperglycemic events or diabetic occurrences in PsA patients receiving TOF therapy for 6 mo[217]. Furthermore, we examined the effects of TOF use in 5 non-diabetic, non-obese PsA patients (1 female and 4 males; age range: 20 to 59 years, with mean age of 41.4 ± 15.5 years) with high baseline IR levels (more than 2.0)[77]. After a 12-wk treatment period (No. 17, Table 4), all cases have decreased articular and dermatological activities as well as reduced HOMA-IR levels (2.01-9.48 to 1.55-4.31, 4.95 ± 2.86 to 3.27 ± 1.23). Our clinical observation suggests a potential of using TOF to improve insulin sensitivity in PsA, a disease susceptible to IR and diabetes.


In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to the development of DM is the resistance of target cells to insulin, i.e. IR, indicating the ineffective strength of signaling transduction from the receptor, downstream to the final substrates of insulin action. IR is a common feature of most metabolic disorders, including atherosclerosis and hypertension, non-alcoholic fatty liver disorder, hyperlipidemia, metabolic syndrome, obesity and type II DM as well as some cases of type I DM. A variety of human inflammatory disorders with increased levels of proinflammatory cytokines, including TNF-α, IL-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including RA, PsA/PsO and AS with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, JAK inhibitor or PDE4 blocker can reduce IR and improve diabetic hyperglycemia in patients with autoimmune-mediated arthritis.


The authors are indebted to the physicians and nurses involved in the diagnosis and management of patients reported from the National Cheng Kung University Hospital (NCKUH). The Institutional Review Board of NCKUH approved this study (No. B-ER-105-108).


Manuscript source: Invited manuscript

Specialty type: Endocrinology and metabolism

Country/Territory of origin: Taiwan

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Qiong L S-Editor: Fan JR L-Editor: A P-Editor: Ma YJ

1.  Saini V. Molecular mechanisms of insulin resistance in type 2 diabetes mellitus. World J Diabetes. 2010;1:68-75.  [PubMed]  [DOI]
2.  Khodabandehloo H, Gorgani-Firuzjaee S, Panahi G, Meshkani R. Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Transl Res. 2016;167:228-256.  [PubMed]  [DOI]
3.  Rachdaoui N. Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020;21.  [PubMed]  [DOI]
4.  Lavin DP, White MF, Brazil DP. IRS proteins and diabetic complications. Diabetologia. 2016;59:2280-2291.  [PubMed]  [DOI]
5.  Copps KD, White MF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia. 2012;55:2565-2582.  [PubMed]  [DOI]
6.  White MF. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem. 1998;182:3-11.  [PubMed]  [DOI]
7.  Virkamäki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest. 1999;103:931-943.  [PubMed]  [DOI]
8.  Ho CK, Sriram G, Dipple KM. Insulin sensitivity predictions in individuals with obesity and type II diabetes mellitus using mathematical model of the insulin signal transduction pathway. Mol Genet Metab. 2016;119:288-292.  [PubMed]  [DOI]
9.  Vollenweider P, Clodi M, Martin SS, Imamura T, Kavanaugh WM, Olefsky JM. An SH2 domain-containing 5' inositolphosphatase inhibits insulin-induced GLUT4 translocation and growth factor-induced actin filament rearrangement. Mol Cell Biol. 1999;19:1081-1091.  [PubMed]  [DOI]
10.  Martin S, Millar CA, Lyttle CT, Meerloo T, Marsh BJ, Gould GW, James DE. Effects of insulin on intracellular GLUT4 vesicles in adipocytes: evidence for a secretory mode of regulation. J Cell Sci. 2000;113 Pt 19:3427-3438.  [PubMed]  [DOI]
11.  Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001;292:1728-1731.  [PubMed]  [DOI]
12.  Nemoto T, Yanagita T, Kanai T, Wada A. Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: the role of GSK-3beta in the maintenance of steady-state levels of insulin receptor signaling molecules and Na(v)1.7 sodium channel in adrenal chromaffin cells. J Pharmacol Sci. 2009;109:157-161.  [PubMed]  [DOI]
13.  Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J. 2014;61:B4890.  [PubMed]  [DOI]
14.  Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016;126:12-22.  [PubMed]  [DOI]
15.  Sesti G. Pathophysiology of insulin resistance. Best Pract Res Clin Endocrinol Metab. 2006;20:665-679.  [PubMed]  [DOI]
16.  Yip SC, Saha S, Chernoff J. PTP1B: a double agent in metabolism and oncogenesis. Trends Biochem Sci. 2010;35:442-449.  [PubMed]  [DOI]
17.  Zabolotny JM, Haj FG, Kim YB, Kim HJ, Shulman GI, Kim JK, Neel BG, Kahn BB. Transgenic overexpression of protein-tyrosine phosphatase 1B in muscle causes insulin resistance, but overexpression with leukocyte antigen-related phosphatase does not additively impair insulin action. J Biol Chem. 2004;279:24844-24851.  [PubMed]  [DOI]
18.  Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science. 1999;283:1544-1548.  [PubMed]  [DOI]
19.  Abdelsalam SS, Korashy HM, Zeidan A, Agouni A. The Role of Protein Tyrosine Phosphatase (PTP)-1B in cardiovascular disease and its Interplay with insulin resistance. Biomolecules. 2019;9:286.  [PubMed]  [DOI]
20.  Koren S, Fantus IG. Inhibition of the protein tyrosine phosphatase PTP1B: potential therapy for obesity, insulin resistance and type-2 diabetes mellitus. Best Pract Res Clin Endocrinol Metab. 2007;21:621-640.  [PubMed]  [DOI]
21.  Pirola L, Ferraz JC. Role of pro- and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity. World J Biol Chem. 2017;8:120-128.  [PubMed]  [DOI]
22.  Luchetti MM, Benfaremo D, Gabrielli A. Biologics in Inflammatory and Immunomediated Arthritis. Curr Pharm Biotechnol. 2017;18:989-1007.  [PubMed]  [DOI]
23.  Straub RH. Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases. Arthritis Res Ther. 2014;16 Suppl 2:S4.  [PubMed]  [DOI]
24.  Nicolau J, Lequerré T, Bacquet H, Vittecoq O. Rheumatoid arthritis, insulin resistance, and diabetes. Joint Bone Spine. 2017;84:411-416.  [PubMed]  [DOI]
25.  Perez-Chada LM, Merola JF. Comorbidities associated with psoriatic arthritis: Review and update. Clin Immunol. 2020;214:108397.  [PubMed]  [DOI]
26.  Kanety H, Feinstein R, Papa MZ, Hemi R, Karasik A. Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem. 1995;270:23780-23784.  [PubMed]  [DOI]
27.  Ruan H, Lodish HF. Insulin resistance in adipose tissue: Direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev. 2003;14:447-455.  [PubMed]  [DOI]
28.  Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293:1673-1677.  [PubMed]  [DOI]
29.  Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271:665-668.  [PubMed]  [DOI]
30.  Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094-2099.  [PubMed]  [DOI]
31.  Ruan H, Miles PD, Ladd CM, Ross K, Golub TR, Olefsky JM, Lodish HF. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: Implications for insulin resistance. Diabetes. 2002;51:3176-3188.  [PubMed]  [DOI]
32.  Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes. 2002;51:1319-1336.  [PubMed]  [DOI]
33.  Tamori Y, Masugi J, Nishino N, Kasuga M. Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes. 2002;51:2045-2055.  [PubMed]  [DOI]
34.  Ruan H, Pownall HJ, Lodish HF. Troglitazone antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB. J Biol Chem. 2003;278:28181-28192.  [PubMed]  [DOI]
35.  Pedroso JAB, Ramos-Lobo AM, Donato J. SOCS3 as a future target to treat metabolic disorders. Hormones (Athens). 2019;18:127-136.  [PubMed]  [DOI]
36.  Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS, Van Obberghen E. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem. 2001;276:47944-47949.  [PubMed]  [DOI]
37.  Winkler G, Salamon F, Harmos G, Salamon D, Speer G, Szekeres O, Hajós P, Kovács M, Simon K, Cseh K. Elevated serum tumor necrosis factor-alpha concentrations and bioactivity in Type 2 diabetics and patients with android type obesity. Diabetes Res Clin Pract. 1998;42:169-174.  [PubMed]  [DOI]
38.  Winkler G, Salamon F, Salamon D, Speer G, Simon K, Cseh K. Elevated serum tumour necrosis factor-alpha levels can contribute to the insulin resistance in Type II (non-insulin-dependent) diabetes and in obesity. Diabetologia. 1998;41:860-861.  [PubMed]  [DOI]
39.  Ibfelt T, Fischer CP, Plomgaard P, van Hall G, Pedersen BK. The acute effects of low-dose TNF-α on glucose metabolism and β-cell function in humans. Mediators Inflamm. 2014;2014:295478.  [PubMed]  [DOI]
40.  Nielsen ST, Lehrskov-Schmidt L, Krogh-Madsen R, Solomon TP, Lehrskov-Schmidt L, Holst JJ, Møller K. Tumour necrosis factor-alpha infusion produced insulin resistance but no change in the incretin effect in healthy volunteers. Diabetes Metab Res Rev. 2013;29:655-663.  [PubMed]  [DOI]
41.  Paquot N, Castillo MJ, Lefèbvre PJ, Scheen AJ. No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J Clin Endocrinol Metab. 2000;85:1316-1319.  [PubMed]  [DOI]
42.  Bernstein LE, Berry J, Kim S, Canavan B, Grinspoon SK. Effects of etanercept in patients with the metabolic syndrome. Arch Intern Med. 2006;166:902-908.  [PubMed]  [DOI]
43.  Stanley TL, Zanni MV, Johnsen S, Rasheed S, Makimura H, Lee H, Khor VK, Ahima RS, Grinspoon SK. TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab. 2011;96:E146-E150.  [PubMed]  [DOI]
44.  Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol. 2009;5:578-582.  [PubMed]  [DOI]
45.  Monaco C, Nanchahal J, Taylor P, Feldmann M. Anti-TNF therapy: past, present and future. Int Immunol. 2015;27:55-62.  [PubMed]  [DOI]
46.  Dessein PH, Joffe BI. Insulin resistance and impaired beta cell function in rheumatoid arthritis. Arthritis Rheum. 2006;54:2765-2775.  [PubMed]  [DOI]
47.  Costa NT, Veiga Iriyoda TM, Kallaur AP, Delongui F, Alfieri DF, Lozovoy MA, Amin RB, Delfino VD, Dichi I, Simão AN. Influence of Insulin Resistance and TNF-α on the Inflammatory Process, Oxidative Stress, and Disease Activity in Patients with Rheumatoid Arthritis. Oxid Med Cell Longev. 2016;2016:8962763.  [PubMed]  [DOI]
48.  Jiang P, Li H, Li X. Diabetes mellitus risk factors in rheumatoid arthritis: a systematic review and meta-analysis. Clin Exp Rheumatol. 2015;33:115-121.  [PubMed]  [DOI]
49.  Liao KP, Gunnarsson M, Källberg H, Ding B, Plenge RM, Padyukov L, Karlson EW, Klareskog L, Askling J, Alfredsson L. Specific association of type 1 diabetes mellitus with anti-cyclic citrullinated peptide-positive rheumatoid arthritis. Arthritis Rheum. 2009;60:653-660.  [PubMed]  [DOI]
50.  Vaidya B, Pearce SH, Charlton S, Marshall N, Rowan AD, Griffiths ID, Kendall-Taylor P, Cawston TE, Young-Min S. An association between the CTLA4 exon 1 polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies. Rheumatology (Oxford). 2002;41:180-183.  [PubMed]  [DOI]
51.  Eyre S, Hinks A, Bowes J, Flynn E, Martin P, Wilson AG, Morgan AW, Emery P, Steer S, Hocking LJ, Reid DM, Harrison P, Wordsworth P; Yorkshire Early Arthritis Consortium; Biologics in RA Control Consortium, Thomson W, Worthington J, Barton A. Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease. Arthritis Res Ther. 2010;12:R175.  [PubMed]  [DOI]
52.  Chatzikyriakidou A, Voulgari PV, Lambropoulos A, Georgiou I, Drosos AA. Validation of the TAGAP rs212389 polymorphism in rheumatoid arthritis susceptibility. Joint Bone Spine. 2013;80:543-544.  [PubMed]  [DOI]
53.  Hollis-Moffatt JE, Chen-Xu M, Topless R, Dalbeth N, Gow PJ, Harrison AA, Highton J, Jones PB, Nissen M, Smith MD, van Rij A, Jones GT, Stamp LK, Merriman TR. Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 Locus in Caucasian sample sets: confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance. Arthritis Res Ther. 2010;12:R116.  [PubMed]  [DOI]
54.  Dubreuil M, Rho YH, Man A, Zhu Y, Zhang Y, Love TJ, Ogdie A, Gelfand JM, Choi HK. Diabetes incidence in psoriatic arthritis, psoriasis and rheumatoid arthritis: a UK population-based cohort study. Rheumatology (Oxford). 2014;53:346-352.  [PubMed]  [DOI]
55.  Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation. 2003;107:1303-1307.  [PubMed]  [DOI]
56.  Solomon DH, Love TJ, Canning C, Schneeweiss S. Risk of diabetes among patients with rheumatoid arthritis, psoriatic arthritis and psoriasis. Ann Rheum Dis. 2010;69:2114-2117.  [PubMed]  [DOI]
57.  Jinesh S. Pharmaceutical aspects of anti-inflammatory TNF-blocking drugs. Inflammopharmacology. 2015;23:71-77.  [PubMed]  [DOI]
58.  Zhao S, Mysler E, Moots RJ. Etanercept for the treatment of rheumatoid arthritis. Immunotherapy. 2018;10:433-445.  [PubMed]  [DOI]
59.  Hamid YH, Urhammer SA, Glümer C, Borch-Johnsen K, Jørgensen T, Hansen T, Pedersen O. The common T60N polymorphism of the lymphotoxin-alpha gene is associated with type 2 diabetes and other phenotypes of the metabolic syndrome. Diabetologia. 2005;48:445-451.  [PubMed]  [DOI]
60.  Upadhyay V, Fu YX. Lymphotoxin organizes contributions to host defense and metabolic illness from innate lymphoid cells. Cytokine Growth Factor Rev. 2014;25:227-233.  [PubMed]  [DOI]
61.  Antohe JL, Bili A, Sartorius JA, Kirchner HL, Morris SJ, Dancea S, Wasko MC. Diabetes mellitus risk in rheumatoid arthritis: reduced incidence with anti-tumor necrosis factor α therapy. Arthritis Care Res (Hoboken). 2012;64:215-221.  [PubMed]  [DOI]
62.  Wood PR, Manning E, Baker JF, England B, Davis L, Cannon GW, Mikuls TR, Caplan L. Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis. World J Diabetes. 2018;9:53-58.  [PubMed]  [DOI]
63.  Seriolo B, Ferrone C, Cutolo M. Longterm anti-tumor necrosis factor-alpha treatment in patients with refractory rheumatoid arthritis: relationship between insulin resistance and disease activity. J Rheumatol. 2008;35:355-357.  [PubMed]  [DOI]
64.  Ferraz-Amaro I, Arce-Franco M, Muñiz J, López-Fernández J, Hernández-Hernández V, Franco A, Quevedo J, Martínez-Martín J, Díaz-González F. Systemic blockade of TNF-α does not improve insulin resistance in humans. Horm Metab Res. 2011;43:801-808.  [PubMed]  [DOI]
65.  Stagakis I, Bertsias G, Karvounaris S, Kavousanaki M, Virla D, Raptopoulou A, Kardassis D, Boumpas DT, Sidiropoulos PI. Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance. Arthritis Res Ther. 2012;14:R141.  [PubMed]  [DOI]
66.  Stavropoulos-Kalinoglou A, Metsios GS, Panoulas VF, Nightingale P, Koutedakis Y, Kitas GD. Anti-tumour necrosis factor alpha therapy improves insulin sensitivity in normal-weight but not in obese patients with rheumatoid arthritis. Arthritis Res Ther. 2012;14:R160.  [PubMed]  [DOI]
67.  Yazdani-Biuki B, Stelzl H, Brezinschek HP, Hermann J, Mueller T, Krippl P, Graninger W, Wascher TC. Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab. Eur J Clin Invest. 2004;34:641-642.  [PubMed]  [DOI]
68.  Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis. 2005;64:765-766.  [PubMed]  [DOI]
69.  Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, Garcia-Porrua C, Sanchez-Andrade A, Martin J, Llorca J. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006;24:83-86.  [PubMed]  [DOI]
70.  Huvers FC, Popa C, Netea MG, van den Hoogen FH, Tack CJ. Improved insulin sensitivity by anti-TNFalpha antibody treatment in patients with rheumatic diseases. Ann Rheum Dis. 2007;66:558-559.  [PubMed]  [DOI]
71.  Rosenvinge A, Krogh-Madsen R, Baslund B, Pedersen BK. Insulin resistance in patients with rheumatoid arthritis: effect of anti-TNFalpha therapy. Scand J Rheumatol. 2007;36:91-96.  [PubMed]  [DOI]
72.  Tam LS, Tomlinson B, Chu TT, Li TK, Li EK. Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis. Clin Rheumatol. 2007;26:1495-1498.  [PubMed]  [DOI]
73.  Oguz FM, Oguz A, Uzunlulu M. The effect of infliximab treatment on insulin resistance in patients with rheumatoid arthritis. Acta Clin Belg. 2007;62:218-222.  [PubMed]  [DOI]
74.  Seriolo B, Paolino S, Ferrone C, Cutolo M. Impact of long-term anti-TNF-alpha treatment on insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2008;26:159-60; author reply 160.  [PubMed]  [DOI]
75.  Corrado A, Colia R, Rotondo C, Sanpaolo E, Cantatore FP. Changes in serum adipokines profile and insulin resistance in patients with rheumatoid arthritis treated with anti-TNF-α. Curr Med Res Opin. 2019;35:2197-2205.  [PubMed]  [DOI]
76.  van den Oever IAM, Baniaamam M, Simsek S, Raterman HG, van Denderen JC, van Eijk IC, Peters MJL, van der Horst-Bruinsma IE, Smulders YM, Nurmohamed MT. The effect of anti-TNF treatment on body composition and insulin resistance in patients with rheumatoid arthritis. Rheumatol Int. 2020;.  [PubMed]  [DOI]
77.  Wang CR, Liu MF. Recombinant Soluble TNF-α Receptor Fusion Protein Therapy Reduces Insulin Resistance in Non-Diabetic Active Rheumatoid Arthritis Patients. ACR Open Rheumatol. 2020;2:401-406.  [PubMed]  [DOI]
78.  Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997;82:4196-4200.  [PubMed]  [DOI]
79.  Fasshauer M, Klein J, Lossner U, Paschke R. Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoproterenol, tumour necrosis factor alpha, growth hormone, and IL-6 in 3T3-L1 adipocytes. Horm Metab Res. 2003;35:147-152.  [PubMed]  [DOI]
80.  Krogh-Madsen R, Plomgaard P, Keller P, Keller C, Pedersen BK. Insulin stimulates interleukin-6 and tumor necrosis factor-alpha gene expression in human subcutaneous adipose tissue. Am J Physiol Endocrinol Metab. 2004;286:E234-E238.  [PubMed]  [DOI]
81.  Kado S, Nagase T, Nagata N. Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol. 1999;36:67-72.  [PubMed]  [DOI]
82.  Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327-334.  [PubMed]  [DOI]
83.  Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res. 2001;9:414-417.  [PubMed]  [DOI]
84.  Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord. 2003;27 Suppl 3:S49-S52.  [PubMed]  [DOI]
85.  Tanaka H, Fujita N, Tsuruo T. 3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling. J Biol Chem. 2005;280:40965-40973.  [PubMed]  [DOI]
86.  Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem. 2002;277:48115-48121.  [PubMed]  [DOI]
87.  Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11:183-190.  [PubMed]  [DOI]
88.  Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 2002;51:3391-3399.  [PubMed]  [DOI]
89.  Weigert C, Hennige AM, Lehmann R, Brodbeck K, Baumgartner F, Schaüble M, Häring HU, Schleicher ED. Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells. J Biol Chem. 2006;281:7060-7067.  [PubMed]  [DOI]
90.  Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem. 2003;278:13740-13746.  [PubMed]  [DOI]
91.  Lagathu C, Bastard JP, Auclair M, Maachi M, Capeau J, Caron M. Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. Biochem Biophys Res Commun. 2003;311:372-379.  [PubMed]  [DOI]
92.  Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2003;301:1045-1050.  [PubMed]  [DOI]
93.  Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003;278:45777-45784.  [PubMed]  [DOI]
94.  Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, Gueripel X, Ellingsgaard H, Schneider MK, Biollaz G, Fontana A, Reinecke M, Homo-Delarche F, Donath MY. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes. 2007;56:2356-2370.  [PubMed]  [DOI]
95.  Rajendran S, Anquetil F, Quesada-Masachs E, Graef M, Gonzalez N, McArdle S, Chu T, Krogvold L, Dahl-Jørgensen K, von Herrath M. IL-6 is present in beta and alpha cells in human pancreatic islets: Expression is reduced in subjects with type 1 diabetes. Clin Immunol. 2020;211:108320.  [PubMed]  [DOI]
96.  Ellingsgaard H, Ehses JA, Hammar EB, Van Lommel L, Quintens R, Martens G, Kerr-Conte J, Pattou F, Berney T, Pipeleers D, Halban PA, Schuit FC, Donath MY. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci USA. 2008;105:13163-13168.  [PubMed]  [DOI]
97.  Bordon Y. Immunometabolism: IL-6, the resistance fighter. Nat Rev Immunol. 2014;14:282-283.  [PubMed]  [DOI]
98.  Mauer J, Chaurasia B, Goldau J, Vogt MC, Ruud J, Nguyen KD, Theurich S, Hausen AC, Schmitz J, Brönneke HS, Estevez E, Allen TL, Mesaros A, Partridge L, Febbraio MA, Chawla A, Wunderlich FT, Brüning JC. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol. 2014;15:423-430.  [PubMed]  [DOI]
99.  Stouthard JM, Oude Elferink RP, Sauerwein HP. Interleukin-6 enhances glucose transport in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 1996;220:241-245.  [PubMed]  [DOI]
100.  Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88:1379-1406.  [PubMed]  [DOI]
101.  Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B, Klarlund Pedersen B. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol. 2000;529 Pt 1:237-242.  [PubMed]  [DOI]
102.  Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, Kemp BE, Pedersen BK, Febbraio MA. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes. 2006;55:2688-2697.  [PubMed]  [DOI]
103.  Huang C, Thirone AC, Huang X, Klip A. Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in l6 myotubes. J Biol Chem. 2005;280:19426-19435.  [PubMed]  [DOI]
104.  Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YD, Hansen AM, Reinecke M, Konrad D, Gassmann M, Reimann F, Halban PA, Gromada J, Drucker DJ, Gribble FM, Ehses JA, Donath MY. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med. 2011;17:1481-1489.  [PubMed]  [DOI]
105.  Nieto-Vazquez I, Fernández-Veledo S, de Alvaro C, Lorenzo M. Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes. 2008;57:3211-3221.  [PubMed]  [DOI]
106.  Akbari M, Hassan-Zadeh V. IL-6 signalling pathways and the development of type 2 diabetes. Inflammopharmacology. 2018;26:685-698.  [PubMed]  [DOI]
107.  Yamaguchi S, Katahira H, Ozawa S, Nakamichi Y, Tanaka T, Shimoyama T, Takahashi K, Yoshimoto K, Imaizumi MO, Nagamatsu S, Ishida H. Activators of AMP-activated protein kinase enhance GLUT4 translocation and its glucose transport activity in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab. 2005;289:E643-9.  [PubMed]  [DOI]
108.  Harder-Lauridsen NM, Krogh-Madsen R, Holst JJ, Plomgaard P, Leick L, Pedersen BK, Fischer CP. Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2014;306:E769-E778.  [PubMed]  [DOI]
109.  Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol. 2012;52:199-219.  [PubMed]  [DOI]
110.  Ogata A, Morishima A, Hirano T, Hishitani Y, Hagihara K, Shima Y, Narazaki M, Tanaka T. Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab. Ann Rheum Dis. 2011;70:1164-1165.  [PubMed]  [DOI]
111.  Qu D, Liu J, Lau CW, Huang Y. IL-6 in diabetes and cardiovascular complications. Br J Pharmacol. 2014;171:3595-3603.  [PubMed]  [DOI]
112.  Kraakman MJ, Kammoun HL, Allen TL, Deswaerte V, Henstridge DC, Estevez E, Matthews VB, Neill B, White DA, Murphy AJ, Peijs L, Yang C, Risis S, Bruce CR, Du XJ, Bobik A, Lee-Young RS, Kingwell BA, Vasanthakumar A, Shi W, Kallies A, Lancaster GI, Rose-John S, Febbraio MA. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab. 2015;21:403-416.  [PubMed]  [DOI]
113.  Walz HA, Härndahl L, Wierup N, Zmuda-Trzebiatowska E, Svennelid F, Manganiello VC, Ploug T, Sundler F, Degerman E, Ahrén B, Holst LS. Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B. J Endocrinol. 2006;189:629-641.  [PubMed]  [DOI]
114.  Atreya R, Mudter J, Finotto S, Müllberg J, Jostock T, Wirtz S, Schütz M, Bartsch B, Holtmann M, Becker C, Strand D, Czaja J, Schlaak JF, Lehr HA, Autschbach F, Schürmann G, Nishimoto N, Yoshizaki K, Ito H, Kishimoto T, Galle PR, Rose-John S, Neurath MF. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med. 2000;6:583-588.  [PubMed]  [DOI]
115.  Robinson R, Srinivasan M, Shanmugam A, Ward A, Ganapathy V, Bloom J, Sharma A, Sharma S. Interleukin-6 trans-signaling inhibition prevents oxidative stress in a mouse model of early diabetic retinopathy. Redox Biol. 2020;34:101574.  [PubMed]  [DOI]
116.  Schultz O, Oberhauser F, Saech J, Rubbert-Roth A, Hahn M, Krone W, Laudes M. Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS One. 2010;5:e14328.  [PubMed]  [DOI]
117.  Mirjafari HW, Wang J, Klearman M, Harari O, Bruce I. FRI0132: Insulin resistance is improved by tocilizumab therapy in rheumatoid arthritis: results from the toward study. Ann Rheum Dis. 2013;72:A12-A15.  [PubMed]  [DOI]
118.  Mirjafari HR, Ruperto N, Brunner HI, Zuber Z, Zulian F, Maldonado-Velázquez MR, Mantzourani E, Murray K, Roth J, Rovensky J, Vougiouka O, Wang J, Harari O, Lovell D, Martini A, De Benedetti F, on behalf of PRINTO and PRCSG. PReS-FINAL-2188: Insulin sensitivity is improved in SJIA children with insulin resistance after tocilizumab treatment: results from the TENDER study. Pediatric Rheumatol. 2014;66:S80-S81.  [PubMed]  [DOI]
119.  Ursini F, Russo E, Letizia Hribal M, Mauro D, Savarino F, Bruno C, Tripolino C, Rubino M, Naty S, Grembiale RD. Abatacept improves whole-body insulin sensitivity in rheumatoid arthritis: an observational study. Medicine (Baltimore). 2015;94:e888.  [PubMed]  [DOI]
120.  Chen DY, Chen YM, Hsieh TY, Hsieh CW, Lin CC, Lan JL. Significant effects of biologic therapy on lipid profiles and insulin resistance in patients with rheumatoid arthritis. Arthritis Res Ther. 2015;17:52.  [PubMed]  [DOI]
121.  Makrilakis K, Fragiadaki K, Smith J, Sfikakis PP, Kitas GD. Interrelated reduction of chemerin and plasminogen activator inhibitor-1 serum levels in rheumatoid arthritis after interleukin-6 receptor blockade. Clin Rheumatol. 2015;34:419-427.  [PubMed]  [DOI]
122.  Tournadre A, Pereira B, Dutheil F, Giraud C, Courteix D, Sapin V, Frayssac T, Mathieu S, Malochet-Guinamand S, Soubrier M. Changes in body composition and metabolic profile during interleukin 6 inhibition in rheumatoid arthritis. J Cachexia Sarcopenia Muscle. 2017;8:639-646.  [PubMed]  [DOI]
123.  Castañeda S, Remuzgo-Martínez S, López-Mejías R, Genre F, Calvo-Alén J, Llorente I, Aurrecoechea E, Ortiz AM, Triguero A, Blanco R, Llorca J, González-Gay MA. Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis. Clin Exp Rheumatol. 2019;37:465-473.  [PubMed]  [DOI]
124.  Virone A, Bastard JP, Fellahi S, Capeau J, Rouanet S, Sibilia J, Ravaud P, Berenbaum F, Gottenberg JE, Sellam J. Comparative effect of tumour necrosis factor inhibitors vs other biological agents on cardiovascular risk-associated biomarkers in patients with rheumatoid arthritis. RMD Open. 2019;5:e000897.  [PubMed]  [DOI]
125.  Toussirot E, Marotte H, Mulleman D, Cormier G, Coury F, Gaudin P, Dernis E, Bonnet C, Damade R, Grauer JL, Abdesselam TA, Guillibert-Karras C, Lioté F, Hilliquin P, Sacchi A, Wendling D, Le Goff B, Puyraveau M, Dumoulin G. Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study. Arthritis Res Ther. 2020;22:224.  [PubMed]  [DOI]
126.  Blair HA, Deeks ED. Abatacept: A Review in Rheumatoid Arthritis. Drugs. 2017;77:1221-1233.  [PubMed]  [DOI]
127.  Fujii M, Inoguchi T, Batchuluun B, Sugiyama N, Kobayashi K, Sonoda N, Takayanagi R. CTLA-4Ig immunotherapy of obesity-induced insulin resistance by manipulation of macrophage polarization in adipose tissues. Biochem Biophys Res Commun. 2013;438:103-109.  [PubMed]  [DOI]
128.  Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519-550.  [PubMed]  [DOI]
129.  Besedovsky HO, Del Rey A. Physiologic vs diabetogenic effects of interleukin-1: a question of weight. Curr Pharm Des. 2014;20:4733-4740.  [PubMed]  [DOI]
130.  Ciampolillo A, Guastamacchia E, Caragiulo L, Lollino G, De Robertis O, Lattanzi V, Giorgino R. In vitro secretion of interleukin-1 beta and interferon-gamma by peripheral blood lymphomononuclear cells in diabetic patients. Diabetes Res Clin Pract. 1993;21:87-93.  [PubMed]  [DOI]
131.  Hussain MJ, Peakman M, Gallati H, Lo SS, Hawa M, Viberti GC, Watkins PJ, Leslie RD, Vergani D. Elevated serum levels of macrophage-derived cytokines precede and accompany the onset of IDDM. Diabetologia. 1996;39:60-69.  [PubMed]  [DOI]
132.  Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia. Diabetologia. 1996;39:1005-1029.  [PubMed]  [DOI]
133.  Nicoletti F, Di Marco R, Barcellini W, Magro G, Schorlemmer HU, Kurrle R, Lunetta M, Grasso S, Zaccone P, Meroni P. Protection from experimental autoimmune diabetes in the non-obese diabetic mouse with soluble interleukin-1 receptor. Eur J Immunol. 1994;24:1843-1847.  [PubMed]  [DOI]
134.  The role of interleukin-1 in the pathogenesis of insulin-dependent diabetes mellitus. Diabetologia. 1994;37:42-43.  [PubMed]  [DOI]
135.  Mandrup-Poulsen T, Pickersgill L, Donath MY. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol. 2010;6:158-166.  [PubMed]  [DOI]
136.  Spranger J, Kroke A, Möhlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes. 2003;52:812-817.  [PubMed]  [DOI]
137.  Matsuki T, Horai R, Sudo K, Iwakura Y. IL-1 plays an important role in lipid metabolism by regulating insulin levels under physiological conditions. J Exp Med. 2003;198:877-888.  [PubMed]  [DOI]
138.  Maedler K, Sergeev P, Ehses JA, Mathe Z, Bosco D, Berney T, Dayer JM, Reinecke M, Halban PA, Donath MY. Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets. Proc Natl Acad Sci USA. 2004;101:8138-8143.  [PubMed]  [DOI]
139.  Jager J, Grémeaux T, Cormont M, Le Marchand-Brustel Y, Tanti JF. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology. 2007;148:241-251.  [PubMed]  [DOI]
140.  Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14:222-231.  [PubMed]  [DOI]
141.  Reimers JI. Interleukin-1 beta induced transient diabetes mellitus in rats. A model of the initial events in the pathogenesis of insulin-dependent diabetes mellitus? Dan Med Bull. 1998;45:157-180.  [PubMed]  [DOI]
142.  Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110:851-860.  [PubMed]  [DOI]
143.  Dinarello CA, Donath MY, Mandrup-Poulsen T. Role of IL-1beta in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes. 2010;17:314-321.  [PubMed]  [DOI]
144.  Mistry A, Savic S, van der Hilst JCH. Interleukin-1 Blockade: An Update on Emerging Indications. BioDrugs. 2017;31:207-221.  [PubMed]  [DOI]
145.  Ruscitti P, Cipriani P, Cantarini L, Liakouli V, Vitale A, Carubbi F, Berardicurti O, Galeazzi M, Valenti M, Giacomelli R. Efficacy of inhibition of IL-1 in patients with rheumatoid arthritis and type 2 diabetes mellitus: two case reports and review of the literature. J Med Case Rep. 2015;9:123.  [PubMed]  [DOI]
146.  Vitale A, Cantarini L, Rigante D, Bardelli M, Galeazzi M. Anakinra treatment in patients with gout and type 2 diabetes. Clin Rheumatol. 2015;34:981-984.  [PubMed]  [DOI]
147.  Dominguez H, Storgaard H, Rask-Madsen C, Steffen Hermann T, Ihlemann N, Baunbjerg Nielsen D, Spohr C, Kober L, Vaag A, Torp-Pedersen C. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes. J Vasc Res. 2005;42:517-525.  [PubMed]  [DOI]
148.  Gupta-Ganguli M, Cox K, Means B, Gerling I, Solomon SS. Does therapy with anti-TNF-alpha improve glucose tolerance and control in patients with type 2 diabetes? Diabetes Care. 2011;34:e121.  [PubMed]  [DOI]
149.  Cohen MD, Keystone E. Rituximab for Rheumatoid Arthritis. Rheumatol Ther. 2015;2:99-111.  [PubMed]  [DOI]
150.  Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, McGee PF, Moran AM, Raskin P, Rodriguez H, Schatz DA, Wherrett D, Wilson DM, Lachin JM, Skyler JS; Type 1 Diabetes TrialNet Anti-CD20 Study Group. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361:2143-2152.  [PubMed]  [DOI]
151.  Iseri K, Iyoda M, Shikida Y, Inokuchi T, Morikawa T, Hara N, Hirano T, Shibata T. Rituximab for the treatment of type B insulin resistance syndrome: a case report and review of the literature. Diabet Med. 2017;34:1788-1791.  [PubMed]  [DOI]
152.  Noorchashm H, Noorchashm N, Kern J, Rostami SY, Barker CF, Naji A. B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice. Diabetes. 1997;46:941-946.  [PubMed]  [DOI]
153.  Pescovitz MD, Greenbaum CJ, Bundy B, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, Moran A, Raskin P, Rodriguez H, Schatz DA, Wherrett DK, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Anti-CD20 Study Group. B-lymphocyte depletion with rituximab and β-cell function: two-year results. Diabetes Care. 2014;37:453-459.  [PubMed]  [DOI]
154.  Lenschow DJ, Ho SC, Sattar H, Rhee L, Gray G, Nabavi N, Herold KC, Bluestone JA. Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J Exp Med. 1995;181:1145-1155.  [PubMed]  [DOI]
155.  Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Raskin P, Rodriguez H, Russell WE, Schatz D, Wherrett D, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Abatacept Study Group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;378:412-419.  [PubMed]  [DOI]
156.  Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356:1517-1526.  [PubMed]  [DOI]
157.  Rissanen A, Howard CP, Botha J, Thuren T; Global Investigators. Effect of anti-IL-1β antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial. Diabetes Obes Metab. 2012;14:1088-1096.  [PubMed]  [DOI]
158.  Ridker PM, Howard CP, Walter V, Everett B, Libby P, Hensen J, Thuren T; CANTOS Pilot Investigative Group. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012;126:2739-2748.  [PubMed]  [DOI]
159.  Cavelti-Weder C, Babians-Brunner A, Keller C, Stahel MA, Kurz-Levin M, Zayed H, Solinger AM, Mandrup-Poulsen T, Dinarello CA, Donath MY. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care. 2012;35:1654-1662.  [PubMed]  [DOI]
160.  Moran A, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Greenbaum CJ, Herold KC, Marks JB, Raskin P, Sanda S, Schatz D, Wherrett DK, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Canakinumab Study Group, Pickersgill L, de Koning E, Ziegler AG, Böehm B, Badenhoop K, Schloot N, Bak JF, Pozzilli P, Mauricio D, Donath MY, Castaño L, Wägner A, Lervang HH, Perrild H, Mandrup-Poulsen T; AIDA Study Group. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381:1905-1915.  [PubMed]  [DOI]
161.  Noe A, Howard C, Thuren T, Taylor A, Skerjanec A. Pharmacokinetic and pharmacodynamic characteristics of single-dose Canakinumab in patients with type 2 diabetes mellitus. Clin Ther. 2014;36:1625-1637.  [PubMed]  [DOI]
162.  van Asseldonk EJ, van Poppel PC, Ballak DB, Stienstra R, Netea MG, Tack CJ. One week treatment with the IL-1 receptor antagonist anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus. Clin Immunol. 2015;160:155-162.  [PubMed]  [DOI]
163.  Timper K, Seelig E, Tsakiris DA, Donath MY. Safety, pharmacokinetics, and preliminary efficacy of a specific anti-IL-1alpha therapeutic antibody (MABp1) in patients with type 2 diabetes mellitus. J Diabetes Complications. 2015;29:955-960.  [PubMed]  [DOI]
164.  Seelig E, Timper K, Falconnier C, Stoeckli R, Bilz S, Oram R, McDonald TJ, Donath MY. Interleukin-1 antagonism in type 1 diabetes of long duration. Diabetes Metab. 2016;42:453-456.  [PubMed]  [DOI]
165.  Stahel M, Becker M, Graf N, Michels S. SYSTEMIC INTERLEUKIN 1β INHIBITION IN PROLIFERATIVE DIABETIC RETINOPATHY: A Prospective Open-Label Study Using Canakinumab. Retina. 2016;36:385-391.  [PubMed]  [DOI]
166.  White PC, Adhikari S, Grishman EK, Sumpter KM. A phase I study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus. Pediatr Diabetes. 2018;19:788-793.  [PubMed]  [DOI]
167.  Ruscitti P, Masedu F, Alvaro S, Airò P, Battafarano N, Cantarini L, Cantatore FP, Carlino G, D'Abrosca V, Frassi M, Frediani B, Iacono D, Liakouli V, Maggio R, Mulè R, Pantano I, Prevete I, Sinigaglia L, Valenti M, Viapiana O, Cipriani P, Giacomelli R. Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial. PLoS Med. 2019;16:e1002901.  [PubMed]  [DOI]
168.  Ruscitti P, Ursini F, Cipriani P, Greco M, Alvaro S, Vasiliki L, Di Benedetto P, Carubbi F, Berardicurti O, Gulletta E, De Sarro G, Giacomelli R. IL-1 inhibition improves insulin resistance and adipokines in rheumatoid arthritis patients with comorbid type 2 diabetes: An observational study. Medicine (Baltimore). 2019;98:e14587.  [PubMed]  [DOI]
169.  Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12:25-36.  [PubMed]  [DOI]
170.  Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 2017;77:521-546.  [PubMed]  [DOI]
171.  Hosseini A, Gharibi T, Marofi F, Javadian M, Babaloo Z, Baradaran B. Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases. J Cell Physiol. 2020;235:5903-5924.  [PubMed]  [DOI]
172.  Sarzi-Puttini P, Ceribelli A, Marotto D, Batticciotto A, Atzeni F. Systemic rheumatic diseases: From biological agents to small molecules. Autoimmun Rev. 2019;18:583-592.  [PubMed]  [DOI]
173.  Caporali R, Zavaglia D. Real-world experience with tofacitinib for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2019;37:485-495.  [PubMed]  [DOI]
174.  Tao JH, Zou YF, Feng XL, Li J, Wang F, Pan FM, Ye DQ. Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases. Mol Biol Rep. 2011;38:4663-4672.  [PubMed]  [DOI]
175.  Corbit KC, Camporez JPG, Tran JL, Wilson CG, Lowe DA, Nordstrom SM, Ganeshan K, Perry RJ, Shulman GI, Jurczak MJ, Weiss EJ. Adipocyte JAK2 mediates growth hormone-induced hepatic insulin resistance. JCI Insight. 2017;2:e91001.  [PubMed]  [DOI]
176.  Bako HY, Ibrahim MA, Isah MS, Ibrahim S. Inhibition of JAK-STAT and NF-κB signalling systems could be a novel therapeutic target against insulin resistance and type 2 diabetes. Life Sci. 2019;239:117045.  [PubMed]  [DOI]
177.  Collotta D, Hull W, Mastrocola R, Chiazza F, Cento AS, Murphy C, Verta R, Alves GF, Gaudioso G, Fava F, Yaqoob M, Aragno M, Tuohy K, Thiemermann C, Collino M. Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice. Mol Metab. 2020;39:101009.  [PubMed]  [DOI]
178.  Chen SK, Lee H, Jin Y, Liu J, Kim SC. Use of biologic or targeted-synthetic disease-modifying anti-rheumatic drugs and risk of diabetes treatment intensification in patients with rheumatoid arthritis and diabetes mellitus. Rheumatol Adv Pract. 2020;4:rkaa027.  [PubMed]  [DOI]
179.  Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214:149-160.  [PubMed]  [DOI]
180.  Bravo A, Kavanaugh A. Bedside to bench: defining the immunopathogenesis of psoriatic arthritis. Nat Rev Rheumatol. 2019;15:645-656.  [PubMed]  [DOI]
181.  Haroon M, Gallagher P, Heffernan E, FitzGerald O. High prevalence of metabolic syndrome and of insulin resistance in psoriatic arthritis is associated with the severity of underlying disease. J Rheumatol. 2014;41:1357-1365.  [PubMed]  [DOI]
182.  Eder L, Jayakar J, Pollock R, Pellett F, Thavaneswaran A, Chandran V, Rosen CF, Gladman DD. Serum adipokines in patients with psoriatic arthritis and psoriasis alone and their correlation with disease activity. Ann Rheum Dis. 2013;72:1956-1961.  [PubMed]  [DOI]
183.  Tam LS, Tomlinson B, Chu TT, Li M, Leung YY, Kwok LW, Li TK, Yu T, Zhu YE, Wong KC, Kun EW, Li EK. Cardiovascular risk profile of patients with psoriatic arthritis compared to controls--the role of inflammation. Rheumatology (Oxford). 2008;47:718-723.  [PubMed]  [DOI]
184.  Dreiher J, Freud T, Cohen AD. Psoriatic arthritis and diabetes: a population-based cross-sectional study. Dermatol Res Pract. 2013;2013:580404.  [PubMed]  [DOI]
185.  Eder L, Chandran V, Cook R, Gladman DD. The Risk of Developing Diabetes Mellitus in Patients with Psoriatic Arthritis: A Cohort Study. J Rheumatol. 2017;44:286-291.  [PubMed]  [DOI]
186.  Nas K, Karkucak M, Durmus B, Karatay S, Capkın E, Kaya A, Ucmak D, Akar ZA, Cevik R, Kilic E, Kilic G, Ozgocmen S. Comorbidities in patients with psoriatic arthritis: a comparison with rheumatoid arthritis and psoriasis. Int J Rheum Dis. 2015;18:873-879.  [PubMed]  [DOI]
187.  Radner H, Lesperance T, Accortt NA, Solomon DH. Incidence and Prevalence of Cardiovascular Risk Factors Among Patients With Rheumatoid Arthritis, Psoriasis, or Psoriatic Arthritis. Arthritis Care Res (Hoboken). 2017;69:1510-1518.  [PubMed]  [DOI]
188.  Marra M, Campanati A, Testa R, Sirolla C, Bonfigli AR, Franceschi C, Marchegiani F, Offidani A. Effect of etanercept on insulin sensitivity in nine patients with psoriasis. Int J Immunopathol Pharmacol. 2007;20:731-736.  [PubMed]  [DOI]
189.  Wambier CG, Foss-Freitas MC, Paschoal RS, Tomazini MV, Simão JC, Foss MC, Foss NT. Severe hypoglycemia after initiation of anti-tumor necrosis factor therapy with etanercept in a patient with generalized pustular psoriasis and type 2 diabetes mellitus. J Am Acad Dermatol. 2009;60:883-885.  [PubMed]  [DOI]
190.  Cheung D, Bryer-Ash M. Persistent hypoglycemia in a patient with diabetes taking etanercept for the treatment of psoriasis. J Am Acad Dermatol. 2009;60:1032-1036.  [PubMed]  [DOI]
191.  da Silva BS, Bonfá E, de Moraes JC, Saad CG, Ribeiro AC, Gonçalves CR, de Carvalho JF. Effects of anti-TNF therapy on glucose metabolism in patients with ankylosing spondylitis, psoriatic arthritis or juvenile idiopathic arthritis. Biologicals. 2010;38:567-569.  [PubMed]  [DOI]
192.  Kimball AB, Bensimon AG, Guerin A, Yu AP, Wu EQ, Okun MM, Bao Y, Gupta SR, Mulani PM. Efficacy and safety of adalimumab among patients with moderate to severe psoriasis with co-morbidities: Subanalysis of results from a randomized, double-blind, placebo-controlled, phase III trial. Am J Clin Dermatol. 2011;12:51-62.  [PubMed]  [DOI]
193.  Pfeifer EC, Saxon DR, Janson RW. Etanercept-Induced Hypoglycemia in a Patient With Psoriatic Arthritis and Diabetes. J Investig Med High Impact Case Rep. 2017;5:2324709617727760.  [PubMed]  [DOI]
194.  Mathieu S, Motreff P, Soubrier M. Spondyloarthropathies: an independent cardiovascular risk factor? Joint Bone Spine. 2010;77:542-545.  [PubMed]  [DOI]
195.  Genre F, López-Mejías R, Miranda-Filloy JA, Ubilla B, Carnero-López B, Blanco R, Pina T, González-Juanatey C, Llorca J, González-Gay MA. Adipokines, biomarkers of endothelial activation, and metabolic syndrome in patients with ankylosing spondylitis. Biomed Res Int. 2014;2014:860651.  [PubMed]  [DOI]
196.  Miranda-Filloy JA, Llorca J, Carnero-López B, González-Juanatey C, Blanco R, González-Gay MA. TNF-alpha antagonist therapy improves insulin sensitivity in non-diabetic ankylosing spondylitis patients. Clin Exp Rheumatol. 2012;30:850-855.  [PubMed]  [DOI]
197.  Ersozlu Bozkirli ED, Bozkirli E, Yucel AE. Effects of infliximab treatment in terms of cardiovascular risk and insulin resistance in ankylosing spondylitis patients. Mod Rheumatol. 2014;24:335-339.  [PubMed]  [DOI]
198.  Jagannathan-Bogdan M, McDonnell ME, Shin H, Rehman Q, Hasturk H, Apovian CM, Nikolajczyk BS. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol. 2011;186:1162-1172.  [PubMed]  [DOI]
199.  Zhang C, Xiao C, Wang P, Xu W, Zhang A, Li Q, Xu X. The alteration of Th1/Th2/Th17/Treg paradigm in patients with type 2 diabetes mellitus: Relationship with diabetic nephropathy. Hum Immunol. 2014;75:289-296.  [PubMed]  [DOI]
200.  Ohshima K, Mogi M, Jing F, Iwanami J, Tsukuda K, Min LJ, Higaki J, Horiuchi M. Roles of interleukin 17 in angiotensin II type 1 receptor-mediated insulin resistance. Hypertension. 2012;59:493-499.  [PubMed]  [DOI]
201.  O'Rielly DD, Rahman P. A review of ixekizumab in the treatment of psoriatic arthritis. Expert Rev Clin Immunol. 2018;14:993-1002.  [PubMed]  [DOI]
202.  Egeberg A, Wu JJ, Korman N, Solomon JA, Goldblum O, Zhao F, Mallbris L. Ixekizumab treatment shows a neutral impact on cardiovascular parameters in patients with moderate-to-severe plaque psoriasis: Results from UNCOVER-1, UNCOVER-2, and UNCOVER-3. J Am Acad Dermatol. 2018;79:104-109.e8.  [PubMed]  [DOI]
203.  Frieder J, Kivelevitch D, Menter A. Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chronic Dis. 2018;9:5-21.  [PubMed]  [DOI]
204.  Gerdes S, Pinter A, Papavassilis C, Reinhardt M. Effects of secukinumab on metabolic and liver parameters in plaque psoriasis patients. J Eur Acad Dermatol Venereol. 2020;34:533-541.  [PubMed]  [DOI]
205.  Hasnain SZ, Borg DJ, Harcourt BE, Tong H, Sheng YH, Ng CP, Das I, Wang R, Chen AC, Loudovaris T, Kay TW, Thomas HE, Whitehead JP, Forbes JM, Prins JB, McGuckin MA. Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nat Med. 2014;20:1417-1426.  [PubMed]  [DOI]
206.  Yiu ZZ, Warren RB. Ustekinumab for the treatment of psoriasis: an evidence update. Semin Cutan Med Surg. 2018;37:143-147.  [PubMed]  [DOI]
207.  Ng CY, Tzeng IS, Liu SH, Chang YC, Huang YH. Metabolic parameters in psoriatic patients treated with interleukin-12/23 blockade (ustekinumab). J Dermatol. 2018;45:309-313.  [PubMed]  [DOI]
208.  Haber SL, Hamilton S, Bank M, Leong SY, Pierce E. Apremilast: A Novel Drug for Treatment of Psoriasis and Psoriatic Arthritis. Ann Pharmacother. 2016;50:282-290.  [PubMed]  [DOI]
209.  Pyne NJ, Furman BL. Cyclic nucleotide phosphodiesterases in pancreatic islets. Diabetologia. 2003;46:1179-1189.  [PubMed]  [DOI]
210.  Puig L, Korman N, Greggio C, Cirulli J, Teng L, Chandran V, Khraishi M, Paris M, Mehta N. Long-term hemoglobin A1c changes with apremilast in patients with psoriasis and psoriatic arthritis: pooled analysis of phase 3 ESTEEM and PALACE trials and phase 3b LIBERATE trial. J Am Acad Dermatol. 2019;81:89.  [PubMed]  [DOI]
211.  Lanna C, Cesaroni GM, Mazzilli S, Bianchi L, Campione E. Small Molecules, Big Promises: Improvement of Psoriasis Severity and Glucidic Markers with Apremilast: A Case Report. Diabetes Metab Syndr Obes. 2019;12:2685-2688.  [PubMed]  [DOI]
212.  Mazzilli S, Lanna C, Chiaramonte C, Cesaroni GM, Zangrilli A, Palumbo V, Cosio T, Dattola A, Gaziano R, Galluzzo M, Chimenti MS, Gisondi P, Bianchi L, Campione E. Real life experience of apremilast in psoriasis and arthritis psoriatic patients: Preliminary results on metabolic biomarkers. J Dermatol. 2020;47:578-582.  [PubMed]  [DOI]
213.  Chen M, Dai SM. A novel treatment for psoriatic arthritis: Janus kinase inhibitors. Chin Med J (Engl). 2020;133:959-967.  [PubMed]  [DOI]
214.  Chimenti MS, Triggianese P, De Martino E, Conigliaro P, Fonti GL, Sunzini F, Caso F, Perricone C, Costa L, Perricone R. An update on pathogenesis of psoriatic arthritis and potential therapeutic targets. Expert Rev Clin Immunol. 2019;15:823-836.  [PubMed]  [DOI]
215.  Gurzov EN, Stanley WJ, Pappas EG, Thomas HE, Gough DJ. The JAK/STAT pathway in obesity and diabetes. FEBS J. 2016;283:3002-3015.  [PubMed]  [DOI]
216.  Dodington DW, Desai HR, Woo M. JAK/STAT - Emerging Players in Metabolism. Trends Endocrinol Metab. 2018;29:55-65.  [PubMed]  [DOI]
217.  Ritchlin CT, Giles JT, Ogdie A, Gomez-Reino JJ, Helliwell P, Young P, Wang C, Wu J, Romero AB, Woolcott J, Stockert L. Tofacitinib in Patients With Psoriatic Arthritis and Metabolic Syndrome: A Post hoc Analysis of Phase 3 Studies. ACR Open Rheumatol. 2020;2:543-554.  [PubMed]  [DOI]