The Role of Iron and Nerve Inflammation in Diabetes Mellitus Type 2-Induced Peripheral Neuropathy

Paeschke, Sabine; Baum, Petra; Toyka, Klaus V.; Blüher, Matthias; Koj, Severin; Klöting, Nora; Bechmann, Ingo; Thiery, Joachim; Kosacka, Joanna; Nowicki, Marcin

doi:10.1016/j.neuroscience.2019.03.005

Cited by 23 publications

(34 citation statements)

References 41 publications

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“…Our results are different from results of rodent models of DPN which showed that iron deficiency rather than iron overload was associated with the risk of DPN [21][22][23]. It is hard to compare the results from human and rodent studies.…”

Section: Discussioncontrasting

confidence: 99%

“…Interestingly, previous studies have shown an association between dietary iron intake and diabetes risk [19,20]. Several rodent models of DPN have shown that iron deficiency rather than iron overload was associated with the risk of DPN [21][22][23]. However, no study has evaluated the association between dietary iron intake and DPN in humans.…”

Section: Introductionmentioning

confidence: 99%

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Association between Iron Intake and Diabetic Peripheral Neuropathy in Type 2 Diabetes: Significance of Iron Intake and the Ratio between Iron Intake and Polyunsaturated Fatty Acids Intake

Kim

Song

et al. 2020

Nutrients

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We aimed to investigate the association of iron and polyunsaturated fatty acid (PUFA) intake with diabetic peripheral neuropathy (DPN) in individuals with type 2 diabetes. This cross-sectional study included 147 individuals with type 2 diabetes. Dietary intake was assessed using three-day food records. DPN was diagnosed on the basis of a Michigan Neuropathy Screening Instrument—Physical Examination score ≥2.5. Adjusted for total energy intake, iron intake was significantly higher in individuals with DPN than in those without DPN (10.9 ± 4.0 mg vs. 9.9 ± 3.6 mg, p = 0.041). In addition, the iron/PUFA ratio was significantly higher in individuals with DPN (1.4 ± 0.8 vs. 1.1 ± 0.4, p = 0.005). Logistic regression analyses showed that iron intake (odds ratio (OR): 1.152; 95% confidence interval (CI): 1.012, 1.311) and iron/PUFA ratio (OR: 2.283; 95% CI: 1.066, 4.887) were associated with DPN after adjustment for total energy intake, sex, age, body mass index, systolic blood pressure, diabetes duration, estimated glomerular filtration rate, glycated hemoglobin, low-density lipoprotein cholesterol, and smoking. In conclusion, high dietary iron intake and an elevated iron/PUFA ratio were associated with the presence of DPN. The present study suggests the importance of the dietary pattern of iron and PUFA intake in individuals with type 2 diabetes.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association between Iron Intake and Diabetic Peripheral Neuropathy in Type 2 Diabetes: Significance of Iron Intake and the Ratio between Iron Intake and Polyunsaturated Fatty Acids Intake

Kim

Song

et al. 2020

Nutrients

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“…NCV and IENFD are known to decrease in patients with diabetes (Sveen et al, 2013). Similarly, several animal and human studies have correlated inflammation with neuropathy phenotype in diabetes (Duksal, Tiftikcioglu, Bilgin, Kose, & Zorlu, 2016; Paeschke et al, 2019; Zeng, Xu, Shi, & Jiang, 2018). Inflammatory cytokines, especially TNF‐α, modulate various signaling pathways including protein kinase C (Matsubara, Fuchimoto, & Orita, 1991), aldose reductase (Iwata et al, 1999) and 5′ adenosine monophosphate‐activated protein kinase (Tse et al, 2017), and all of which are known to play a vital role in the pathogenesis of diabetic neuropathy (Yamakawa et al, 2011).…”

Section: Discussionmentioning

confidence: 94%

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin‐2 and pyruvate dehydrogenase kinase‐2 axis in the dorsal root ganglion

Bhusal

Rahman

Lee

et al. 2020

Glia

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Diabetic peripheral neuropathy (DPN) is a common complication of uncontrolled diabetes. The pathogenesis of DPN is associated with chronic inflammation in dorsal root ganglion (DRG), eventually causing structural and functional changes. Studies on DPN have primarily focused on neuronal component, and there is limited knowledge about the role of satellite glial cells (SGCs), although they completely enclose neuronal soma in DRG. Lipocalin‐2 (LCN2) is a pro‐inflammatory acute‐phase protein found in high levels in diverse neuroinflammatory and metabolic disorders. In diabetic DRG, the expression of LCN2 was increased exclusively in the SGCs. This upregulation of LCN2 in SGCs correlated with increased inflammatory responses in DRG and sciatic nerve. Furthermore, diabetes‐induced inflammation and morphological changes in DRG, as well as sciatic nerve, were attenuated in Lcn2 knockout (KO) mice. Lcn2 gene ablation also ameliorated neuropathy phenotype as determined by nerve conduction velocity and intraepidermal nerve fiber density. Mechanistically, studies using specific gene KO mice, adenovirus‐mediated gene overexpression strategy, and primary cultures of DRG SGCs and neurons have demonstrated that LCN2 enhances the expression of mitochondrial gate‐keeping regulator pyruvate dehydrogenase kinase‐2 (PDK2) through PPARβ/δ, thereby inhibiting pyruvate dehydrogenase activity and increasing production of glycolytic end product lactic acid in DRG SGCs and neurons of diabetic mice. Collectively, our findings reveal a crucial role of glial LCN2‐PPARβ/δ‐PDK2‐lactic acid axis in progression of DPN. Our results establish a link between pro‐inflammatory LCN2 and glycolytic PDK2 in DRG SGCs and neurons and propose a novel glia‐based mechanism and drug target for therapy of DPN. Main Points Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase‐2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG). Glial LCN2‐PDK2‐lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.

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“…These adhesion mediators stimulate the migration of retinal capillary endothelium and angiogenesis in the progression of diabetic retinopathy. In addition, evidence of the role of inflammatory signals in the development of diabetic neuropathy has been shown in experimental models of diabetes [4,5] and in clinical studies [6,7]. Diabetic patients with painful peripheral neuropathy have higher levels of inflammatory markers than subjects without pain, and the elevation of interleukin (IL)-1, IL-6, and tumor necrosis factor α (TNF-α) are correlated with the progression of degenerative changes in the peripheral nerves.…”

Section: Inflammatory Mediators In Diabetic Kidney Disease (Dkd)mentioning

confidence: 99%

Unraveling the Role of Inflammation in the Pathogenesis of Diabetic Kidney Disease

Matoba

Takeda²,

Nagai³

et al. 2019

IJMS

149

118

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Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress has been made to inhibit the acceleration of DKD, current standards of care reduce but do not eliminate the risk of DKD. There is growing appreciation for the role of inflammation in modulating the process of DKD. The focus of this review is on providing an overview of the current status of knowledge regarding the pathologic roles of inflammation in the development of DKD. Finally, we summarize recent therapeutic advances to prevent DKD, with a focus on the anti-inflammatory effects of newly developed agents.

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The Role of Iron and Nerve Inflammation in Diabetes Mellitus Type 2-Induced Peripheral Neuropathy

Cited by 23 publications

References 41 publications

Association between Iron Intake and Diabetic Peripheral Neuropathy in Type 2 Diabetes: Significance of Iron Intake and the Ratio between Iron Intake and Polyunsaturated Fatty Acids Intake

Association between Iron Intake and Diabetic Peripheral Neuropathy in Type 2 Diabetes: Significance of Iron Intake and the Ratio between Iron Intake and Polyunsaturated Fatty Acids Intake

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin‐2 and pyruvate dehydrogenase kinase‐2 axis in the dorsal root ganglion

Unraveling the Role of Inflammation in the Pathogenesis of Diabetic Kidney Disease

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