Type 2 diabetes (T2D) is a metabolic disease characterized by insulin resistance and insulin deficiency that affects hundreds of millions of people worldwide. Subjects with long term T2D develop pathologies related to diabetes such as cardiovascular, renal, neuropathic and inflammatory diseases [1,2]. T2D also affects brain function and several studies have demonstrated the association between T2D and the risk to develop neurodegenerative pathologies, cognitive decline and dementia [3-6].

One widely recognized early symptom of neurodegeneration is the olfactory dysfunction (OD) [7,8], this condition is also reported in patients with T2D that show decreased odor threshold, discrimination and identification [9,10]. The molecular basis of olfactory impairment in neurodegeneration of olfactory structures has been associated with the presence of neurofibrillary tangles, amyloid plaques, Lewy bodies and Lewy neurites in the olfactory bulb (OB), olfactory epithelium, anterior olfactory nucleus and entorhinal cortex [7,11]. Brain dysfunction and cognitive decline in T2D has been related with β amyloid deposition, inflammation, hyperglycemia, altered insulin signaling and oxidative stress [12,13]. However, the mechanisms through which olfactory structures are altered by T2D to produce olfactory dysfunction have remained largely understudied.

In a recent study we investigated the participation of microRNAs in the OD induced in a rat model of T2D [14]. microRNAs (miRs) are small RNAs that negatively regulate gene expression preventing mRNA translation. These molecules are involved in biological processes such as proliferation, metabolism, apoptosis, and differentiation; furthermore, they are also involved in pathological processes [15,16]. After a single neonatal administration of streptozotocin (STZ) to induce T2D in rats, we evaluated the olfactory function in the adult animals and the OB expression of miRs 146a, 206, 451 and 34a. We observed that after 14 weeks of STZ administration, when T2D rats presented significantly higher fast and fed blood glucose levels than controls, the olfactory function of T2D rats was compromised showing lower odor detection, and olfactory memory impairment at week 18 [14]. These results were in agreement with previous observations made in other rat models of T2D [17,18]. Insulin signaling impairment is the principal hallmark in T2D, interestingly, OB expresses high insulin concentration and insulin receptor density, moreover, development of insulin resistance in OB has been found in Zucker and Wistar Kyoto obese rats, evidenced by the decreased binding of insulin to the insulin receptor and the impaired tyrosine phosphorylation of this receptor [19].

Remarkably, our results also demonstrated that OD in T2D correlated with miR-146a overexpression, which is considered a regulator of inflammatory responses [14,20]. In diabetes progression, inflammatory processes can affect the microRNAs expression and consequently modify the expression of inflammatory factors [21]. In line with this evidence, OB of T2D rats also expressed significantly higher levels of IL-1β when compared to controls [14]. The reciprocal regulation between miR-146a and IL-1β has been described in several works. The stimulation of monocytes with IL-1β showed a gradual increase of miR-146a associated with TRAF6 and IRAK1 downregulation. Likewise, miR-146a is induced in the innate immunity by NF-κB activation through the TLR/IL-1R signaling [22]. Moreover, miR-146a was identified as a mediator of the inflammatory response in tubular cells exposed to IL-1β during renal injury, and its expression was abolished by the inhibition of NF-κB, indicating that this signaling is important for miR-146a induction during inflammation [23]. In agreement with these observations, the upregulation of miR-146a by IL-1β was also observed in chondrocytes and in a spinal cord injury model, being associated with the downregulation of Smad4, IL-1β, NF-κB, IL-6, TNFα, iNOS and PGE2 [24,25]; altogether, this evidence suggests that the interplay between miR-146a and IL-1β is a conserved mechanism that modulates inflammatory responses.

Other studies have observed the miR-146a downregulation in leptin receptor knockout mice and fat diet-induced T2D rodent model [13,26]. Additionally, miR-146a has been associated with diabetic complications and showed inverse correlation with glycated hemoglobin, insulin resistance and the expression of pro-inflammatory mediators such as NF-κB [1]. Inflammation plays a key role in the pathogenesis of diseases associated with diabetes. In this regard, the expression of miR-146a was upregulated in peritoneal and intrarenal macrophages of diabetic mice and the knockout of miR-146a increased the expression of inflammatory cytokines including IL-1β and IL-18, polarizing the macrophages to a pro-inflammatory profile (M1) [27]. In conclusion, this information suggests that miR-146a expression could exert a protective effect against inflammation in response to the increase of IL-1β, and this effect can also be present in the OB of T2D. Therefore, further investigation should be performed to elucidate the contribution of miR-146a and IL-1β in the OB inflammation and OD of diabetic subjects.

None of the authors declare any conflict of interest.

This work was supported by grants from the Fondo Sectorial de Investigación en Salud y Seguridad Social Convocatoria 2015-01 by the Consejo Nacional de Ciencia y Tecnología, CONACyT (261481), and a postdoctoral fellowship (Adriana Jiménez) from Programa de Becas Posdoctorales de la Dirección General de Asuntos del Personal Académico (DGAPA), División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM).