PROFESSOR SHAHRAD TAHERI (Orcid ID : 0000-0001-8314-1500)

Accepted Article
Article type : Review

Title: Diabetic Medicine

Created by: Maria Davie
Email proofs to: staheri@me.com
Article no.: DME-2017-00399
Article type: Review Article
Short title/Authors running head: Association between diabetes and olfactory dysfunction • H. Zaghloul et al.

Review Article

Association between diabetes mellitus and olfactory

dysfunction: current perspectives and future directions

H. Zaghloul1–3, M. Pallayova1–3, O. Al-Nuaimi4,5, K. R. Hovis4,5 and S. Taheri1–3

1
Clinical Research Core and 2Department of Medicine, Weill Cornell Medicine, Doha, Qatar,
3
Weill Cornell Medicine, New York, NY, USA, 4Carnegie Mellon University, Doha, Qatar

and 5Carnegie Mellon University, Pittsburgh, PA, USA

Accepted

Correspondence: Shahrad Taheri. E-mail: staheri@me.com

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/dme.13542
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 What's new?
Accepted Article
• Despite the important role of olfaction in safety, nutrition, social interaction and

quality of life, it is often overlooked, and olfactory dysfunction is underdiagnosed.

• This review summarizes current evidence for the link between diabetes and its

complications and olfactory dysfunction.

• The review also examines some of the putative pathological mechanisms that could be

responsible for olfactory dysfunction in diabetes.

Abstract

The increasing global prevalence of diabetes mellitus presents a significant challenge to

healthcare systems today. Although diabetic retinopathy, nephropathy and neuropathy are

well-established complications of diabetes, there is a paucity of research examining the

impact of dysglycaemia on the olfactory system. Olfaction is an important sense, playing a

role in the safety, nutrition and quality of life of an individual, but its importance is often

overlooked when compared with the other senses. As a result, olfactory dysfunction is often

underdiagnosed. The present review article aims to present and discuss the available evidence

on the relationship between diabetes and olfaction. It also explores the associations between

olfactory dysfunction and diabetes complications that could explain the underlying

pathogenesis. Finally, it summarizes the putative pathological mechanisms underlying

olfactory dysfunction in diabetes that require further investigation.

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 Introduction
Accepted Article
Diabetes mellitus, which affects more than 400 million people worldwide, presents a major

global public health challenge [1]. Diabetes can lead to devastating micro- and macrovascular

complications, which are associated with significant morbidity, decreased quality of life,

early mortality and increased health costs. The onset and progression of diabetes

complications are strongly linked to dysglycaemia [2], with downstream oxidative stress-

induced damage to the retina, renal glomeruli and peripheral nerves [4]. While the impact of

diabetes on vision is well established, little is known about the impact of diabetes on other

special senses such as olfaction. The sense of smell is often overlooked and is not assessed in

daily clinical practice.

Olfaction, the sense of smell, is one of the most primitive of the special senses. It provides

critical information about the environment and plays an important role in safety and survival,

nutrition, social interactions, sexual function and maintenance of quality of life [6–8]. Loss of

smell and taste sensations may result in depression [9]. The sense of smell is a unique

sensory–perceptual modality. Unlike other senses, it bypasses the thalamic relay, and can

thus be used as a tool to assess directly the functional integrity of the orbitofrontal cortex

responsible for the integration and interpretation of sensory stimuli. Importantly, changes in

odour reception and olfactory discrimination may be a marker for certain conditions and

diseases.

Olfactory testing has been used as a preclinical indicator to predict the development and onset

of diseases such as Parkinson’s disease [10], multi-infarct dementia [11], multiple sclerosis

[12] and Alzheimer’s disease [11]. Previous studies have further reported a relationship

between olfactory dysfunction and diabetes [13–18], as well as an inverse relationship

between olfactory identification and discrimination scores and the presence of diabetic

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 complications [13,14,16,19,20]. Some authors have suggested that screening for olfactory
Accepted Article dysfunction could serve as an early detector for the presence of diabetic microvascular

complications, such as diabetic neuropathy [16,19]. The problems associated with olfactory

dysfunction may extend beyond the reduced quality of life in diabetes. Because olfaction is

believed to alter feeding states [21], the changes in dietary habits and/or desire for certain

foods that accompany altered olfaction could affect metabolic control, with long-term

consequences.

The present review highlights and discusses the potential links between diabetes and

olfaction. It will outlines the putative mechanisms underlying olfactory dysfunction in

diabetes that could direct future efforts towards improvements in health and quality of life in

people with diabetes.

Search strategy

For this narrative review, we searched PubMed, Medline and Embase, from inception until

February 2017, for relevant studies. The literature search included the following terms (with

synonyms and closely related words): diabetes mellitus; smell; olfactory; and olfaction.

Searches were not restricted by study design or language of publications. Further studies were

identified by examining the reference lists of all included articles and using the expertise of

the review team.

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 Clinical physiology of olfaction
Accepted Article
Olfactory sensory neurons are first-order bipolar sensory neurons which extend their

dendrites into the olfactory mucosa, located in the superior part of the nasal cavity. Olfactory

receptors (extero-receptors) on the dendrites of bipolar neurons respond to the presence of

volatile external chemical cues. Each neuron expresses the genes for receptors engaged by a

single odorant. Besides olfactory receptors, the olfactory epithelium also contains supporting

(sustentacular) cells and basal stem cells, which confer the unique ability for these neurons to

regenerate every 2–4 weeks [22].

Olfactory neurons convey information along the olfactory nerve, which passes through the

cribriform plate before terminating in spherical collections of neuropil call glomeruli in the

olfactory bulb, at the base of the brain’s frontal cortex (Fig. 1). Here, olfactory sensory

neurons synapse with olfactory bulb mitral cells, which are the primary output neurons of the

olfactory system. Information from mitral cells then travels via the lateral olfactory tract to

several downstream brain areas, including the piriform cortex, the amygdala, anterior

olfactory nucleus, olfactory tubercle and entorhinal cortex [23]. From there, information is

sent via the thalamic medio-dorsal nucleus onto the orbitofrontal cortex where higher-order

neurons integrate olfactory information along with relevant taste, and visual and cognitive

inputs [24]. Some evidence suggests that the activity of these higher-order neurons

represents the reward value of food, contributing to satiety and, in turn, meal termination. In

this way, the olfactory system may directly regulate feeding behaviour [24–26].

Primates also have a pathway that sends olfactory information from the thalamus to the

hypothalamus, which controls food intake and metabolism, as well as other key homeostatic

mechanisms. The lateral hypothalamus is commonly known as the feeding centre, with

lesions of this area resulting in satiety in animals and humans, while the ventromedial

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 hypothalamus is the satiety centre, with lesions resulting in obesity and diabetes. Thus, the
Accepted Article olfactory system may regulate the activity of key neurons in the hypothalamus that regulate

food intake and body weight [27].

The ability to identify smells decreases with age (presbyosmia), with >75% of individuals

aged > 80 years having abnormalities in smell sensation [23]. Olfactory discrimination may

also vary with gender and pregnancy (e.g. pregnant women commonly become oversensitive

to smells), and feeding states (sensitivity is greater with increasing hunger) [21]. A number of

conditions can lead to quantitative and qualitative changes in chemosensory ability (Table 1).

According to epidemiological studies, the prevalence of olfactory loss ranges from 19% to

24% [28–30], yet many people are unaware of olfactory loss and remain undiagnosed [30].

Clinical evaluation of olfactory dysfunction

Because olfactory dysfunction is often undetected, its prevalence according to self-reported

measures results in underestimation compared with its prevalence reported using objective

measures. The clinical assessment of olfactory dysfunction begins with a thorough history-

taking and physical examination to determine the nature and onset of the chemosensory

problem and associated disease conditions (e.g. previous surgery, current medications,

smoking history and medical conditions leading to olfactory dysfunction). The physical

examination includes a full otolaryngological examination with anterior rhinoscopy and nasal

endoscopy, cranial nerve and optic disc examination (for elevated intracranial pressure). This

is usually followed by olfactory function testing, which may include psychophysical,

electrophysiological and neuropsychological testing to determine the type and degree of

olfactory dysfunction.

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 Of the many tools available for psychophysical olfactory testing, the development of
Accepted Article validated tools such as 'Sniffin' Sticks' [31], together with calculation of the Threshold

Discrimination Identification (TDI) score, and the University of Pennsylvania Smell

Identification test [32], used for testing olfactory performance, have enabled more accurate

assessments of olfaction. The University of Pennsylvania smell identification test consists of

four booklets with 10 odorants in each, requiring responses out of four choices. The

participant’s score is compared according to his/her age group and gender [33]. Sniffin'

Sticks is a test that uses pen-like odour-dispensing devices and assesses three aspects of

olfactory function: odour threshold; odour discrimination; and odour identification. An

individual’s TDI score is the sum of all three subtests [34]. TDI scores >30.5 represent

functional normosmia, while scores between 30.5 and 16.5 define functional hyposmia and

scores <16.5 define functional anosmia. Electrophysiological tests such as the electro-

olfactogram and odour event-related potentials are available, but their use in daily clinical

practice is limited [35]. Given the strong associations of Alzheimer’s disease and Parkinson’s

disease with olfactory dysfunction, brief neuropsychological testing is necessary in some

cases to identify any cognitive dysfunction. Although not routinely indicated, neuroimaging

studies (e.g. high-resolution computed tomography and functional magnetic resonance

imaging) may be used in the diagnostic evaluation of neurodegenerative disorders, tumours

and head trauma, especially in cases of idiopathic olfactory dysfunction. The measurement of

the elevated olfactory epithelial mucosal microRNA-206 levels (obtained from the intranasal

olfactory biopsy) has been suggested as a biomarker for the diagnosis of early Alzheimer’s

disease, including mild cognitive impairment [36].

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 Diabetes mellitus and olfactory dysfunction
Accepted Article
To date, there are no large prospective studies examining the relationship between diabetes

and the development and progression of olfactory dysfunction. Limited cross-sectional

studies have explored associations between diabetes and olfaction [13–20,37] with

inconsistent findings (Table 2 [11–18,35,38–40]). The variability in outcomes may be

attributed to several methodological inconsistencies, such as selection bias, small sample

sizes, comorbidities, lack of objective measures, and differences in diagnostic tests for

olfactory dysfunction, and diabetes and its complications.

Weinstock et al. [13] performed detailed olfactory testing in 111 adults with Type 1 and Type

2 diabetes using the Odorant Confusion Matrix, a test used to quantify olfactory function by

the number of correct odorants identified [38]. Overall, a decreased ability to identify

odorants (67.8% of correct identifications) was found in study participants that was strongly

predicted by an increasing age and presence of macrovascular disease (coronary artery

disease and peripheral vascular disease) [13]. No associations were found with glycaemic

control, type/duration of diabetes, and diabetes microvascular complications (neuropathy,

retinopathy, nephropathy) [13]. These findings suggest that the olfactory dysfunction in

diabetes could be attributable to ischaemic damage to the olfactory system.

In a cross-sectional study of 68 people with diabetes and 30 controls, Le Floch et al. [14]

used the Smell Recognition Score (SRS) to examine olfactory function. The score was

determined by using a set of 24 common flavours, and asking the participants to identify

them from a list. The score was lower in participants with diabetes compared with controls

(12.4±0.5 vs 15.1±0.5; P˂0.001). In contrast to the study by Weinstock et al., in this study,

olfactory dysfunction was associated with the presence of diabetes microvascular

complications. The SRS was found to be associated with both microalbuminuria (12.1± 0.8

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 vs 14.4 ± 0.9, P<0.05) and peripheral neuropathy (10.3 ± 1.0 vs 14.1 ±0.9, P< 0.01);
Accepted Article however, no significant association was found between SRS and presence of retinopathy [14].

In a large cross-sectional, population-based epidemiological study in Swedish adults

(n=1900) [15], no relationship was found between impaired olfaction and self-reported

diabetes in 1387 participants; however, the risk of anosmia increased with the presence of

diabetes [odds ratio 2.6, (95% CI 1.3–5.5)] [15] and nasal polyps [odds ratio 3.8 (95% CI,

1.6–8.8)] [15].

A study in 154 adults conducted by Gouveri et al. [16] found that people with Type 2

diabetes had a lower odour threshold (6.51±2.52 vs 8.70±2.96; P<0.001), lower odour

discrimination (10.56±2.47 vs 11.82±2.11; P=0.008), lower odour identification (12.28±2.00

vs 14.67±1.17; P<0.001), and lower TDI scores (29.29±5.24 vs 34.86±3.72; P<0.001)

compared with those without diabetes. Interestingly, the type of treatment (insulin vs oral

hypoglycaemic agents), BMI, diabetes duration and HbA1c value were not associated with

olfactory dysfunction in people with diabetes [16]. After adjusting for multiple factors,

diabetes and hypertension were the only independent predictors of the lower TDI scores in

the entire cohort (R2=0.281; for type 2 diabetes: β=−3.73, SE =1.074, P=0.001; for

hypertension: β=−3.774, SE = 1.159, P=0.002) [16]. This finding is not consistent with other

studies, which reported no such association [13,39].

A study in 30 people with diabetes and 30 control participants used 'absorbent perfumer’s

paper strips', a test using phenyl ethyl alcohol as an odorant and propylene glycol as a

solvent. The phenyl ethyl alcohol is diluted and the absorbent paper strips inserted into each

of the eight serial dilutions, after which the participant is asked to smell each of the dilutions

three to four times) [37]. The study reported a significant difference in both the median and

mode values for the olfactory threshold between the two groups; however, the effect size was

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 not reported. While 60% of participants with diabetes had some degree of olfactory
Accepted Article dysfunction, no associations were found between olfactory disturbances and treatment

duration or with any of the microvascular diabetes complications [37].

A recent study examining 39 participants with non-complicated Type 1 diabetes and 31

healthy control participants used the Sniffin’ Sticks test to perform psychophysical olfactory

testing. No significant difference was found between the groups in any of the olfactory tests

[odour thresholds (P=0.66); odour discrimination (P=0.24); odour identification (P=0.69);

TDI score (P=0.37)] [40]. Another similar study, also using Sniffin’ Sticks to assess olfactory

function in participants with and without Type 1 diabetes, also found no significant difference

in olfaction between the groups; however, multivariate linear regression subsequently showed

that olfactory impairment was independently associated with neuropathy (β=–0.3, P=0.005).

Also, multivariate logistic regression showed that duration of diabetes, and olfactory

identification scores were independently associated with neuropathy [41].

The majority of the studies mentioned above had small sample sizes and were conducted

using varying methodology. Also, all of the studies were cross-sectional, and causal inference

cannot be made.

Olfactory dysfunction and diabetes complications

To further explore the associations between olfactory dysfunction and diabetes, several cross-

sectional studies have investigated the links between olfaction and micro- and macrovascular

diabetes complications. Most studies have shown that participants with diabetes

complications exhibited more olfactory dysfunction than those without complications

[14,16,19,42].

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 Le Floch et al. [14] reported associations of olfactory dysfunction with both
Accepted Article microalbuminuria (P<0.05) and peripheral neuropathy (P<0.01). In a study by Gouveri et al.

[16], participants with diabetes complications had lower odour threshold (6.11±2.31 vs

7.29±2.72; P=0.026), odour identification (11.95±1.98 vs 13.29±1.86; P=0.002) and TDI

scores (28.55±4.85 vs 31.62±5.59; P=0.006) than those without complications; the number of

diabetic complications was inversely associated with TDI score (P=0.007). While people

with diabetic retinopathy had lower TDI and odour identification scores, those with diabetic

neuropathy had lower TDI and odour identification scores and lower odour thresholds [16].

No associations of olfactory scores with diabetic nephropathy, cardiovascular disease or

peripheral vascular disease were found [16].

In an attempt to examine associations between diabetic kidney disease and olfaction, Gascon

et al. [42] evaluated the sense of smell in 61 participants with diabetes using the Barcelona

Smell Test-24, which consists of 24 chemical odours isolated in individual containers.

Although there was no association between HbA1c and olfactory sensation, the study reported

an inverse relationship between the percentage of correct responses and albuminuria. The

difference in mean values between those with normo-albuminuria and those with

microalbuminuria was 14.79 odours (95% CI 1.51–28.07; P=0.03). There were positive

correlations of GFR with both the identification of odours through the olfactory nerve

(P=0.029) and the percentage of correct responses (P=0.03) [42].

Although Duda-Sobczak et al. [41] found no significant difference between olfactory scores

in participants with Type 1 diabetes and control participants, further analysis of data

comparing odour identification scores between groups with and without diagnosed

microvascular complications showed lower scores in participants with neuropathy and

retinopathy. Participants with neuropathy had lower scores than those without [mean

(interquartile range) 8 (7–9) points vs 10 (9–11) points; P=0.005], as did participants with

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 retinopathy compared with those without retinopathy [mean (interquartile range) 9 (8–11)
Accepted Article points vs 10 (9–11) points; P=0.03]. Stepwise multivariate linear regression analysis showed

that neuropathy was an independent predictor of olfactory function. Furthermore, univariate

logistic regression showed that olfactory identification score was a predictor of neuropathy. A

multivariate logistic regression analysis identified olfactory identification score as an

independent predictor of retinopathy [41].

On the basis of previous findings that pain was associated with elevated olfactory thresholds

in the absence of diabetes [43], Brady et al. [19] sought to assess the potential impact of

neurological pain caused by diabetic peripheral neuropathy on olfactory function. The study

showed that those with neuropathic pain experienced loss of general olfaction, and had

reduced odour detection thresholds, reduced discrimination between odour qualities, reduced

odour identification, and increased thresholds for odour intensity [19], in line with some

previous findings [13,14]. In addition to the possibility of neurological pain per se affecting

olfactory function, other factors in the presence of chronic pain (e.g. central neuroplasticity,

altered attention and concentration in response to injury) may contribute to the olfactory

dysfunction and account for the olfactory performance findings [44,45].

Although no associations were found between the impaired sense of smell and diabetes

microvascular complications in a study by Weinstock et al. [13], the decreased ability to

identify odorants was correlated with presence of diabetes-associated macrovascular disease.

In contrast to the above positive studies, Naka et al. [20] did not find any difference in

olfactory dysfunction (based on a five-item odour identification screening test) among 29

participants with uncomplicated diabetes, 24 participants with diabetic micro- and/or

macrovascular complications, and 29 controls. However, diminished olfactory function was

observed in those with other complicating illnesses (e.g. renal or hepatic failure), suggesting

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 that the olfactory dysfunction could be attributable to the complicating illnesses rather than to
Accepted Article diabetes and/or its complications [20]. The study also revealed lower olfactory sensitivity

when those with Type 2 diabetes were compared with those with Type 1 diabetes (olfactory

test scores 3.4±1.2 vs 4.0±0.9, t=2.16; P=0.034) [20]. In another non-positive study,

Mehdizadeh et al. [37] did not find any associations between olfactory disturbances and any

of the chronic diabetes complications. A study in 60 participants, 30 with diabetes and 30

controls, found no associations with age, treatment duration and olfactory threshold.

Finally, olfactory dysfunction has been shown to precede the clinical signs of Alzheimer’s

disease [46]. Importantly, diabetes-related cognitive impairment has been reported among

people with Type 2 diabetes with central manifestations of diabetic neuropathy [47]. Sanke et

al. [48] aimed to determine whether there was an association between olfactory dysfunction

and cognitive impairment in elderly people with diabetes. The study in 250 elderly Japanese

people with Type 2 diabetes and no evident impairment in cognition evaluated their olfaction

and cognitive function using the Open Essence test and Mini Mental State Examination,

respectively [48]. Multivariate regression analysis showed that the Open Essence test scores

independently correlated with Mini Mental State Examination score (β=0.542, R2= 0.478;

P<0.01) in addition to education level, HbA1c and serum adiponectin levels [48].

Putative mechanisms for olfactory dysfunction in diabetes

The underlying mechanisms for the potential development and progression of olfactory

dysfunction in diabetes are currently unknown. Several hypotheses have been proposed,

including microvascular [14,19,42] and macrovascular [13] changes, and central diabetic

neuropathy [49], owing to direct damage to the olfactory nerve [16] and/or resulting from

other abnormalities of the afferent conduction of stimulus-induced neural impulses, including

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 impairment of ascending subcortical pathways [49] that may occur as a result of diabetes
Accepted Article (Fig. 1). Moreover, the olfactory system has been linked to endocrine systems which regulate

or modify the body’s energy balance [21], suggesting various metabolic and endocrine

pathways related to food intake, energy balance, insulin resistance, low-grade chronic

inflammation, and the hypothalamus–pituitary–adrenal axis modifications, which may play a

role in the modulation of olfactory pathways (Fig.1).

In addition to the hypothesis that olfactory dysfunction could be accelerated by glucose

toxicity and oxidative stress underlying micro- and macrovascular complications, Gouveri et

al. [16] proposed a mechanism via olfactory nerve impairment, a central manifestation of

diabetic neuropathy. Dysfunction of the central nervous system with vascular lesions and

brain atrophy has been described among people with diabetes and may play a role in Type 2

diabetes-related cognitive impairment [47]. While isolated cranial neuropathy

(mononeuropathy) is a well-established manifestation of diabetic neuropathy [50], the

presence of multiple cranial nerve palsies in diabetes may represent midbrain ischaemia (e.g.

brainstem infarction) [51].

The olfactory bulb and olfactory mucosa are also targets for metabolic factors, suggesting the

metabolic modulation may begin at the sensory level [52]. The actions of various molecules,

such as ghrelin, orexins (hypocretins) [53,54], neuropeptide Y, insulin, leptin [55,56], and

cholecystokinin, that are involved in the regulation of food intake and olfactory function [21],

are altered in diabetes, obesity and other metabolic disorders. As a result, olfactory function

is modulated in response to changing levels of these molecules.

The ghrelin receptor (growth hormone secretagogue receptor 1a) is expressed on olfactory

neurons, and exogenous intranasal ghrelin results in sensitization of olfactory neurons;

however, ghrelin itself is not found in the olfactory epithelium. The adipocytokine

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 adiponectin appears to have a similar effect on olfactory neurons as ghrelin [57]. This
Accepted Article observation is of particular interest, given the findings of Sanke et al. [48] in elderly people

with diabetes.

The lateral hypothalamus is a key brain area for glucose sensing [58], glucose regulation and

olfaction. Orexin (hypocretin) neurons in the lateral hypothalamus project to the olfactory

bulb. A key abnormality in the sleep disorder narcolepsy is the loss of orexin neurons [59].

Interestingly, olfactory dysfunction has been reported in individuals with narcolepsy [60,61].

In a study of 130 individuals with narcolepsy, using Sniffin' Sticks, a quarter had

mild/moderate olfactory impairment [62]. Olfactory dysfunction in narcolepsy has been

reported to be reversed by intranasal orexin A (hypocretin 1) [63]. Animal studies have

observed that orexin neurons are glucose-sensing, being inhibited by glucose [64]; thus,

hyperglycaemia in people with diabetes may affect olfactory function through actions on

orexin neurons in the lateral hypothalamus. Melanin concentrating hormone neurons, whose

cell bodies are also located in the lateral hypothalamus, are glucose-excited and have been

observed to have a potential role in olfactory function. Melanin concentrating hormone

knockout mice demonstrate deficits in olfactory-related behaviours including food finding,

and mating and maternal behaviours [65].

Previous animal studies in both diet- and genetic-induced obesity models in rodents have

shown that insulin resistance also develops in the olfactory bulb [66]. Figlewicz et al. [67]

demonstrated decreased insulin binding in the olfactory bulb of obese fa/fa Zucker rats and

in fa/fa Wistar Kyoto rats [66] compared with lean controls. Additionally, obese insulin-

resistant Zucker Fa/Fa rats were found to have an abnormally reduced content of

phosphotyrosine containing-proteins detected in the hippocampus, piriform cortex and

olfactory bulb. After demonstrating that immunoreactive insulin concentrations were higher

in the hypothalamus and olfactory bulb than in other brain regions [68], Baskin et al. [69]

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 further showed that the genetically obese Fa/Fa rats had markedly reduced concentrations of
Accepted Article immunoreactive insulin, indicating defective insulin metabolism. This evidence collectively

supports the hypothesis that humans could develop insulin resistance of the olfactory bulb in

a manner similar to rodents. In turn, this could play a role in the disruption of olfactory

function.

Moreover, voltage-gated potassium channels Kv1.3 are expressed in many insulin-sensitive

tissues [70], where they play a role in the regulation of glucose uptake and insulin sensitivity

[71]. A genotype–phenotype association study [72] showed that a variant in the promoter of

the Kv1.3 gene in humans was associated with impaired glucose tolerance and lower insulin

sensitivity. In rodent studies, Fadool et al. [21,73] identified a Kv1.3 channel in the olfactory

bulb to which the potassium current was suppressed by insulin through multiple

phosphorylation of the Shaker ion channel. Kv1.3 knockout through gene deletion in mice led

to increased insulin sensitivity and improved glucose metabolism [71] coupled with a 'super

smeller' phenotype (lower olfactory detection threshold and higher olfactory discrimination

scores) [74]. Consistent with this finding was a significant olfactory impairment in male

homozygous carriers of a polymorphism of the human Kv1.3 (resulting in an additional

Kv1.3 channel), leading to impairment of olfactory function [75]. Acute application of insulin

to mitral cells obtained from lean mice led to increased excitability of in a Kv1.3-dependant

manner through tyrosine phosphorylation [21,76]; however, in mice that were made

prediabetic via diet-induced obesity, intranasal insulin delivery was observed to prevent

autophosphorylation of Kv1.3 [77] and to modify the baseline firing of the mitral cells as well

as prevent Kv1.3 modulation of olfactory function [78]. In mice in which intranasal insulin

was chronically administered, there was either an elevation in basal firing frequency or the

firing of a single cluster of action potentials. After prolonged chronic administration of the

hormone, however, mitral cells were actually inhibited by application of insulin acutely,

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 rather than excited [78]. These findings, together with the abundant expression of Kv1.3
Accepted Article channels in the olfactory bulb [73], suggest that this channel may play an important role in

olfactory function in people with diabetes.

Controversies in research

As mentioned previously, the variability in outcomes and inconsistency of findings can be

attributed to several methodological issues. The assessment of diabetic status was not always

consistent, with many of the studies relying on self-reported measures of diabetic status.

Many of the conducted studies did not stratify participants according to the type of diabetes,

thereby not recognizing key underlying pathophysiological differences between people with

Type 1 and Type 2 diabetes. The analysis of data based on type of diabetes could support or

refute the theory that hormonal modulation may play a role in the development of olfactory

dysfunction in diabetes. Methodological differences in evaluating olfactory function could

also contribute to the discrepancies in findings. Certain comorbidities, medications, and

ageing—all known to contribute to chemosensory dysfunction in diabetes—remain

biologically important conditions even after they are statistically adjusted for. Finally, studies

have been cross-sectional, and causality cannot be determined.

Based on the results of the previous studies, controversies over olfactory dysfunction in

diabetes research fall into two categories: (1) relation to diabetes microvascular and

macrovascular complications and (2) the underlying mechanisms of olfactory dysfunction in

diabetes.

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 With respect to the link with diabetes microvascular complications, Le Floch et al. [14],
Accepted Article Weinstock et al. [13], and Jorgensen and Buch [17] all found no association between

olfactory dysfunction and diabetic retinopathy; however, Gouveri et al. [16] reported

significantly lower olfactory and TDI scores in people with Type 2 diabetes and retinopathy

compared with those without retinopathy. With regard to diabetic neuropathy, while Le Floch

et al. [14], Brady et al. [19] and Gouveri et al. [16] all found neuropathy to be associated with

olfactory dysfunction and lower olfactory scores, Weinstock et al. [13] found no such

association. Finally, Weinstock et al. [13] and Gouveri et al. [16] found no association

between diabetic kidney disease and olfactory dysfunction, but the results of Le Floch et al.

[14] and Gascon et al. [42] were contradictory.

Only two studies have investigated the association between olfactory dysfunction and

macrovascular diabetes complications. Weinstock et al. [13] reported a positive association

of coronary and peripheral artery disease with olfactory dysfunction, suggesting that

ischaemia and macrovascular disease might play a role in the underlying pathology. The

findings reported by Gouveri et al. [16] from a multivariate analysis were contradictory, and

cardiovascular disease was not found to be an independent predictor of olfactory dysfunction.

Although Gouveri et al. [16] further reported that hypertension was an independent risk

factor for the presence of olfactory dysfunction in diabetes, Weinstock et al. [13], as well as

Hawkins and Pearlson [39], found no association. However, no studies examined the effect of

antihypertensive medications on olfactory dysfunction in diabetes, some of which are known

to alter the sense of smell. Further studies on the effect of various medications used for

diabetes and/or its complications and comorbidities are therefore warranted.

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 Future directions
Accepted Article
Olfaction is an important sense that requires attention in diabetes, but this has largely been

overlooked, with only limited data available. The limited number of studies that have

explored the relationship between olfaction and diabetes have suggested a significantly

higher prevalence of olfactory dysfunction in people with vs those without diabetes. The

mechanisms underlying impairment of olfaction in diabetes remain incompletely understood.

The increased risk of olfactory dysfunction associated with ageing, smoking, diabetic

neuropathy, and with other factors/conditions, suggests a multi-factorial pathogenesis. The

presence of supporting evidence for the link between diabetes and olfaction warrants further

investigation into the aetiology, pathogenesis, and treatment of this condition. The findings

from future studies can also offer clinical implications of olfactory testing in diabetes, and

thus provide additional preventive and diagnostic approaches in the management of a

significant number of individuals with diabetes worldwide.

To date, there are no prospective cohort studies that would help determine risk factors for

olfactory dysfunction in diabetes or the impact of olfactory dysfunction on those with

diabetes. These studies are currently hampered by the difficulties of implementing measures

of olfactory function, which can be time-consuming. Although the hormonal modulation of

the olfactory pathway has been studied in animals, it is yet to be unequivocally demonstrated

in humans. While several studies did not find any association between glycaemic control and

olfactory dysfunction [13,14,20], to date, no studies have been conducted to assess the impact

of acute hyperglycaemia, rapid changes in glucose concentrations, and continuously

measured glucose variability on olfaction in humans. Based on previous findings from rodent

studies, we can hypothesize that glucose sensitivity of olfactory bulb neurons conveyed by

This article is protected by copyright. All rights reserved.

 voltage-gated potassium channels is modified in response to acute hyperglycaemia, which
Accepted Article can contribute to modification of olfaction during rapid glucose changes.

Current data indicate that different forms of diabetic neuropathy (with or without

neurological pain) are associated with impaired olfaction, possibly playing a role in the

aetiology of diabetes-related olfactory dysfunction. Future studies should investigate

olfactory performance in relation to different forms of diabetic neuropathy and account for

neurological pain (a potential confounding factor), quantified by psychometric testing.

Although not the focus of the present review, it is difficult to ignore taste when discussing

olfaction. Clinically, smell and taste disorders are often considered simultaneously. For this

reason, several studies have assessed both concurrently [17,20]. Jorgensen and Buch [17]

reported impaired olfactory function in participants with diabetes, but, unexpectedly, they

found no such association with gustatory function. As with olfactory function, Naka et al.

[20] reported no difference in gustatory function between participants with uncomplicated

diabetes and those without. Le Floch et al. [14] were among the first to recognise the need to

determine the effects of olfactory impairment on taste and food choices in people with

diabetes; they observed a close relationship between smell recognition and gustatory

threshold. Further studies are needed to determine the effects of both smell and taste

disorders on food preference, food intake, and metabolic control in diabetes.

Finally, it would be essential to determine how new findings can be translated from bench to

bedside to help improve the outcomes and quality of life in diabetes, especially with an

increasingly ageing diabetes patient population. As for the clinical implications, further

studies are needed to build on the current findings to determine if olfactory testing could be

used as a tool for early detection of the central diabetic neuropathy including diabetes-related

cognitive impairment [48], or even to be used as a marker of diabetes control in future.

This article is protected by copyright. All rights reserved.

 Funding sources
Accepted Article
H.Z., M.P. and S.T. are funded by the Biomedical Research Program at Weill Cornell

Medicine in Qatar, supported by Qatar Foundation. S.T. also receives funding from the

following grants from the Qatar National Research Fund: NPRP 4-1392-3-345 and NPRP 8-

912-3-192. The funder had no input into the preparation and content of this review.

Competing interests

None declared.

References

1. IDF. International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels,

Belgium. 2013.

2. Effect of intensive therapy on the development and progression of diabetic

nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and

Complications (DCCT) Research Group. Kidney Int 1995; 47:1703–1720.

3. Monnier L, Colette C, Owens DR. Glycemic variability: the third component of the

dysglycemia in diabetes. Is it important? How to measure it? J Diabetes Sci Technol 2008;

2:1094–1100.

4. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev 2013;

93:137–188.

5. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism.

Diabetes 2005; 54:1615–1625.

6. Croy I, Nordin S, Hummel T. Olfactory disorders and quality of life–an updated

review. Chem Senses 2014; 39:185–194.

This article is protected by copyright. All rights reserved.

 7. Smeets MA, Veldhuizen MG, Galle S, Gouweloos J, de Haan AM, Vernooij J et al.
Accepted Article Sense of smell disorder and health-related quality of life. Rehab Psychol 2009; 54:404–412.

8. Hummel T, Nordin S. Olfactory disorders and their consequences for quality of life.

Acta Otolaryngol 2005;125:116–121.

9. Miwa T, Furukawa M, Tsukatani T, Costanzo RM, DiNardo LJ, Reiter ER. Impact of

olfactory impairment on quality of life and disability. Arch Otolaryngol Head Neck Surg

2001;127:497–503.

10. Siderowf A, Jennings D, Eberly S, Oakes D, Hawkins KA, Ascherio A et al. Impaired

olfaction and other prodromal features in the Parkinson At-Risk Syndrome Study. Mov

Disord 2012; 27: 406–412.

11. Gray AJ, Staples V, Murren K, Dhariwal A, Bentham P. Olfactory identification is

impaired in clinic-based patients with vascular dementia and senile dementia of Alzheimer

type. Int J Geriatr Psychiatry 2001;16: 513–517.

12. Lutterotti A, Vedovello M, Reindl M, Ehling R, DiPauli F, Kuenz B et al. Olfactory

threshold is impaired in early, active multiple sclerosis. Mult Scler 2011; 17: 964–969.

13. Weinstock RS, Wright HN, Smith DU. Olfactory dysfunction in diabetes mellitus.

Physiol Behav 1993; 53: 17–21.

14. Le Floch JP, Le Lievre G, Labroue M, Paul M, Peynegre R, Perlemuter L. Smell

dysfunction and related factors in diabetic patients. Diabetes Care 1993;16: 934–937.

15. Bramerson A, Johansson L, Ek L, Nordin S, Bende M. Prevalence of olfactory

dysfunction: the skovde population-based study. Laryngoscope 2004; 114:733–737.

16. Gouveri E, Katotomichelakis M, Gouveris H, Danielides V, Maltezos E, Papanas N.

Olfactory dysfunction in type 2 diabetes mellitus: an additional manifestation of

microvascular disease? Angiology 2014; 65: 869–876.

This article is protected by copyright. All rights reserved.

 17. Jorgensen MB, Buch NH. Studies on the sense of smell and taste in diabetics. Acta
Accepted Article Otolaryngol 1961;53:539–545.

18. Patterson DS, Turner P, Smart JV. Smell threshold in diabetes mellitus. Nature 1966;

209: 625.

19. Brady S, Lalli P, Midha N, Chan A, Garven A, Chan C et al. Presence of neuropathic

pain may explain poor performances on olfactory testing in diabetes mellitus patients. Chem

Senses 2013; 38: 497–507.

20. Naka A, Riedl M, Luger A, Hummel T, Mueller CA. Clinical significance of smell

and taste disorders in patients with diabetes mellitus. Eur Arch Otorhinolaryngol 2010; 267:

547–550.

21. Palouzier-Paulignan B, Lacroix MC, Aime P, Baly C, Caillol M, Congar P et al.

Olfaction under metabolic influences. Chem Senses 2012; 37: 769–797.

22. Costanzo RM. Regeneration of olfactory receptor cells. Ciba Found Symp

1991;160:233–242; discussion 43-8.

23. Barrett KE. Ganong's Review of Medical Physiology, 25th edn. New York: McGraw-

Hill Education/Medical; 2015. 768 p.

24. Rolls ET. Taste, olfactory, and food texture processing in the brain, and the control of

food intake. Physiol Behav 2005; 85:45–56.

25. Kringelbach ML, O'Doherty J, Rolls ET, Andrews C. Activation of the human

orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness.

Cereb Cortex 2003;13:1064–1071.

26. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous

system control of food intake and body weight. Nature 2006; 443: 289–295.

27. Schwartz MW, Woods SC, Porte D, Jr, Seeley RJ, Baskin DG. Central nervous

system control of food intake. Nature 2000;404: 661–671.

This article is protected by copyright. All rights reserved.

 28. Vennemann MM, Hummel T, Berger K. The association between smoking and smell
Accepted Article and taste impairment in the general population. J Neurol 2008; 255:1121–1126.

29. Bramerson A, Nordin S, Bende M. Clinical experience with patients with olfactory

complaints, and their quality of life. Acta Otolaryngol 2007;127:167–174.

30. Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM.

Prevalence of olfactory impairment in older adults. JAMA 2002; 288: 2307–2312.

31. Wolfensberger M, Schnieper I, Welge-Lussen A. Sniffin'Sticks: a new olfactory test

battery. Acta Otolaryngol 2000;120:303–306.

32. Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell

Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope

1984;94(2 Pt 1):176–178.

33. Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell

Identification Test: a standardized microencapsulated test of olfactory function. Physiol

Behav 1984;32:489–502.

34. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. 'Sniffin' sticks': olfactory

performance assessed by the combined testing of odor identification, odor discrimination and

olfactory threshold. Chem Senses 1997; 22:39–52.

35. Lorig TS. The application of electroencephalographic techniques to the study of

human olfaction: a review and tutorial. Int J Psychophysiol 2000;36:91–104.

36. Moon J, Lee ST, Kong IG, Byun JI, Sunwoo JS, Shin JW et al. Early diagnosis of

Alzheimer's disease from elevated olfactory mucosal miR-206 level. Sci Rep 2016;6:20364.

37. Mehdizadeh Seraj J, Mehdizadeh Seraj S, Zakeri H, Bidar Z, Hashemi S, Mahdavi

Parsa F et al. Olfactory dysfunction in Iranian diabetic patients. Acta Med Iran

2015;53(4):204-6.

This article is protected by copyright. All rights reserved.

 38. Wright HN. Characterization of olfactory dysfunction. Arch Otolaryngol Head Neck
Accepted Article Surg 1987;113:163–168.

39. Hawkins KA, Pearlson GD. Age and gender but not common chronic illnesses predict

odor identification in older African Americans. Am J Geriatr Psychiatry 2011;19:777–782.

40. Altundag A, Ay SA, Hira S, Salihoglu M, Baskoy K, Deniz F et al. Olfactory and

gustatory functions in patients with non-complicated type 1 diabetes mellitus. Eur Arch

Otorhinolaryngol 2017; 274:2621–2627.

41. Duda-Sobczak A, Araszkiewicz A, Urbas M, Borucki L, Kulas K, Chudzinski M et

al. Impaired olfactory function is related to the presence of neuropathy in adults with type 1

diabetes. Diab Vasc Dis Res 2017;14:139–143.

42. Gascon C, Santaolalla F, Martinez A, Sanchez Del Rey A. Usefulness of the BAST-

24 smell and taste test in the study of diabetic patients: a new approach to the determination

of renal function. Acta Otolaryngol 2013;133:400–404.

43. Siviero M, Teixeira MJ, de Siqueira JT, Siqueira SR. Somesthetic, gustatory,

olfactory function and salivary flow in patients with neuropathic trigeminal pain. Oral Dis

2010;16:482–487.

44. Oosterman JM, Derksen LC, van Wijck AJ, Veldhuijzen DS, Kessels RP. Memory

functions in chronic pain: examining contributions of attention and age to test performance.

Clin J Pain 2011; 27:70–75.

45. Seifert F, Maihofner C. Functional and structural imaging of pain-induced

neuroplasticity. Curr Opin Anaesthesiol 2011;24:515–523.

46. Devanand DP, Michaels-Marston KS, Liu X, Pelton GH, Padilla M, Marder K et al.

Olfactory deficits in patients with mild cognitive impairment predict Alzheimer's disease at

follow-up. Am J Psychiatry 2000;157:1399–1405.

This article is protected by copyright. All rights reserved.

 47. Biessels GJ. Brain MRI correlates of cognitive dysfunction in type 2 diabetes: the
Accepted Article needle recovered from the haystack? Diabetes Care 2013;36:3855–3856.

48. Sanke H, Mita T, Yoshii H, Yokota A, Yamashiro K, Ingaki N et al. Relationship

between olfactory dysfunction and cognitive impairment in elderly patients with type 2

diabetes mellitus. Diabetes Res Clin Pract 2014;106:465–473.

49. Varkonyi T, Korei A, Putz Z, Kempler P. Olfactory dysfunction in diabetes: a further

step in exploring central manifestations of neuropathy? Angiology 2014;65:857–860.

50. Greco D, Gambina F, Pisciotta M, Abrignani M, Maggio F. Clinical characteristics

and associated comorbidities in diabetic patients with cranial nerve palsies. J Endocrinol

Invest 2012;35:146–149.

51. Papanas N, Heliopoulos I, Piperidou H, Maltezos E. Simultaneous, painless,

homolateral oculomotor and trochlear nerve palsies in a patient with type 2 diabetes mellitus.

Neuropathy or brainstem infarction? Acta Diabetologica 2006;43:19–21.

52. Lacroix MC, Badonnel K, Meunier N, Tan F, Schlegel-Le Poupon C, Durieux D et al.

Expression of insulin system in the olfactory epithelium: first approaches to its role and

regulation. J Neuroendocrinol 2008;20:1176–1190.

53. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA et al. Ghrelin

causes hyperphagia and obesity in rats. Diabetes 2001;50:2540–2547.

54. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S et al. The novel

hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.

Endocrinology 2000;141:4325–4328.

55. Taheri S, Hafizi S. The orexins/hypocretins: hypothalamic peptides linked to sleep

and appetite. Psychol Med 2002; 32: 955–958.

56. Taheri S, Bloom S. Orexins/hypocretins: waking up the scientific world. Clin

Endocrinol 2001; 54:421–429.

This article is protected by copyright. All rights reserved.

 57. Loch D, Heidel C, Breer H, Strotmann J. Adiponectin enhances the responsiveness of
Accepted Article the olfactory system. PloS One 2013;8:e75716.

58. Taheri S, Mahmoodi M, Opacka-Juffry J, Ghatei MA, Bloom SR. Distribution and

quantification of immunoreactive orexin A in rat tissues. FEBS Lett 1999;457:157–161.

59. Burdakov D, Luckman SM, Verkhratsky A. Glucose-sensing neurons of the

hypothalamus. Philos Trans R Soc Lond B Biol Sci 2005;360(1464):2227-35.

60. Taheri S, Zeitzer JM, Mignot E. The role of hypocretins (orexins) in sleep regulation

and narcolepsy. Ann Rev Neurosci 2002;25:283–313.

61. Buskova J, Klaschka J, Sonka K, Nevsimalova S. Olfactory dysfunction in narcolepsy

with and without cataplexy. Sleep Med 2010; 11:558–561.

62. Bayard S, Plazzi G, Poli F, Serra L, Ferri R, Dauvilliers Y. Olfactory dysfunction in

narcolepsy with cataplexy. Sleep Med 2010;11:876–881.

63. Baier PC, Weinhold SL, Huth V, Gottwald B, Ferstl R, Hinze-Selch D. Olfactory

dysfunction in patients with narcolepsy with cataplexy is restored by intranasal Orexin A

(Hypocretin-1). Brain 2008;131(Pt 10):2734–2741.

64. Kosse C, Gonzalez A, Burdakov D. Predictive models of glucose control: roles for

glucose-sensing neurones. Acta Physiologica 2015; 213:7–18.

65. Adams AC, Domouzoglou EM, Chee MJ, Segal-Lieberman G, Pissios P, Maratos-

Flier E. Ablation of the hypothalamic neuropeptide melanin concentrating hormone is

associated with behavioral abnormalities that reflect impaired olfactory integration. Behav

Brain Res 2011; 224:195–200.

66. Figlewicz DP, Ikeda H, Hunt TR, Stein LJ, Dorsa DM, Woods SC et al. Brain insulin

binding is decreased in Wistar Kyoto rats carrying the 'fa' gene. Peptides 1986; 7:61–65.

This article is protected by copyright. All rights reserved.

 67. Figlewicz DP, Dorsa DM, Stein LJ, Baskin DG, Paquette T, Greenwood MR et al.
Accepted Article Brain and liver insulin binding is decreased in Zucker rats carrying the 'fa' gene.

Endocrinology 1985;117:1537–1543.

68. Baskin DG, Porte D, Jr, Guest K, Dorsa DM. Regional concentrations of insulin in the

rat brain. Endocrinology 1983;112:898–903.

69. Baskin DG, Stein LJ, Ikeda H, Woods SC, Figlewicz DP, Porte D, Jr et al.

Genetically obese Zucker rats have abnormally low brain insulin content. Life Sci 1985;

36:627–633.

70. Stuhmer W, Ruppersberg JP, Schroter KH, Sakmann B, Stocker M, Giese KP et al.

Molecular basis of functional diversity of voltage-gated potassium channels in mammalian

brain. EMBO J 1989; 8:3235–3244.

71. Xu J, Wang P, Li Y, Li G, Kaczmarek LK, Wu Y et al. The voltage-gated potassium

channel Kv1.3 regulates peripheral insulin sensitivity. Proc Natl Acad Sci U S A

2004;101:3112–3117.

72. Tschritter O, Machicao F, Stefan N, Schafer S, Weigert C, Staiger H, et al. A new

variant in the human Kv1.3 gene is associated with low insulin sensitivity and impaired

glucose tolerance. J Clin Endorinol Metab 2006;91:654–658.

73. Fadool DA, Levitan IB. Modulation of olfactory bulb neuron potassium current by

tyrosine phosphorylation. J Neurosci 1998; 18:6126–6137.

74. Fadool DA, Tucker K, Perkins R, Fasciani G, Thompson RN, Parsons AD et al.

Kv1.3 channel gene-targeted deletion produces "Super-Smeller Mice" with altered glomeruli,

interacting scaffolding proteins, and biophysics. Neuron 2004; 41: 389–404.

75. Guthoff M, Tschritter O, Berg D, Liepelt I, Schulte C, Machicao F, et al. Effect of

genetic variation in Kv1.3 on olfactory function. Diabetes Metab Res Rev 2009;25:523–527.

This article is protected by copyright. All rights reserved.

 76. Fadool DA, Tucker K, Phillips JJ, Simmen JA. Brain insulin receptor causes activity-
Accepted Article dependent current suppression in the olfactory bulb through multiple phosphorylation of

Kv1.3. J Neurophysiol 2000;83:2332–2348.

77. Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA. Awake intranasal insulin

delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J

Neurosci 2009;29:6734–6751.

78. Fadool DA, Tucker K, Pedarzani P. Mitral cells of the olfactory bulb perform

metabolic sensing and are disrupted by obesity at the level of the Kv1.3 ion channel. PloS

One 2011;6:e24921.

FIGURE 1 Proposed pathways for the metabolic modulation of the olfactory system.

Several pathophysiological mechanisms may contribute to the association between diabetes

and olfactory dysfunction. These include alterations in peptide hormones, adipocytokines,

and neurotransmitters as a result of alterations in metabolism including hyperglycaemia,

insulin resistance, changes in Kv1.3 channel expression, vascular dysfunction, hypoxaemia,

and oxidative stress, neurodegeneration, and the impact of drugs.

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 Table 1 Types of olfactory disorder and their causes
Accepted Article Quantitative disorders
Disorder Definition
Hyperosmia Increased ability to detect
odours
Hyposmia Reduced ability to detect
odours
Partial/specific/total anosmia Loss of smell sense
Qualitative disorders
Dysosima Distortion of smell sensation
Parosmias Abhorrent perceptions of
• Troposmias smell:
in the presence of an
• Phantosmias odour
in the absence of an
odour (olfactory
hallucination)
This article is protected by copyright. All rights reserved.
Causes
• Sinus and upper respiratory
tract infections
• Obstructive nasal and paranasal
sinus disease/surgery
• Head trauma/surgery
• Ageing
• Nasal tumours/polyps
• Neurological disorders
(Alzheimer’s disease,
Parkinson’s disease, epilepsy,
stroke, encephalitis, olfactory
nerve damage)
• Toxic exposure, radiation
therapy
• Tumours (Foster Kennedy
syndrome)
• Human immunodeficiency virus
infection
• Congenital dysfunction
(hypogonadotrophic
hypogonadism; Kallmann
Syndrome)
• Sinus and upper respiratory
tract infections
• Obstructive nasal and paranasal
sinus disease/surgery
• Head trauma/surgery
• Neuropsychiatric disorders
(depression, schizophrenia,
Alzheimer’s disease,
Parkinson’s disease, migraine,
stroke),
• Tumours (frontal lobe tumour)
• Toxic exposure
• Drug withdrawal
• Poor dental hygiene
 Table 2 Summary table of studies investigating the relationship between olfactory
dysfunction and diabetes mellitus
Accepted Article
Authors Study Number of Diabetes type Method of Association Predictors of
design participants assessment between olfactory
of olfactory olfactory dysfunction
function dysfunction
and diabetes
1. Jorgensen Cross- 69 with Not specified Qualitative: 60% of
et al., 1960 sectional diabetes identify participants
[15] known had impaired
odorous sense of smell
substances;
quantitative:
Ellsberg and
Levy’s
method
2. Patterson Cross- 118 (59 with Not specified, Modified No significant
et al., 1966 sectional diabetes and Ellsberg and difference
[16] 59 controls) Levy’s between
method participants
with diabetes
and controls

3. Cross- 111 with Type 1 and Odorant Olfactory Increased age,

Weinstock sectional diabetes Type 2 Confusion ability was macrovascular
et al., 1993 Matrix overall disease
[11] impaired in
diabetes group
(67.8%)
compared
with control
group (≥ 80%)
4. Le Floch Cross- 98 (68 with Type 1 and SRS SRS was Diabetes duration,
et al., 1993 sectional diabetes and Type 2 lower in microalbuminuria,
[12] 30 controls) participants peripheral
with diabetes neuropathy
than in
controls
(12.4± 0.5 vs
15.1 ± 0.5; P
˂ 0.001)
5. Cross- 1900 Not specified Scandinavian No significant
Bramerson sectional (random (self-reported) Odour relationship
et al., 2004 sample of Identification between
[13] 1900 Test (SOIT) impaired
individuals olfaction and
aged ≥20 diabetes, but
years) in an analysis
of a group
composed
entirely of
participants
with diabetes
it was found
to be a risk
factor for
anosmia
6. Naka et Cross- 105 (76 with Type 1 and 2 5-item odour Participants BMI

This article is protected by copyright. All rights reserved.

 al., 2010 sectional diabetes and identification with Type 2
[18] 29 controls) test diabetes had
Accepted Article lower
olfactory
scores than
those with
Type 1 (3.4 ±
1.2 vs 4.0 ±
0.9, t=2.16;
P= 0.034).
Those with
uncomplicated
diabetes
showed no
significant
loss of
olfactory
function.
Those with
diabetes +
other diseases
showed
significantly
lower smell
scores than
participants
with diabetes
without other
illness
(P=0.024) and
controls (P=
0.004)
7. Hawking Cross- 288 (63 with Type 2 Brief Smell Those with
and sectional diabetes, Identification and without
Pearson, 225 controls Test (BSIT) diabetes
2011 [37] performed at
near identical
levels
8. Gascon et Cross- 61 with Not specified Barcelona No significant Albuminuria,
al., 2013 sectional diabetes smell test-24 relationship decreased GFR
[40] (BAST-24) between
olfactometry
and Hb1Ac
9.Brady et Cross- 70 (51 with Type 2 Sniffin’ Those with Neuropathic pain
al., sectional diabetes, 19 Sticks diabetes had
2013 [17] controls) reduced odour
detection
thresholds
(P=0.03),
reduced
ability to
discriminate
between odour
qualities
(P<0.01),
reduced
ability to
identify
odours
(P=0.02), and

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 rated odours
as less intense
Accepted Article (P<0.01) than
the control
group.
10. Gouveri Cross- 154 (119 Type 2 “Sniffin’ Those with Presence and
et al., 2014 sectional with Sticks” diabetes had number of
[14] diabetes, 35 lower odour diabetic
controls) threshold complications,
(6.51 ±2.52 vs diabetic
8.70 ± 2.96; retinopathy,
P<0.001), diabetic
odour peripheral
discrimination neuropathy
(10.56 ± 2.47
vs 11.82 ±
2.11;
P=0.008),
odour
identification
(12.28 ± 2 vs
14.67 ± 1.17;
P<0.001) and
TDI scores
(29.9 ± 5.24
vs 34.86
±3.72;
P<0.001) than
controls
11. Case– 60 (30 with Not specified Absorbent 60% of those
Mehdizadeh control diabetes, 30 perfumer with diabetes
et al., 2015 controls) paper strips were found to
[35] have some
degree of
olfactory
dysfunction
(P<0.01)
12. Duda- Cross- 136 (106 Type 1 Sniffin’ No significant Neuropathy,
Sobczack et sectional with sticks difference in Diabetes duration,
al., 2017 diabetes, 30 olfactory BMI
[39] controls) scores
between
participants
with and
without Type
1 diabetes
13. Cross- 70 (39 with Type 1, Sniffin’ No significant
Altundag et sectional diabetes and uncomplicated sticks difference in
al., 2017 31 controls) olfactory
[38] scores
between
participants
with and
without Type
1 diabetes

TDI, Threshold Discrimination Identification; SRS, Smell Recognition Score.

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Accepted Article Insulin Resistance Vascular Dysfunction
Changes in Kv1.3 Channel Oxidative Stress

Alteration in
Function of Glucose
Responsive Neurons
Lateral
lf t
Olfactory
Mitral cell

Tufted cell

Olfactory
Anterior Olfactory Piriform Amygdala Entorhinal
olfactory b l t

Hypothala

Contralate
l
Hippocam

Ghrelin
Adiponectin Thalamus
Frontal
Oh id Drugs
Orbitofron
t l t

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