Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin

Abstract

Recent data suggest that olfactory deficits could represent an early marker and a pathogenic mechanism at the basis of cognitive decline in type 2 diabetes (T2D). However, research is needed to further characterize olfactory deficits in diabetes, their relation to cognitive decline and underlying mechanisms.The aim of this study was to determine whether T2D impairs odour detection, olfactory memory as well as neuroplasticity in two major brain areas responsible for olfaction and odour coding: the main olfactory bulb (MOB) and the piriform cortex (PC), respectively. Dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used T2D drugs exerting also beneficial effects in the brain. Therefore, we aimed to determine whether DPP-4i could reverse the potentially detrimental effects of T2D on the olfactory system.Non-diabetic Wistar and T2D Goto-Kakizaki rats, untreated or treated for 16 weeks with the DPP-4i linagliptin, were employed. Odour detection and olfactory memory were assessed by using the block, the habituation-dishabituation and the buried pellet tests. We assessed neuroplasticity in the MOB by quantifying adult neurogenesis and GABAergic inhibitory interneurons positive for calbindin, parvalbumin and carletinin. In the PC, neuroplasticity was assessed by quantifying the same populations of interneurons and a newly identified form of olfactory neuroplasticity mediated by post-mitotic doublecortin (DCX) + immature neurons.We show that T2D dramatically reduced odour detection and olfactory memory. Moreover, T2D decreased neurogenesis in the MOB, impaired the differentiation of DCX+ immature neurons in the PC and altered GABAergic interneurons protein expression in both olfactory areas. DPP-4i did not improve odour detection and olfactory memory. However, it normalized T2D-induced effects on neuroplasticity.The results provide new knowledge on the detrimental effects of T2D on the olfactory system. This knowledge could constitute essentials for understanding the interplay between T2D and cognitive decline and for designing effective preventive therapies.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0517-1) contains supplementary material, which is available to authorized users.

Retinal Deficits Precede Cognitive and Motor Deficits in a Rat Model of Type II Diabetes

“…However, previous studies in GK rats only revealed deficits at later times, including deficits in novel object recognition observed at 24 weeks of age, 48 deficits in memory retention observed at 10 weeks, 49 and deficits in olfactory memory at 6 to 10 months. 35…”

“…The GK rat is a non-insulin-dependent, polygenic, nonobese model that develops impaired glucose-induced Copyright 2019 The Authors iovs.arvojournals.org j ISSN: 1552-5783 insulin secretion by 2 weeks and fasting hyperglycemia by 4 weeks. 30,31 Retinal 32,33 and cognitive deficits [34][35][36] and reduced motor nerve conduction 37 have been reported in the GK rat. However, the temporal appearance of these deficits and the relationship between them has not been described.…”

Olfactory Memory in Depression: State and Trait Differences between Bipolar and Unipolar Disorders

“…Olfactory memory is affected in Alzheimer's disease [16]. Lietzau et al showed that type 2 diabetes may impair olfactory memory and odor detection and decreases neurogenesis in the olfactory bulb [17]. Several hypotheses have been made to try to explain the olfactory dysfunction in diabetes, including the possibility that endocrine and vascular changes may lead to neuropathy and damage to the olfactory nerve [18,19].…”

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

“…A population‐based study showed patients using pioglitazone as an antidiabetic drug are at lower risk of developing dementia when compared with other drugs used to treat the same (Lu, Yang, Li, Hsieh, & Ou, ; Thabit & El, ). Also, DPP‐4 inhibitors like linagliptin and vildagliptin showed reduced memory impairment when used as a treatment approach in rats (Lietzau et al, ; Zhang et al, ). Moreover, probucol showed a decline in cognitive impairment in an insulin resistant mouse by protecting its blood–brain barrier (Mamo et al, ).…”

“…inhibitors like linagliptin and vildagliptin showed reduced memory impairment when used as a treatment approach in rats (Lietzau et al, 2018;Zhang et al, 2018). Moreover, probucol showed a decline in cognitive impairment in an insulin resistant mouse by protecting its bloodbrain barrier (Mamo et al, 2018).…”