Olfactory Dysfunction: A Complication of Diabetes or a Factor That Complicates Glucose Metabolism? A Narrative Review

The present narrative review presents emerging data regarding the association between diabetes mellitus and olfactory dysfunction and discusses the role of olfactory dysfunction in glucose metabolism. We searched relevant published articles in PubMed and Google Scholar until October 2021. Main key words included “olfactory dysfunction”, “diabetes mellitus”, and “glucose metabolism”. Olfactory dysfunction has been associated with diabetes mellitus. Furthermore, it has been proposed to be a diabetic complication, given that it has been linked with microvascular complications, such as diabetic peripheral neuropathy. Interestingly, it has been suggested that olfactory dysfunction is a manifestation of central neuropathy in diabetes, a hypothesis based on the observation that diabetes, olfactory dysfunction, and cognitive decline often coexist. However, evidence is limited and inconsistent. More importantly, olfactory and endocrine systems are closely linked, and olfactory dysfunction plays a significant role in glucose metabolism and obesity. Indeed, food behaviour and energy balance are influenced by olfaction status.

Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction

Earlier, it was shown that reversing the downregulation of neuritin expression in the brain improves central neuropathy in diabetic rats. We investigated the protective mechanism of neuritin in diabetic cognitive dysfunction via astrocytes. Further, the impact of the overexpression of neuritin in the cortex and the hippocampus on diabetic cognitive dysfunction and astrogliosis in type 2 diabetic (db/db) mice was assessed. Antagonists were used to inhibit the JAK2/STAT3 signaling pathway in U-118MG, an astrocyte cell line. Immunofluorescence, Western blotting, and real-time PCR were performed. Neuritin overexpression in the hippocampus of db/db mice significantly ameliorated cognitive dysfunction, hippocampal neuronal impairment, and synaptic plasticity deterioration, and inhibited astrogliosis and the JAK2/STAT3 signaling pathway in the hippocampus. Neuritin suppressed the JAK2/STAT3 signaling pathway to inhibit lipopolysaccharide-induced gliosis in U-118MG cells. It was observed that neuritin regulates the JAK2/STAT3 signaling pathway in astrocytes to inhibit astrogliosis and improve diabetic cognitive dysfunction.

Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action or both. Diabetes affects many systems and produces complications in the human body, in those complications one is diabetic central neuropathy. The pathological mechanisms involved in the central neuropathy include chronic hyperglycaemia, hypoglycaemic episodes, angiopathy and blood–brain barrier dysfunction. Diabetic central neuropathy is detected by using of brainstem auditory evoked response (BAER), Visual evoked potential (VEP), somatosensory evoked potential (SEP). These abnormalities are present at different levels and may appear before appearance of overt complications. The central nervous system abnormalities are more frequent in patients with peripheral neuropathy but evoked potentials can be abnormal even in patients without neuropathy. The BAER is a physiological recording technique to study the auditory pathway and does not require subject’s attention and generates waves during the first 10 ms after the sound stimulus. Each BAER wave is generated by the activation of a sub-cortical component of the auditory pathway with 90% sensitivity and 70–90% of specificity.

Diabetic Central Neuropathy: A Cause of Central Sleep Apnea

Diabetes Mellitus, prolonged hyperglycemia, causes peripheral and central nervous system dysfunction. Chronic hyperglycemia causes changes in the sorbitol, inositol and taurine content of peripheral and central nervous system tissue. The proteins in these tissues are also altered by glycosylation end products. The changes in metabolites impair growth and development of nerves and the increased glycosylation end products make the proteins stiff, sticky and prone to physical injury. This activity stimulated by hyperglycemia impairs the normal function of the peripheral and central nervous system. Manifestations of this tissue injury have been loss of sensation and increased pain in the extremities, loss of proprioception when standing, dysregulation of gastrointestinal motility, and heart rate. Also noted in children are delayed maturation of cognitive function during childhood and more rapid decline of cognitive function with increasing age and increasing HbA1c. Sleep apnea has become an important cause of heart failure and death commonly linked to type 2 diabetes and obesity. Continuous pressure airway pressure (CPAP) does overcome the periods of obstruction and prevents the morbidity associated with obstructive sleep apnea (OSA). Forty-Six percent of type 1 diabetic patients have absence of effort sleep apnea which means it is a central lack of drive to breath. There is evidence of change of structure in the medulla of subjects with type 1 diabetes as well as evidence of injuries in the medulla that cause cessation of breathing. These observations indicate that central neuropathy caused by hyperglycemia does cause central sleep apnea and possibly death.

The DPP-4 inhibitor sitagliptin alters the gut microbiota and prevents neuronal damage of hippocampus in STZ induced type 2 diabetic rats

Background : Type 2 Diabetes mellitus is characterized by impaired glucose metabolism and insulin resistance with increasing risk of specific complication, including central neuropathy. Dipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to regulate hyperglicemia through increasing the half-life of incretins. Although they are administered orally, their effects on central neuropathy and gut microbiota remain unclear. Our objective was aimed to identify the impact of the DPP-4 inhibitor sitagliptin on gut microbiota and central neuropathy in a rat model of streptozotocin (STZ)-induced diabetes Methods: Diabetic rats were induced by a high-fat diet and streptozotocin injection. Diabetic rats were orally administered a dose of sitagliptin (10mg/kd/d), and normal diet for 12 weeks. Fecal DNA extraction and sequencing based on analysis of 16S rRNA genes was used to determine the overall structure of microbiota in fecal samples. Then rats were killed, of which the brain tissue sections were observed for changes of neurons in the hippocampus by HE staining. Results: Sequencing of the V3-V4 regions of 16S rRNA genes revealed that sitagliptin significantly altered the gut microbiota. Compared to the diabetic group, Shannon index and the abundance of phylum Bacteroidetes decreased significantly, whereas the proportion of phylum Firmicutes increased significantly in the sitagliptin-treated rats. Moreover, higher abundance of a few putative short-chain fatty acid-producing bacteria, including Clostridium and Fusobacterium was observed remarkably after sitaglitin treatment. Genera Lactobacillus , Streptococcus and Clostridium, which could produce some neurotransmitters, were also found increased substantially in the sitagliptin-treated rats. Notably, we found that sitagliptin treatment could ameliorate the abnormal changes of pyramidal neurons in hippocampus with HE staining. Conclusions: Our study demonstrated that sitagliptin prevented the neuronal damage of hippocampus in type 2 diabetic rats, accompanied by changes of gut microbiome. It indicated that sitagliptin might alleviate diabetic central neuropathy through triggering “microbiota-gut-brain” axis.

Evaluation of central neuropathy in type 2 diabetes mellitus: a case control study

Background: Diabetes mellitus (DM) is a global pandemic affecting almost every organ in the body. Peripheral nervous system involvement in diabetes is well known but there are not many studies on central nervous system involvement. Visual evoked potential (VEP) is a sensitive, non-invasive test to detect central demyelination of optic nerve. The objective was to compare the visual evoked potentials in type-2 DM patients with that of healthy controls and to find out if any correlation is there with the duration and glycaemic control of the disease and to compare incidence of peripheral and central neuropathy in DM patients.Methods: Author included 50 DM patients and 50 age and sex matched controls. Patients with previous stroke, demyelination, diabetic retinopathy and other ophthalmological disorders were excluded. VEP was recorded using pattern reversal stimulation with EMG RMS MARK II machine and p100 latency was measured.Results: P100 latencies (ms) was significantly prolonged in diabetics with mean±SD of (111.24±5.28 ms) as compared to controls (101.30±1.66 ms) with p value <0.003. Also, there was significant correlation between duration of DM and P100 latency prolongation, but no significant correlation was present when compared with glycaemic control.Conclusions: Central neuropathy is very common in DM. It is related to duration of DM and not HbA1c unlike PNP which is related to both. Central neuropathy occurs even prior to development of retinopathy or PNP. Hence, VEP is a non-invasive and sensitive screening tool for early neurological involvement in DM.