Loss of Synaptic Connectivity, Particularly in Second Order Neurons Is a Key Feature of Diabetic Retinal Neuropathy in the Ins2Akita Mouse

Retinal neurodegeneration is a key component of diabetic retinopathy (DR), although the detailed neuronal damage remains ill-defined. Recent evidence suggests that in addition to amacrine and ganglion cell, diabetes may also impact on other retinal neurons. In this study, we examined retinal degenerative changes in Ins2^Akita diabetic mice. In scotopic electroretinograms (ERG), b-wave and oscillatory potentials were severely impaired in 9-month old Ins2^Akita mice. Despite no obvious pathology in fundoscopic examination, optical coherence tomography (OCT) revealed a progressive thinning of the retina from 3 months onwards. Cone but not rod photoreceptor loss was observed in 3-month-old diabetic mice. Severe impairment of synaptic connectivity at the outer plexiform layer (OPL) was detected in 9-month old Ins2Akita mice. Specifically, photoreceptor presynaptic ribbons were reduced by 25% and postsynaptic boutons by 70%, although the density of horizontal, rod- and cone-bipolar cells remained similar to non-diabetic controls. Significant reductions in GABAergic and glycinergic amacrine cells and Brn3a+ retinal ganglion cells were also observed in 9-month old Ins2^Akita mice. In conclusion, the Ins2^Akita mouse develops cone photoreceptor degeneration and the impairment of synaptic connectivity at the OPL, predominately resulting from the loss of postsynaptic terminal boutons. Our findings suggest that the Ins2^Akita mouse is a good model to study diabetic retinal neuropathy.

Retinal nerve fibre layer thinning associated with diabetic peripheral neuropathy

Aims
To investigate the relationship between retinal nerve fibre layer thickness and peripheral neuropathy in patients with Type 2 diabetes, particularly in those who are at higher risk of foot ulceration.

Methods
Global and sectoral retinal nerve fibre layer thicknesses were measured at 3.45 mm diameter around the optic nerve head using optical coherence tomography (OCT). The level of neuropathy was assessed in 106 participants (82 with Type 2 diabetes and 24 healthy controls) using the 0–10 neuropathy disability score. Participants were stratified into four neuropathy groups: none (0–2), mild (3–5), moderate (6–8), and severe (9–10). A neuropathy disability score ‡ 6 was used to define those at higher risk of foot ulceration. Multivariable regression analysis was performed to assess the effect of neuropathy disability scores, age, disease duration and retinopathy on RNFL thickness.

Results
Inferior (but not global or other sectoral) retinal nerve fibre layer thinning was associated with higher neuropathy disability scores (P = 0.03). The retinal nerve fibre layer was significantly thinner for the group with neuropathy disability scores ‡ 6 in the inferior quadrant (P < 0.005). Age, duration of disease and retinopathy levels did not significantly influence retinal nerve fibre layer thickness. Control participants did not show any significant differences in thickness measurements from the group with diabetes and no neuropathy (P > 0.24 for global and all sectors).

Conclusions
Inferior quadrant retinal nerve fibre layer thinning is associated with peripheral neuropathy in patients with Type 2 diabetes, and is more pronounced in those at higher risk of foot ulceration.

Visual sensitivity loss in the central 30° of visual field is associated with diabetic peripheral neuropathy

Aims/hypothesis
Impaired central vision has been shown to predict diabetic peripheral neuropathy (DPN). Several studies have demonstrated diffuse retinal neurodegenerative changes in diabetic patients prior to retinopathy development, raising the prospect that non-central vision may also be compromised by primary neural damage. We hypothesise that type 2 diabetic patients with DPN exhibit visual sensitivity loss in a distinctive pattern across the visual field, compared with a control group of type 2 diabetic patients without DPN.

Methods
Increment light sensitivity was measured by standard perimetry in the central 30° of visual field for two age-matched groups of type 2 diabetic patients, with and without neuropathy (n = 40/30). Neuropathy status was assigned using the neuropathy disability score. Mean visual sensitivity values were calculated globally, for each quadrant and for three eccentricities (0–10°, 11–20° and 21–30°). Data were analysed using a generalised additive mixed model (GAMM).

Results
Global and quadrant between-group visual sensitivity mean differences were marginally but consistently lower (by about 1 dB) in the neuropathy cohort compared with controls. Between-group mean differences increased from 0.36 to 1.81 dB with increasing eccentricity. GAMM analysis, after adjustment for age, showed these differences to be significant beyond 15° eccentricity and monotonically increasing. Retinopathy levels and disease duration were not significant factors within the model (p = 0.90).

Conclusions/interpretation
Visual sensitivity reduces disproportionately with increasing eccentricity in type 2 diabetic patients with peripheral neuropathy. This sensitivity reduction within the central 30° of visual field may be indicative of more consequential loss in the far periphery.

Postural control and functional balance in individuals with diabetic peripheral neuropathy

A Neuropatia diabética periférica (NDP) cursa com redução somatossensitiva que pode levar a alterações no controle postural. O objetivo do estudo foi avaliar o controle postural na postura ereta, em diferentes condições, e o equilíbrio funcional em indivíduos com NDP, correlacionar os resultados obtidos na avaliação do controle postural com os valores do teste do equilíbrio funcional e comparar os resultados obtidos no grupo neuropata com o grupo controle, verificando as possíveis diferenças entre as condições de avaliação em ambos os grupos. Participaram do estudo 13 mulheres com NDP (GN) e 17 mulheres não diabéticas (GC). A avaliação do controle postural foi realizada por cinemetria nas condições: olhos abertos (OA), olhos fechados (OF) e semi tandem (ST). Após processamento no MATLAB, foram geradas as variáveis: amplitude média de oscilação (AMO) na direção ântero-posterior (AP) e médio-lateral (ML); e velocidade média de oscilação (VMO) na direção AP e ML. O equilíbrio funcional foi avaliado pelo Timed Up and Go Test. Houve diferença significante entre os grupos (p<0,005) na AMO-AP OA e OF, AMO-ML of e ST e VMO-ML ST. Houve diferença entre as condições OA e ST (p<0,005) e of e ST (p<0,005) para as variáveis AMO-ML e VMO-ML, com maior prejuízo para o GN, que também apresentou um menor equilíbrio funcional (p=0,001). A instabilidade ML foi correlacionada positivamente com o desequilíbrio funcional. Os resultados nos mostram uma alteração no sistema de controle postural na NDP, o que pode levar estes indivíduos a um maior risco a quedas e prejuízos funcionais.

Diabetic peripheral neuropathy in ankles and feet: muscle strength and plantar pressure

This study aims to evaluate and correlate the vascular, sensory and motor components related to the plantar surface in individuals with diabetic peripheral neuropathy. 68 patients were categorized into two groups: 28 in the neuropathic group and 40 in the control group. In each patient, we assessed: circulation and peripheral perfusion of the lower limbs; somatosensory sensitivity; ankle muscle strength; and pressure on the plantar surface in static, dynamic and gait states. We used the Mann-Whitney test and analysis of variance (ANOVA and MANOVA) for comparison between groups, and performed Pearson and Spearman linear correlations amongst the variables (P < 0.05). The somatosensory sensitivity, peripheral circulation and ankle muscle strength were reduced in the neuropathic group. In full peak plantar pressures, no differences were seen between groups, but differences did appear when the foot surface was divided into regions (forefoot, midfoot and hindfoot). In the static condition, the plantar surface area was greater in the neuropathic group. In the dynamic state, peak pressures in the neuropathic group, were higher in the forefoot and lower in the hindfoot, as well as lower in the hindfoot during gait. There were positive or negative correlations between the sensitivity deficit, dorsal ankle flexor strength, plantar surface area, and peak pressure by plantar region. The sensitivity deficit contributed to the increased plantar surface area.

Gait stability in diabetic peripheral neuropathy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Balance and ankle muscle strength predict spatiotemporal gait parameters in individuals with diabetic peripheral neuropathy

The aims of this study were to evaluate aspects of balance, ankle muscle strength and spatiotemporal gait parameters in individuals with diabetic peripheral neuropathy (DPN) and verify whether deficits in spatiotemporal gait parameters were associated with ankle muscle strength and balance performance. Thirty individuals with DPN and 30 control individuals have participated. Spatiotemporal gait parameters were evaluated by measuring the time to walk a set distance during self-selected and maximal walking speeds. Functional mobility and balance performance were assessed using the Functional Reach and the Time Up and Go tests. Ankle isometric muscle strength was assessed with a handheld digital dynamometer. Analyses of variance were employed to verify possible differences between groups and conditions. Multiple linear regression analysis was employed to uncover possible predictors of gait deficits. Gait spatiotemporal, functional mobility, balance performance and ankle muscle strength were affected in individuals with DPN. The Time Up and Go test performance and ankle muscle isometric strength were associated to spatiotemporal gait changes, especially during maximal walking speed condition. Functional mobility and balance performance are damaged in DPN and balance performance and ankle muscle strength can be used to predict spatiotemporal gait parameters in individuals with DPN.

Diabetic patients with and without peripheral neuropathy reveal different hip and ankle biomechanical strategies during stair descent

Background: The progression of diabetes and the challenge of daily tasks may result in changes in biomechanical strategies. Descending stairs is a common task that patients have to deal with, however it still has not been properly studied in this population. Objectives: We describe and compare the net joint moments and kinematics of the lower limbs in diabetic individuals with and without peripheral neuropathy and healthy controls during stair descent. Method: Forty-two adults were assessed: control group (13), diabetic group (14), and neuropathic diabetic group (15). The flexor and extensor net moment peaks and joint angles of the hip, knee, and ankle were described and compared in terms of effect size and ANOVAs (p<0.05). Results: Both diabetic groups presented greater dorsiflexion [large effect size] and a smaller hip extensor moment [large effect size] in the weight acceptance phase. In the propulsion phase, diabetics with and without neuropathy showed a greater hip flexor moment [large effect size] and smaller ankle extension [large effect size]. Conclusion: Diabetic patients, even without neuropathy, revealed poor eccentric control in the weight acceptance phase, and in the propulsion phase, they showed a different hip strategy, where they chose to take the leg off the ground using more flexion torque at the hip instead of using a proper ankle extension function.

Diagnosis of diabetic autonomic neuropathy: a multivariate approach

In the diagnosis of diabetic autonomic neuropathy (DAN) various autonomic tests are used. We took a novel statistical approach to find a combination of autonomic tests that best separates normal controls from patients with DAN.

Bilateral posterior ischaemic optic neuropathy after severe diabetic ketoacidosis, cardiopulmonary resuscitation and respiratory failure

A 44-year-old male European with type I diabetes mellitus fell into diabetic ketoacidosis. In the emergency room, he developed an episode of asystole and respiratory failure requiring one cycle of cardiopulmonary resuscitation and extracorporeal membrane oxygenation (ECMO). Waking up 7 days later, he presented a bilateral complete loss of vision. Ophthalmological examination including funduscopy on days 1 and 10, after extubation, showed bilateral large round pupils non-reactive to light and a normal fundus. Neuroimaging studies, including MRI and MRA of the brain, were all within normal limits. A lumbar puncture and comprehensive serological testing excluded an infectious or rheumatic cause. An empirical high-dose intravenous steroid treatment administered for 5 days had no effect on his vision. His eye examination at 1.5 months follow-up showed a normal fundus except for progressive bilateral optic nerve disc pallor, which pointed towards the diagnosis of a posterior ischaemic optic neuropathy.

Analyzing systolic-diastolic interval interaction characteristics in diabetic cardiac autonomic neuropathy progression

Cardiac autonomic neuropathy (CAN), one of the major complications in diabetes, if detected at the subclinical stage allows for effective treatment and avoiding further complication including cardiovascular pathology. Surface ECG (Electrocardiogram)-based diagnosis of CAN is useful to overcome the limitation of existing cardiovascular autonomic reflex tests traditionally used for CAN identification in clinical settings. The aim of this paper is to analyze the changes in the mechanical function of the ventricles in terms of systolic-diastolic interval interaction (SDI) from a surface ECG to assess the severity of CAN progression [no CAN, early CAN (ECAN) or subclinical CAN, and definite CAN (DCAN) or clinical CAN]. ECG signals recorded in supine resting condition from 72 diabetic subjects without CAN (CAN-) and 70 diabetic subjects with CAN were analyzed in this paper. The severity of CAN was determined by Ewing's Cardiovascular autonomic reflex tests. Fifty-five subjects of the CAN group had ECAN and 15 subjects had DCAN. In this paper, we propose an improved version of the SDI parameter (i.e., TQ/RR interval ratio) measured from the electrical diastolic interval (i.e., TQ interval) and the heart rate interval (i.e., RR interval). The performance of the proposed SDI measure was compared with the performance of the existing SDI measure (i.e., QT/TQ interval ratio). The proposed SDI parameter showed significant differences among three groups (no CAN, ECAN, and DCAN). In addition, the proposed SDI parameter was found to be more sensitive in detecting CAN progression than other ECG interval-based features traditionally used for CAN diagnosis. The modified SDI parameter might be used as an alternative measure for the Ewing autonomic reflex tests to identify CAN progression for those subjects who are unable to perform the traditional tests. These findings could also complement the echocardiographic findings of the left ventricular diastolic dysfunction by providing additional information about alteration in systolic and diastolic intervals in heart failure.