Prevalence and risk factors of glomerular hyperfiltration in adults with type 2 diabetes: A population-based study.

AIMS: Glomerular hyperfiltration characterises the earliest stage of diabetic nephropathy and predicts adverse kidney and cardiovascular outcomes. We aimed to assess the prevalence and risk factors of glomerular hyperfiltration in a population-based contemporary cohort of individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: The prevalence of unequivocal glomerular hyperfiltration (defined by an estimated glomerular filtration rate >120 mL/min/1.73 m2 ) and its associated risk factors were identified in a cohort of 202,068 adult patients with T2D receiving specialist care in 2021-2022, whose center-aggregated data were automatically extracted from electronic medical records of 75 diabetes clinics in Italy. RESULTS: Glomerular hyperfiltration was identified in 1262 (0.6%) participants. The prevalence of glomerular hyperfiltration varied widely across centers (0%-3.4%) and correlated with mean center age, HbA1c , body mass index (BMI), and low-density lipoprotein cholesterol. Patients in centers with high glomerular hyperfiltration prevalence (>0.8%) were more often men and had lower age and BMI, but more frequent albuminuria and worse glucose, lipid, and blood pressure control, compared with low-normal prevalence centers. CONCLUSIONS: Unequivocal glomerular hyperfiltration can be identified in up to 3.4% of patients receiving up-to-date specialist diabetes care. Glomerular hyperfiltration prevalence varies across centers and substantially increases with suboptimal control of metabolic risk factors, which would require improved management to mitigate the negative health consequences of this pathological condition.

The role of dietitian in the multidisciplinary treatment of PCOS.

It is well accepted by the medical literature that polycystic ovary syndrome (PCOS) is an extremely heterogeneous condition and that a multidisciplinary approach, involving gynecologists, endocrinologists, primary healthcare providers, mental health professionals, and nutritional professionals, especially dietitians, is fundamental to provide an immediate care and to counteract long-term risk factors related to the comorbidity of PCOS. Although lifestyle modifications are the first step intervention in the treatment of PCOS, unfortunately, the involvement of dietitian in clinical practice remains sporadic. The goal of this viewpoint is to put a greater emphasis on the role of dietitian in the management of PCOS by highlighting frequently faced difficulties in the clinical settings and the importance of a three-step nutritional care: accurate assessment; lifestyle, nutritional, and supplementary intervention; long-term follow-up. The intention is to raise awareness among dietitians themselves and other health providers as well as to express an exceeding necessity of evidence-based guidelines formulated specifically for nutritional professionals, which would allow a uniform approach with respect to heterogeneity and complexity of PCOS at the international level.

Autonomic Nervous System in Obesity and Insulin-Resistance-The Complex Interplay between Leptin and Central Nervous System.

The role of the autonomic nervous system in obesity and insulin-resistant conditions has been largely explored. However, the exact mechanisms involved in this relation have not been completely elucidated yet, since most of these mechanisms display a bi-directional effect. Insulin-resistance, for instance, can be caused by sympathetic activation, but, in turn, the associated hyperinsulinemia can activate the sympathetic branch of the autonomic nervous system. The picture is made even more complex by the implicated neural, hormonal and nutritional mechanisms. Among them, leptin plays a pivotal role, being involved not only in appetite regulation and glucose homeostasis but also in energy expenditure. The purpose of this review is to offer a comprehensive view of the complex interplay between leptin and the central nervous system, providing further insights on the impact of autonomic nervous system balance on adipose tissue and insulin-resistance. Furthermore, the link between the circadian clock and leptin and its effect on metabolism and energy balance will be evaluated.

Glycemic Status Assessment by the Latest Glucose Monitoring Technologies.

The advanced and performing technologies of glucose monitoring systems provide a large amount of glucose data that needs to be properly read and interpreted by the diabetology team in order to make therapeutic decisions as close as possible to the patient's metabolic needs. For this purpose, new parameters have been developed, to allow a more integrated reading and interpretation of data by clinical professionals. The new challenge for the diabetes community consists of promoting an integrated and homogeneous reading, as well as interpretation of glucose monitoring data also by the patient himself. The purpose of this review is to offer an overview of the glycemic status assessment, opened by the current data management provided by latest glucose monitoring technologies. Furthermore, the applicability and personalization of the different glycemic monitoring devices used in specific insulin-treated diabetes mellitus patient populations will be evaluated.

Flavonoids and Insulin-Resistance: From Molecular Evidences to Clinical Trials.

Insulin-resistance is one of the main factors responsible for the onset and progression of Metabolic Syndrome (MetS). Among all polyphenols, the effects of flavonoids and their main food sources on insulin sensitivity have been widely evaluated in molecular and clinical studies. The aim of this review is to analyse the data observed in vitro, in vivo and in clinical trials concerning the effects of flavonoids on insulin resistance and to determine the molecular mechanisms with which flavonoids interact with insulin signaling.

Single Retinal Layer Evaluation in Patients with Type 1 Diabetes with No or Early Signs of Diabetic Retinopathy: The First Hint of Neurovascular Crosstalk Damage between Neurons and Capillaries?

PURPOSE: To analyze the retinal-choroidal changes in type 1 diabetes mellitus (DM1) patients with no or early signs of diabetic retinopathy (DR). METHODS: Seventy-six eyes of 38 DM1 patients and 26 control eyes were included. Nine individual retinal layer thickness measurements were obtained using the spectral domain-optical coherence tomography automated segmentation algorithm. RESULTS: The retinal nerve fiber layer was slightly thinner in all explored quadrants, even if the reduction was not significant in DM1 eyes versus control eyes. The inner nuclear layer (INL) thickness was thicker in all DM1 eyes versus control eyes in all quadrants (p < 0.050). Analyses adjusting for inner retinal thickness in all sectors confirmed INL thickening by about 4%, and also found a significant thinning of the ganglion cell layer (GCL) by about 3.5% in all DM1 subjects versus controls (p < 0.050). CONCLUSION: DM1 patients with no or early signs of DR present retinal changes particularly at the INL and GCL that might be correlated to initial findings of neurodegeneration.

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care.

INTRODUCTION: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. METHODS: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. RESULTS: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42% < 5 years), and a minority (15.6%) had a history of cardiovascular events. Importantly, oral semaglutide was started in subjects with various disease durations and background therapies. Notably, its initiation was accompanied by de-prescription of sulfonylureas, pioglitazone, DPP-4 inhibitors, and insulin. Choice of oral semaglutide was influenced by patient profiles and ongoing glucose-lowering regimens. Factors such as younger age, higher HbA1c, and ongoing SGLT-2 inhibitor therapy drove the choice of oral semaglutide with the aim of improving glycemic control. Projected glycemic effectiveness analysis revealed that oral semaglutide could potentially lead HbA1c to target in > 60% of patients, and more often than sitagliptin or empagliflozin. CONCLUSION: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management.

In vivo assessment of associations between photoreceptors structure and macular perfusion in type 1 diabetes.

PURPOSE: To explore the potential relationships between macular vascular network and different adaptive optics (AO) metrics in patients with type 1 diabetes mellitus (DM1) with no signs (NoDR) or mild non-proliferative diabetic retinopathy (NPDR). DESIGN: Observational cross-sectional study. METHODS: Forty eyes of consecutive patients with DM1 (12 NoDR and 28 NPDR) and 10 healthy age-matched control subjects were included. All patients and controls were imaged using AO retinal camera and PLEX Elite 9000 optical coherence tomography (OCT) angiography (OCTA). The AO outcome measures to evaluate the cone photoreceptor mosaic characteristics were as follows: (1) Cone density (CD); (2) Linear Dispersion Index (LDi) and (3) Heterogeneity Packing Index (HPi). The OCTA outcome measures included: (1) superficial capillary plexus (SCP) perfusion density (PD); (2) deep capillary plexus (DCP) PD and (3) the choriocapillaris (CC) flow deficit percentage (FD%). RESULTS: NPDR group exhibited a close relationship between cone metrics and CC FD. Notably, CC FD% increase along with LDi (p=0.035), while the increasing CC FD% were associated with reducing CD (p=0.042) and the HPi (p=0.017). Furthermore, the OCTA parameters, including PD SCP and DCP, showed a significant negative correlation with CD. CONCLUSIONS: Our results demonstrated the relationship between macular perfusion at both retinal and choroidal levels and the cone mosaic in patients with DM1 interpolating swept-source-OCTA and AO metrics. In NPDR eyes, the photoreceptor damage was accompanied by CC insufficiency since the early stages of the disease.

Progression Biomarkers of Microvascular and Photoreceptor Changes Upon Long-Term Evaluation in Type 1 Diabetes.

Purpose: To assess demographic, metabolic, and imaging predictors influencing microvasculature and photoreceptors changes over a 4-year follow-up in type 1 diabetes mellitus (DM1). Methods: This prospective cohort study enrolled patients with DM1 with mild non-proliferative diabetic retinopathy. Complete medical records, glycosylated hemoglobin (HbA1c), optical coherence tomography angiography, and adaptive optics were collected for the 4 years of follow-up. The main outcome measures included perfusion density at the superficial capillary plexus (SCP) and deep capillary plexus (DCP), choriocapillaris (CC) flow deficits (FDs, %), cone density, linear dispersion index (LDi), and heterogeneity packing index (HPi). Results: The SCP presented a dichotomic perfusion trend, with increasing PD at 1 and 2 years and a subsequent decline (P < 0.001). DCP presented a similar trend in the first 2 years (P < 0.01) but not at the following time points, whereas CC FDs constantly increased over time (P < 0.01). The best-fitted model for the microvascular parameters demonstrated that the main factors affecting SCP included time (P < 0.001), duration of diabetes (P = 0.007), and HbA1c (P = 0.03), whereas the DCP was influenced by LDi modifications (P = 0.006). The LDi and HPi were mainly influenced by SCP and CC perfusion in the parafovea (P = 0.02). Conclusions: This study demonstrated an initial vasodilatory phenomenon resulting from a compensatory mechanism from the superficial vasculature, followed by capillary dropout. Initially, it would seem that there was an adaptive response by the DCP to the needs of the photoreceptors. Although the SCP may initially support the DCP, when the microvascular damage becomes diffuse and involves the SCP and CC it directly affects photoreceptor integrity.

Knowledge, experiences, and perceptions relating to obesity management among primary care physicians in the Lazio Region, Italy.

Background: Primary care providers (PCPs) play an essential role in obesity care as they represent the first contact for patients seeking weight loss interventions. Objective: This study explored the knowledge, experiences, and perceptions of PCPs in the Lazio Region of Italy in the management of obesity. Design and subjects: We conducted an anonymous survey delivered from March to July 2022 via the newsletter of Rome Provincial Order of Physicians and Dentists and at the annual meeting of the regional section of the Italian Obesity Society. Approach: The survey consisted of 24 closed-ended questions grouped into 5 sections: sociodemographic and work information; assessment of obesity; management of obesity; connections with regional Centres for Obesity Management; attitudes towards obesity. Key results: A total of 92 PCPs accessed the survey. Of those, 2.2% were excluded because they did not see any patients with obesity. A total of 68 PCPs (75.6%) had complete questionnaires and were included in this analysis. All participants reported asking their patients about their eating habits, lifestyle, and clinical complications at the first assessment. Body weight and blood pressure were measured by 98.5% of participants and 82% calculate body mass index (BMI), while a small proportion of PCPs analysed body composition and fat distribution. Over 80% prescribed laboratory tests and ECG. Approximately 40% of PCPs did not refer patients for nutritional counselling, and most prescribed a low-calorie diet. Sixty-three percent referred patients to an endocrinologist, 48.5% to a psychotherapist, and a minority to specialists for obesity complications. Twenty-three percent prescribed anti-obesity medications and 46.5% referred patients for bariatric surgery only in severe cases. Ninety-one percent stated that obesity is "a complex and multifactorial disease" and 7.4% considered obesity to be secondary to other conditions. Conclusions: Despite most PCPs adopt a correct approach to manage patients with obesity, many aspects could be improved to ensure optimal and multidisciplinary management.

MG53 marks poor beta cell performance and predicts onset of type 2 diabetes in subjects with different degrees of glucose tolerance.

AIM: MG53 is a myokine modulating insulin signaling in several tissues; its relationship to glucose tolerance or risk of developing type 2 diabetes mellitus (T2DM) is unknown. This observational, prospective study aimed at evaluating the relationship between MG53 and glucose tolerance, testing whether its circulating levels may be associated with disease progression in a cohort at high risk of T2DM. METHODS: Five hundred and fifteen subjects who underwent a deep characterization of their glucose tolerance in the years 2003-2005 participated in this study. MG53 levels were measured at baseline. Glucose tolerance status was available over a follow-up of 15 ± 2 years for 283 of them; their vital status as of December 2020 was also retrieved. RESULTS: MG53 levels were significantly lower in subjects with normal glucose tolerance than in subjects with impaired glucose regulation (IGR) or T2DM. Individuals in the highest MG53 levels quartile had more frequently 1h-post load glucose ≥ 155 mg/dL (54% vs 39%; p = 0.015), worse proportional control of ß-cell function (p < 0.05-0.01), as determined by mathematical modeling, and worse Disposition Index (DI) (0.0155 ± 0.0081 vs 0.0277 ± 0.0030; p < 0.0001). At follow-up, baseline MG53 levels were higher in progressors than in non-progressors (120.1 ± 76.7 vs 72.7 ± 63.2 pg/ml; p = 0.001; ROC curve area for incident diabetes of 0.704). In a multivariable regression with classic risk factors for T2DM and DI, MG53 remained independently associated with progression with T2DM. CONCLUSION: MG53 may be a novel biomarker of glucose dysregulation associated with ß-cell dysfunction, likely improving our ability to identify, among high-risk subjects, those more likely to develop T2DM.

A Novel Algorithm for the Evaluation of Corneal Nerve Beadings by in vivo Confocal Microscopy in Patients With Type 1 Diabetes Mellitus.

Purpose: Peripheral neuropathy could complicate diabetes mellitus (DM). In vivo confocal microscopy (IVCM) is an ocular examination for the diagnosis of small fiber neuropathies and the detection of the earliest corneal sub-basal nerve plexus (SBP) alterations. Corneal SBP characteristics include focal enlargement along with the nerve fiber, called corneal beadings. These dilatations represent a mitochondrial accumulation induced by the reactive oxygen stress, as a consequence of hyperglycemia. For this reason, corneal beadings are considered indicative of metabolic activity. This study aimed to describe the corneal characteristics of a population of type 1 diabetes mellitus (T1DM) well metabolically controlled, using a new algorithm for the analysis of corneal beading size (BS). Methods: Patients aged ≥18 years affected by T1DM were compared with healthy subjects who underwent IVCM (Confoscan 4; Nidek Technologies Padova, Italy). Starting from the coordinates of the beadings detected by the IVCM, we implemented a new algorithm for automatically measuring BS in corneal SBP images. Results: We compared 20 eyes of T1DM patients with 26 healthy controls. The corneal nerves' fiber length (p = 0.008), corneal nerves' fiber length density (p = 0.008), and the number of fibers (p = 0.017) were significantly lower in the diabetic group compared with controls. There was no difference between diabetic and healthy eyes in the mean number of corneal beadings both in the frame of analysis (p = 0.606) and for 0.1 mm of SBP nerve (p = 0.145). Regarding the BS, patients with T1DM had corneal beadings larger than controls (p = 0.036). Conclusions: We found that the corneal beadings parameters are similar in healthy and T1DM individuals. Nevertheless, measuring the BS with our algorithm, we showed that corneal beadings are enlarged in patients affected by T1DM when compared with healthy controls. Identifying beading expansion in corneal nerve fiber using IVCM should become a useful tool to predict peripheral neuropathy at an early stage.

Advice of General Practitioner, of Surgeon, of Endocrinologist, and Self-determination: the Italian Road to Bariatric Surgery.

PURPOSE: Bariatric surgery (BS) is considered the most efficient treatment for severe obesity. International guidelines recommend multidisciplinary approach to BS (general practitioners, endocrinologists, surgeons, psychologists, or psychiatrists), and access to BS should be the final part of a protocol of treatment of obesity. However, there are indications that general practitioners (GPs) are not fully aware of the possible benefits of BS, that specialty physicians are reluctant to refer their patients to surgeons, and that patients with obesity choose self-management of their own obesity, including internet-based choices. There are no data on the pathways chosen by physicians and patients to undergo BS in the real world in Italy. METHODS: An exploratory exam was performed for 6 months in three pilot regions (Lombardy, Lazio, Campania) in twenty-three tertiary centers for the treatment of morbid obesity, to describe the real pathways to BS in Italy. RESULTS: Charts of 2686 patients (788 men and 1895 women, 75.5% in the age range 30-59 years) were evaluated by physicians and surgeons of the participating centers. A chronic condition of obesity was evident for the majority of patients, as indicated by duration of obesity, by presence of several associated medical problems, and by frequency of previous dietary attempts to weight loss. The vast majority (75.8%) patients were self-presenting or referred by bariatric surgeons, 24.2% patients referred by GPs and other specialists. Self-presenting patients were younger, more educated, more professional, and more mobile than patients referred by other physicians. Patients above the age of 40 years or with a duration of obesity greater than 10 years had a higher prevalence of all associated medical problems. CONCLUSIONS: The majority of patients referred to a tertiary center for the treatment of morbid obesity have a valid indication for BS. Most patients self-refer to the centers, with a minority referred by a GP or by specialists. Self-presenting patients are younger, more educated, more professional, and more mobile than patients referred by other physicians. Older patients and with a longer duration of obesity are probably representative of the conservative approach to BS, often regarded as the last resort in an endless story.

Methods of investigation for cardiac autonomic dysfunction in human research studies.

This consensus document provides evidence-based guidelines regarding the evaluation of diabetic cardiovascular autonomic neuropathy (CAN) for human research studies; the guidelines are the result of the work of the CAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group. The subcommittee critically reviewed the limitations and strengths of the available diagnostic approaches for CAN and the need for developing new tests for autonomic function. It was concluded that the most sensitive and specific approaches currently available to evaluate CAN in clinical research are: (1) heart rate variability, (2) baroreflex sensitivity, (3) muscle sympathetic nerve activity, (4) plasma catecholamines, and (5) heart sympathetic imaging. It was also recommended that efforts should be undertaken to develop new non-invasive and safe CAN tests to be used in clinical research, with higher sensitivity and specificity, for studying the pathophysiology of CAN and evaluating new therapeutic approaches.

Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.

The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non-dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost-effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN.

Metformin Benefits: Another Example for Alternative Energy Substrate Mechanism?

Since the UK Prospective Diabetes Study (UKPDS), metformin has been considered the first-line medication for patients with newly diagnosed type 2 diabetes. Though direct evidence from specific trials is still lacking, several studies have suggested that metformin may protect from diabetes- and nondiabetes-related comorbidities, including cardiovascular, renal, neurological, and neoplastic diseases. In the past few decades, several mechanisms of action have been proposed to explain metformin's protective effects, none being final. It is certain, however, that metformin increases lactate production, concentration, and, possibly, oxidation. Once considered a mere waste product of exercising skeletal muscle or anaerobiosis, lactate is now known to act as a major energy shuttle, redistributed from production sites to where it is needed. Through the direct uptake and oxidation of lactate produced elsewhere, all end organs can be rapidly supplied with fundamental energy, skipping glycolysis and its possible byproducts. Increased lactate production (and consequent oxidation) could therefore be considered a positive mechanism of action of metformin, except when, under specific circumstances, metformin and lactate become excessive, increasing the risk of lactic acidosis. We are proposing that, rather than considering metformin-induced lactate production as dangerous, it could be considered a mechanism through which metformin exerts its possible protective effect on the heart, kidneys, and brain and, to some extent, its antineoplastic action.

Neuropathic damage in the diabetic eye: clinical implications.

In recent years, emerging evidence support that the eye is target of diabetes neuropathy. There are two components of the eye that are mainly involved in the neurodegenerative process induced by diabetes: the retina and the cornea. The study of functional and structural changes in these components of the eye will provide useful information to identify subjects with diabetes at risk of diabetic peripheral neuropathy and dementia. In this review the state of the art regarding the evidence and clinical implications of this emerging concept will be provided. In addition, the relationship between retinal and corneal neurodegeneration with peripheral neuropathy and cognitive decline will be analyzed. Finally, the scientific gaps than need to be covered and will be critically examined.

Microvascular impairment as a biomarker of diabetic retinopathy progression in the long-term follow up in type 1 diabetes.

This study aimed to explore differences in vascular and structural parameters using optical coherence tomography angiography in patients with type 1 diabetes (DM1) with mild signs of diabetic retinopathy (DR) over a two-year follow-up period. Parafoveal vessel density (PVD) and foveal avascular zone (FAZ) area were analyzed. The thickness of three predefined retinal slabs was measured, including the inner limiting membrane (ILM)-inner plexiform layer (IPL), IPL-inner nuclear layer (INL), and the IPL-outer nuclear layer (ONL). Twenty-two patients with DM1 and 21 controls were included. There was no significant difference in the FAZ area, perimeter and acircularity index between cohorts over time. Baseline superficial capillary plexus PVD was approximately 10% lower in patients with diabetes than in controls (p = 0.001), and was 12% lower at 2 years (p = 0.002). There was no difference in the annual linear trend between the groups (- 0.5% in diabetics vs. controls, p = 0.736). Baseline deep capillary plexus (DCP) PVD was slightly lower in diabetics than in controls (- 4.4%, p = 0.047) and the difference increased at 2 years (- 12.6%, p < 0.001). The annual linear trend was - 2.7% in diabetic patients compared to controls (p = 0.009). In addition, the PVD of the DCP and the intermediate capillary plexus (ICP) were evaluated separately. Regarding the DCP PVD, no statistically significant difference at any time points in diabetic patients compared to controls and no statistically significant difference in the linear trend was found (p > 0.1). Conversely, no difference was recorded for parafoveal ICP density at individual time points (p > 0.1), but a statistically significant difference in the linear trend over time in diabetic patients compared to controls was recoded (- 3.2% per year, p = 0.001). Despite the apparent intergroup differences at baseline in structural OCT parameters, the differences including ILM-IPL (p = 0.273), IPL-INL (p = 0.708), and IPL-ONL (p = 0.054) were modest and not statistically significant with time. Therefore, the microvascular change of the deeper vessels might be a robust biomarker to evaluate the clinical progression of DR in DM1.

Activation of retinal Müller cells in response to glucose variability.

PURPOSE: In the earliest stages of diabetic retinopathy (DR), a dysfunction of Müller cells, characterized by high levels of glial fibrillary acidic protein (GFAP), and aquaporins (AQP), has been observed. Although chronic hyperglycemia causes the activation of Müller cells, the effect of glycemic fluctuations is yet unknown. The aim of the study was to analyze the impact of glucose variability on rat retinal Müller cells (rMC-1) adapted to either normal (5 mM) or high (25 mM) glucose levels. METHODS: rMC-1 were cultured in a medium containing either 5 mM (N cells) or 25 mM of glucose (H cells) and then incubated for 96 h in a medium containing (a) low glucose (either 1-3 or 5 mM), (b) basal glucose (either 5 or 25 mM), (c) high glucose (either 25 or 45 mM), (d) basal and high glucose alternated every 24 h; (e) low- and high glucose alternated every 24 h; (f) basal glucose with episodes of low glucose for 30 min twice a day. Müller cells activation was evaluated by measuring the levels of GFAP, AQP4, and phospho-active extracellular signal-regulated kinase (pERK). RESULTS: Under both basal and high glucose concentrations rMC-1 were viable, but their response to glucose excursions was different. In N cells kept under normal (5 mM) glucose, a significant glial activation was measured not only in response to constant high glucose but also to alternating low/high glucose. In H cells, adapted to 25 mM glucose, a significant response was observed only after exposition to a lower (5 mM) glucose concentration. CONCLUSION: Our results highlight Müller cells activation in response to glucose variability and a different susceptibility depending on the basal glucose conditions.