Early Treatment of Acute Stage 0/1 Diabetic Charcot Foot Can Avoid Major Amputations at One Year.

Background: If unrecognized, Charcot neuro-osteoarthropathy (CNO) can be a devastating complication of diabetes. Methods: The aim of this retrospective study was to evaluate the outcomes in a cohort of diabetic patients diagnosed with active CNO managed in a tertiary level diabetic foot clinic (DFC). We included consecutive patients with active CNO, stage 0-1, according to the Eichenholtz-Shibata classification, who were referred from 1 January 2019 to 27 September 2022. Diagnosis of CNO was based on clinical signs and imaging (X-rays and magnetic resonance). All patients were completely offloaded by a total-contact cast (TCC) or removable knee-high device. Each patient was closely monitored monthly until CNO remission or another outcome. At 12 months of follow-up, the following outcomes were analyzed: remission, time to remission, major amputations (any above the ankle), and surgical indication. Results: Forty-three patients were included. The mean age was 57.6 ± 10.8 years; 65% were males and 88.4% had type 2 diabetes, with a mean duration of 20.6 ± 9.9 years. At baseline, 32.6% was affected by peripheral artery disease. Complete remission was recorded in 40/43 patients (93%), with a mean time to remission of 5.6 ± 1.5 months; major amputation and surgical indication occurred, respectively in 1/43 patients (2.3%) and 3/43 patients (7%). Conclusions: Early treatment of active Stage 0/1 CNO leads to high rates of remission and limb salvage.

Omega-3-Enriched Diet Improves Metabolic Profile in Prdx6-Deficient Mice Exposed to Microgravity.

BACKGROUND: Space travel has always been one of mankind's greatest dreams. Thanks to technological innovation, this dream is becoming more of a reality. Soon, humans (not only astronauts) will travel, live, and work in space. However, a microgravity environment can induce several pathological alterations that should be, at least in part, controlled and alleviated. Among those, glucose homeostasis impairment and insulin resistance occur, which can lead to reduced muscle mass and liver dysfunctions. Thus, it is relevant to shed light on the mechanism underlaying these pathological conditions, also considering a nutritional approach that can mitigate these effects. METHODS: To achieve this goal, we used Prdx6-/- mice exposed to Hindlimb Unloading (HU), a well-established experimental protocol to simulate microgravity, fed with a chow diet or an omega-3-enriched diet. RESULTS: Our results innovatively demonstrated that HU-induced metabolic alterations, mainly related to glucose metabolism, may be mitigated by the administration of omega-3-enriched diet. Specifically, a significant improvement in insulin resistance has been reported. CONCLUSIONS: Although preliminary, our results highlight the importance of specific nutritional approaches that can alleviate microgravity-induced harmful effects. These findings should be considered soon by those planning trips around the earth.

Hospital Readmission in Patients With Diabetic Foot Ulcers: Prevalence, Causes, and Outcomes.

The aim of the current study was to evaluate the rate of readmission in patients affected by diabetes and foot ulcers (DFUs), and causes and outcomes of patients requiring a new hospitalization. The current study is a retrospective observational study including patients who have required hospitalization since January 2019 to September 2022 due to a DFU. Once patients were discharged, they were regularly followed as outpatients. Within 6 months of follow-up, the rate of hospital readmission for a diabetic foot problem was recorded. According to the readmission or not, patients were divided into 2 groups, readmitted and not readmitted patients, respectively. Hence, all patients were followed for 6 months more and outcomes of the 2 groups were analyzed and compared. Overall, 310 patients were included. The mean age was 68 ± 12 years, the majority of patients reported type 2 diabetes (>90%), and the mean diabetes duration was approximately 20 years. Sixty-eight (21.9%) patients were readmitted. The main reason for hospital readmission was the presence of critical limb ischemia (CLI) in the contralateral limb (6.1%), the recurrence of CLI in the previous treated limb (4.5%), and the onset of new infected DFU in the contralateral foot (4.5%). Readmitted patients reported lower rate of healing (51.5% vs 89.2%, P < .0001) and higher rate of major amputation (10.3% vs 4.5%, P = .2) in comparison to not readmitted patients. Critical limb ischemia resulted in the only independent predictor of hospital readmission. Hospital readmission is a frequent issue among patients with DFUs, and readmitted patients showed a lower chance of wound healing. Critical limb ischemia resulted in the main cause of new hospitalization.

Peripheral Blood Mononuclear Cells: A New Frontier in the Management of Patients with Diabetes and No-Option Critical Limb Ischaemia.

The current study aimed to evaluate the effectiveness of peripheral blood mononuclear cell (PB-MNC) therapy as adjuvant treatment for patients with diabetic foot ulcers (DFUs) and no-option critical limb ischaemia (NO-CLI). The study is a prospective, noncontrolled, observational study including patients with neuro-ischaemic DFUs and NO-CLI who had unsuccessful revascularization below the ankle (BTA) and persistence of foot ischaemia defined by TcPO2 values less than 30 mmHg. All patients received three cycles of PB-MNC therapy administered through a "below-the-ankle approach" in the affected foot along the wound-related artery according to the angiosome theory. The primary outcome measures were healing, major amputation, and survival after 1 year of follow-up. The secondary outcome measures were the evaluation of tissue perfusion by TcPO2 and foot pain defined by the numerical rating scale (NRS). Fifty-five patients were included. They were aged >70 years old and the majority were male and affected by type 2 diabetes with a long diabetes duration (>20 years); the majority of DFUs were infected and nearly 90% were assessed as gangrene. Overall, 69.1% of patients healed and survived, 3.6% healed and deceased, 10.9% did not heal and deceased, and 16.4% had a major amputation. At baseline and after PB-MNC therapy, the TcPO2 values were 17 ± 11 and 41 ± 12 mmHg, respectively (p < 0.0001), while the pain values (NRS) were 6.8 ± 1.7 vs. 2.8 ± 1.7, respectively (p < 0.0001). Any adverse event was recorded during the PB-MNC therapy. Adjuvant PB-MNC therapy seems to promote good outcomes in patients with NO-CLI and neuro-ischaemic DFUs.

Prevalence and risk of new-onset diabetes mellitus after COVID-19: a systematic review and meta-analysis.

Aims: After the acute phase of SARS-CoV-2 infection, the onset of glycemic impairment and diabetes have been reported. Nevertheless, the exact burden of glycemic impairment and diabetes after COVID-19 has not been clearly described. Materials and methods: Electronic search was run in Pubmed (MEDLINE), Web of Science, Scopus, and ClinicalTrial.org for reports published from database inception to September 2022. We included observational studies reporting quantitative data on diabetes prevalence or its onset in subjects with a history of SARS-CoV-2 infection from at least 60 days. Risk of bias was assessed by the JBI's critical appraisal checklist. Random effect model was used to calculate pooled data. The review protocol was registered on PROSPERO (CRD42022310722). Results: Among 1,630 records screened, 20 studies were included in the analysis. The mean or median age of participants ranged from ~ 35 to 64 years, with a percentage of males ranging from 28% to 80%. Only two studies were considered at low risk of bias. The estimate of diabetes prevalence, calculated on a total of 320,948 participants pooled with 38,731 cases, was 16% (95%CI: 11-22%). The estimate of proportion of incident cases of diabetes was 1.6% (95%CI: 0.8-2.7%). Subgroup analysis showed that previous hospitalization increased the prevalence of diabetes and the proportion of incident cases. Conclusion: Diabetes is common in individuals who have experienced SARS-CoV-2 infection, especially if they required hospitalization. This data may be helpful to screen for diabetes and manage its complications in individuals who experienced COVID-19. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022310722, identifier CRD42022310722.

A multidisciplinary team reduces in-hospital clinical complications and mortality in patients with diabetic foot ulcers.

AIMS: The current study aims to evaluate the effectiveness of a multidisciplinary diabetic foot team (MDFT) in the management of in-patients affected by diabetic foot problems. MATERIALS AND METHODS: The study was a retrospective observational study. Consecutive patients with a diabetic foot problem requiring hospitalisation were included. All patients were managed by a MDFT led by diabetologists according to the guidance. The rate of in-hospital complications (IHCs), major amputation, and survival were recorded at the end of patient's hospitalisation. IHC was defined as any new infection different from wound infection, cardiovascular events, acute renal injury, severe anaemia requiring blood transfusion, and any other clinical problem not present at the assessment. RESULTS: Overall, 350 patients were included. The mean age was 67.9 ± 12.6 years, 254 (72.6%) were males, 323 (92, 3%) showed Type 2 diabetes with a mean duration of 20.2 ± 9.6 years; 224 (64%) had ischaemic diabetic foot ulcers (DFUs) and 299 (85.4%) had infected DFUs. IHCs were recorded in 30/350 (8.6%) patients. The main reasons for IHCs were anaemia requiring blood transfusion (2.8%), pneumonia (1.7%), acute kidney failure (1.1%). Patients with IHCs showed a higher rate of major amputation (13.3 vs. 3.1%, p = 0.02) and mortality (16.7 vs. 0.6%, p < 0.0001) in comparison to those without. Ischaemic heart disease (IHD) and wound duration at the assessment (>1 month) were independent predictors of IHC, whereas IHCs, heart failure, and dialysis were independent predictors of in-hospital mortality. CONCLUSIONS: The multidisciplinary management of diabetic foot problems leads to an IHC rate of 8%. The risk of IHCs is higher in patients with IHD and long wound duration.

Surgical treatment of post-menopausal ovarian hyperandrogenism improves glucometabolic profile alongside clinical hirsutism.

Hyperandrogenism during menopause is often underestimated by clinicians and attributed to the natural aging process. Hyperandrogenism can be associated with some metabolic abnormalities linked together in a vicious circle by insulin resistance. We present the case of an elderly woman affected with type 2 diabetes and obesity who reported the occurrence of clinical hirsutism after physiological menopause at the age of 47 years. At presentation, physical examination and Ferriman-Gallwey score revealed a condition of moderate hirsutism, with markedly increased levels of plasma testosterone and delta-4-androstenedione, obesity (body mass index 31.9), and inadequate glycemic control (glycated hemoglobin 65 mmol/mol). The patient underwent a thorough differential diagnosis by a multidisciplinary team approach, including the various causes of hyperandrogenism during menopause. After choosing surgical option as the appropriate treatment, clinical resolution of hirsutism was observed alongside patient satisfaction and marked improvement of the glucometabolic profile.

Glucose variability: a new risk factor for cardiovascular disease.

AIMS AND DATA SYNTHESIS: Glucose variability (GV) is increasingly considered an additional index of glycemic control. Growing evidence indicates that GV is associated with diabetic vascular complications, thus being a relevant point to address in diabetes management. GV can be measured using various parameters, but to date, a gold standard has not been identified. This underscores the need for further studies in this field also to identify the optimal treatment. CONCLUSIONS: We reviewed the definition of GV, the pathogenetic mechanisms of atherosclerosis, and its relationship with diabetic complications.

Microbiological and Clinical Characteristics of Infected Diabetic Foot Ulcers Managed in a Tertiary Level Diabetic Foot Service.

The study aimed to evaluate the clinical and microbiological characteristics of diabetic foot infections (DFIs) in patients referring to a specialized diabetic foot service (DFS). The study is a retrospective observational study conducted in a single center, including patients who were referred for a new DFI. All patients were managed through a limb salvage protocol according to international guidelines. The following items were recorded: type of bacteria, presence of single or polymicrobial infection, and the antibiotic resistance. Overall, 268 patients were included. The mean age was 68.9 ± 10.9 years, 75% were male, and 97.2% had type 2 diabetes with a mean diabetes duration of 16 ± 9 years. One hundred thirty-nine (51.9%) DFU were ischemic, 120 (44.7%) patients had osteomyelitis, 107 (39.9%) had gangrene, 37 (13.9%) had phlegmon/abscess/cellulitis and 4 (1.5%) had necrotizing fasciitis. Among 370 bacteria isolated, gram positive were found in 207 (55.9%) cases, and gram negative in 163 (44.1%) cases. The higher rates of isolates were Staphylococcus aureus (32.9%), Pseudomonas aeruginosa (10.8%), and Enterococcus faecalis (8.9%). Polymicrobial infection was reported in 33.6% of cases and antibiotic resistance was recorded in 16.5% of isolates. Among them, 10.3% were methicillin-resistant S. aureus (MRSA). Antibiotic resistance was detected in 40.9% of cases in association with gangrene and osteomyelitis. The current study shows as polymicrobial infections and antibiotic resistance is frequently reported in DFIs, and antibiotic resistance was more associated with gangrene and osteomyelitis. Among bacteria reporting antimicrobial resistance, the highest rate was found for MRSA.

Recent Pharmacological Options in Type 2 Diabetes and Synergic Mechanism in Cardiovascular Disease.

Diabetes Mellitus is a multifactorial disease with a critical impact worldwide. During prediabetes, the presence of various inflammatory cytokines and oxidative stress will lead to the pathogenesis of type 2 diabetes. Furthermore, insulin resistance and chronic hyperglycemia will lead to micro- and macrovascular complications (cardiovascular disease, heart failure, hypertension, chronic kidney disease, and atherosclerosis). The development through the years of pharmacological options allowed us to reduce the persistence of chronic hyperglycemia and reduce diabetic complications. This review aims to highlight the specific mechanisms with which the new treatments for type 2 diabetes reduce oxidative stress and insulin resistance and improve cardiovascular outcomes.

Hypocalcemia is associated with adverse outcomes in patients hospitalized with COVID-19.

PURPOSE: Calcium ions are involved in the regulation of several cellular processes and may also influence viral replication. Hypocalcemia has been frequently reported during infectious diseases and in critically ill patients, including also COVID-19 patients, significantly related with the pro-inflammatory state and mortality. The aim of this study is to investigate the prevalence of hypocalcemia at admission in patients hospitalized for COVID-19 (Coronavirus disease 2019) and to evaluate association of hypocalcemia with in-hospital COVID-19 outcomes. METHODS: Retrospective analysis on 118 consecutive patients, hospitalized for COVID-19 between March and May 2020. Clinical characteristics, inflammation markers, biochemical routine and mineral metabolism parameters at admission were collected. Hypocalcemia was defined as total serum calcium <2.2 mmol/L. Population was stratified by tertiles of total serum calcium. Primary outcome was the composite of in-hospital death or admission to intensive care unit (ICU). Secondary outcomes included in-hospital death, admission to ICU and need for non-invasive ventilation as separate events. Associations were tested by logistic regression and Cox-regression analysis with survival curves. RESULTS: Overall prevalence of hypocalcemia was 76.6%, with just 6.7% of patients reporting levels of 25-(OH)-vitamin D > 30 ng/ml. Total serum calcium was inversely related with selected inflammatory biomarkers (p < 0.05) and poorer outcome of COVID-19 during hospitalization. Lower tertile of total calcium (≤2.02 mmol/L) had increased risk of in-hospital mortality (HR 2.77; 1.28-6.03, p = 0.01) compared with other groups. CONCLUSION: Total serum calcium detected on admission is inversely related with proinflammatory biomarkers of severe COVID-19 and is useful to better define risk stratification for adverse in-hospital outcome.

The Impact of Diet and Physical Activity on Fat-to-Lean Mass Ratio.

In this retrospective study, we evaluated the efficacy of a personalised low-calorie Mediterranean Diet (MD) in promoting fat mass (FM) reduction while preserving fat-free mass (FFM). This study involved 100 Caucasian adults aged 18-65 years who followed a tailored low-calorie MD for two months. The total energy expenditure was assessed using a multi-sensor armband. The change in body composition (BC) was evaluated using the Δ% FM-to-FFM ratio, calculated as the difference in the FM to FFM ratio before and after the diet, divided by the ratio before the diet, and multiplied by 100. A negative value indicates a greater decrease in FM than FFM, while a positive value suggests a greater increase in FM than FFM. This study demonstrated a significant FM reduction, with an average decrease of 5% (p < 0.001). However, the relationship between caloric reduction and the Δ% FM-to-FFM ratio showed a weak negative correlation (r = -0.03, p > 0.05). This suggests that the calorie deficit had a minimal direct impact on the BC changes. Subjects over the age of 30 showed an increase in muscle mass, while younger subjects showed no significant changes. Moreover, a direct correlation was observed between the changes in MET (Metabolic Equivalent of Task) values and the Δ% FM-to-FFM ratio, indicating that improved average physical activity intensity positively influences BC. In the female subgroup, high protein intake, exercise intensity, and the duration of physical activity were positively correlated with an improvement in the Δ% FM-to-FFM ratio. However, for individuals with BMI 20-25 kg/m2, high fibre intake was surprisingly negatively correlated with the Δ% FM-to-FFM ratio. This study underscores the intricate interplay between calorie restriction, physical activity intensity, and BC changes. It also suggests that individual factors, including age, gender, and BMI, may influence the response to a low-calorie MD. However, further prospective studies with larger sample sizes are necessary to confirm and expand upon these findings.

Treatment of HFpEF beyond the SGLT2-Is: Does the Addition of GLP-1 RA Improve Cardiometabolic Risk and Outcomes in Diabetic Patients?

Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, and so on. It is a multifactorial disease with different phenotypic aspects that share left ventricular diastolic dysfunction, and is the cause of about 50% of hospitalizations for heart failure in the Western world. Due to the complexity of the disease, no specific therapies have been identified for a long time. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2-Is) and Glucagon-Like Peptide Receptor Agonists (GLP-1 RAs) are antidiabetic drugs that have been shown to positively affect heart and kidney diseases. For SGLT2-Is, there are precise data on their potential benefits in heart failure with reduced ejection fraction (HFrEF) as well as in HFpEF; however, insufficient evidence is available for GLP-1 RAs. This review addresses the current knowledge on the cardiac effects and potential benefits of combined therapy with SGLT2-Is and GLP-1RAs in patients with HFpEF.

The Neuro-Ischaemic Charcot Foot: Prevalence, Characteristics and Severity of Peripheral Arterial Disease in Acute Charcot Neuro-Arthropathy.

The study aimed to evaluate the prevalence, characteristics and outcomes of patients affected by Charcot neuro-arthropathy (CN) and peripheral arterial disease (PAD) compared to CN without PAD. Consecutive patients presenting with an acute CN were included. The sample size was calculated by the power analysis by adopting the two-tailed tests of the null hypothesis with alfa = 0.05 and a value of beta = 0.10 as the second type error and, therefore, a test power equal to 90%. Seventy-six patients were identified. Twenty-four patients (31.6%) had neuro-ischaemic CN; they were older (66 vs. 57yrs), p = 0.03, had a longer diabetes duration (19 vs. 14yrs), p < 0.001, and more cases of end-stage-renal-disease (12.5 vs. 0%), p = 0.04 and ischaemic heart disease (58.3 vs. 15.4%), p < 0.0001 than neuropathic CN. Fifty patients (65.8%) had concomitant foot ulcers, 62.5% and 67.3% (p = 0.3), respectively, in CN with and without PAD. Neuro-ischaemic CN show arterial lesions of 2.9 vessels, and PAD was located predominantly below-the-knee (75%) but not below-the-ankle (16.7%). The outcomes for neuro-ischaemic and neuropathic CN patients were, respectively: wound healing (86.7 vs. 94.3%), p = 0.08; minor amputation (25 vs. 7.7%), p = 0.003; major amputation (8.3 vs. 1.9%), p = 0.001; hospitalization (75 vs. 23%), p = 0.0001. The study showed a frequent association between CN and PAD, leading to a neuro-ischaemic Charcot foot type. Neuro-ischaemic CN leaded to an increased risk of minor and major amputation and hospitalization, compared to neuropathic CN.

The New Role of SGLT2 Inhibitors in the Management of Heart Failure: Current Evidence and Future Perspective.

The sodium-glucose transporter 2 inhibitors (SGLT2i) are a relatively new class of medication used in the management of type 2 diabetes. Recent clinical trials and research have demonstrated this class's effectiveness in treating heart failure, since they reduce the risk of cardiovascular events, hospitalization, and mortality. The mechanism by which they do so is unclear; however, SGLT2i inhibit the tubular reabsorption of glucose, lowering the interstitial volume. This mechanism leads to a reduction in blood pressure and an improvement of endothelial function. As a result, improvements in hospitalization and mortality rate have been shown. In this review, we focus on the primary outcome of the clinical trials designed to investigate the effect of SGLT2i in heart failure, regardless of patients' diabetic status. Furthermore, we compare the various SGLT2i regarding their risk reduction to investigate their potential as a treatment option for patients with reduced ejection fraction and preserved ejection fraction.

Below-the-ankle arterial disease: a new marker of coronary artery disease in patients with diabetes and foot ulcers.

AIM: The aim of the current study is to evaluate the association between below-the-ankle (BTA) arterial disease and coronary artery disease (CAD) in patients with diabetic foot ulcers (DFUs). METHODS: The study group was composed of patients with an active neuro-ischaemic DFUs managed in a tertiary care diabetic foot clinic. All patients received a pre-set limb salvage protocol including lower limb revascularization. By a retrospective analysis of individual angiograms, patients were divided in two groups: below-the-ankle (BTA) and above-the-ankle (ATA) arterial disease groups. The rate of CAD at baseline assessment and the new events of acute myocardial ischaemia (AMI) during 1-year of follow-up were evaluated and compared between the two groups. RESULTS: Two hundreds seventy-two (272) patients were included, 120 (44.1%) showed BTA arterial disease while 152 (55.9%) ATA arterial disease. The mean age was 68.9 ± 9.6 years, 198 (72.8%) were male, 246 (90.4%) had type 2 diabetes, the mean diabetes duration was 20.7 ± 11.6 years, the mean HbA1c was 7.8 ± 4.2% (62 ± 22 mmmol/mol). The whole population reported CAD in 172 cases (63.4%), and the rate in the BTA group was significantly higher than in ATA group, respectively, 90 (75.4%) vs 82 (54.1%), p < 0.0001. During the follow-up, BTA group had 5% of new cases of AMI in comparison to 1.3% in ATA group (p < 0.001). At the multivariate analysis BTA resulted an independent marker of CAD [OR 1.9 CI 9 5% (1.3-4.5) p = 0.0001]. CONCLUSION: The current study shows a significant association between BTA arterial disease and CAD. A close cardiovascular screen should be required in patients with DFUs.

Diabetes and cognitive decline.

Epidemiologic studies have documented an association between diabetes and increased risk of cognitive decline in the elderly. Based on animal model studies, several mechanisms have been proposed to explain such an association, including central insulin signaling, neurodegeneration, brain amyloidosis, and neuroinflammation. Nevertheless, the exact mechanisms in humans remain poorly defined. It is reasonable, however, that many pathways may be involved in these patients leading to cognitive impairment. A major aim of clinicians is identifying early onset of neurologic signs and symptoms in elderly diabetics to improve quality of life of those with cognitive impairment and reduce costs associated with long-term complications. Several biomarkers have been proposed to identify diabetics at higher risk of developing dementia and diagnose early stage dementia. Although biomarkers of brain amyloidosis, neurodegeneration and synaptic plasticity are commonly used to diagnose dementia, especially Alzheimer disease, their role in diabetes remains unclear. The aim of this review is to explore the molecular mechanisms linking diabetes with cognitive decline and present the most important findings on the clinical use of biomarkers for diagnosing and predicting early cognitive decline in diabetics.

Influence of Nutritional Status and Physical Exercise on Immune Response in Metabolic Syndrome.

Metabolic Syndrome (MetS) is a cluster of metabolic alterations mostly related to visceral adiposity, which in turn promotes glucose intolerance and a chronic systemic inflammatory state, characterized by immune cell infiltration. Such immune system activation increases the risk of severe disease subsequent to viral infections. Strong correlations between elevated body mass index (BMI), type-2-diabetes and increased risk of hospitalization after pandemic influenza H1N1 infection have been described. Similarly, a correlation between elevated blood glucose level and SARS-CoV-2 infection severity and mortality has been described, indicating MetS as an important predictor of clinical outcomes in patients with COVID-19. Adipose secretome, including two of the most abundant and well-studied adipokines, leptin and interleukin-6, is involved in the regulation of energy metabolism and obesity-related low-grade inflammation. Similarly, skeletal muscle hormones-called myokines-released in response to physical exercise affect both metabolic homeostasis and immune system function. Of note, several circulating hormones originate from both adipose tissue and skeletal muscle and display different functions, depending on the metabolic context. This review aims to summarize recent data in the field of exercise immunology, investigating the acute and chronic effects of exercise on myokines release and immune system function.

Peroxiredoxin 6 Modulates Insulin Secretion and Beta Cell Death via a Mitochondrial Dynamic Network.

In pancreatic beta cells, mitochondrial metabolism controls glucose-stimulated insulin secretion (GSIS) by ATP production, redox signaling, and calcium (Ca2+) handling. Previously, we demonstrated that knockout mice for peroxiredoxin 6 (Prdx6-/- ), an antioxidant enzyme with both peroxidase and phospholipase A2 activity, develop a mild form of diabetes mellitus with a reduction in GSIS and in peripheral insulin sensitivity. However, whether the defect of GSIS present in these mice is directly modulated by Prdx6 is unknown. Therefore, the main goal of the present study was to evaluate if depletion of Prdx6 affects directly GSIS and pancreatic beta ß-cell function. Murine pancreatic ß-cell line (ßTC6) knockdown for Prdx6 (Prdx6KD) was employed, and insulin secretion, ATP, and intracellular Ca2+ content were assessed in response to glucose stimulation. Mitochondrial morphology and function were also evaluated through electron microscopy, and by testing mitochondrial membrane potential, oxygen consumption, and mitochondrial mass. Prdx6KD cells showed a significant reduction in GSIS as confirmed by decrease in both ATP release and Ca2+ influx. GSIS alteration was also demonstrated by a marked impairment of mitochondrial morphology and function. These latest are mainly linked to mitofusin downregulation, which are, in turn, strictly related to mitochondrial homeostasis (by regulating autophagy) and cell fate (by modulating apoptosis). Following a pro-inflammatory stimulus (typical of diabetic subjects), and in agreement with the deregulation of mitofusin steady-state levels, we also observed an enhancement in apoptotic death in Prdx6KD compared to control cells. We analyzed molecular mechanisms leading to apoptosis, and we further demonstrated that Prdx6 suppression activates both intrinsic and extrinsic apoptotic pathways, ultimately leading to caspase 3 and PARP-1 activation. In conclusion, Prdx6 is the first antioxidant enzyme, in pancreatic ß-cells, that by controlling mitochondrial homeostasis plays a pivotal role in GSIS modulation.