A Breakthrough in the Treatment of Necrobiosis Lipoidica? Update on Treatment, Etiopathogenesis, Diagnosis, and Clinical Presentation.

Necrobiosis lipoidica (NL) is a rare granulomatous disease of a not fully understood etiopathogenesis. Classically, NL is associated with insulin-dependent diabetes mellitus. The disease often fails to respond to conventional treatments and adversely affects patients' quality of life. First-line medications are usually topical corticosteroids, but patients respond to them with varying degrees of success. Other options include tacrolimus, phototherapy, cyclosporine, fumaric acid esters, and biologics (adalimumab, etanercept, and infliximab). Our review aims to present new therapeutic approaches potentially effective in patients with refractory lesions, describe the presumed etiopathogenesis, and provide diagnostic guidance for clinicians. The review concludes that Janus kinase inhibitors and biologics such as ustekinumab and secukinumab can be used effectively in patients with recalcitrant NL. Another promising treatment option is tapinarof (an aryl hydrocarbon receptor agonist). However, studies on larger groups of patients are still needed to evaluate the effectiveness of different therapeutic options and to define consistent treatment regimens for NL. It is advisable to improve the awareness of physicians of various specialties regarding necrobiosis lipoidica as lesions diagnosed earlier usually have a better response to treatment.

High dose cholecalciferol supplementation causing morning blood pressure reduction in patients with type 1 diabetes mellitus and cardiovascular autonomic neuropathy.

We evaluated the association of cardiovascular autonomic neuropathy (CAN), blood pressure (BP) and Vitamin D (VD) levels before and after high-dose cholecalciferol supplementation (4000/10,000) UI/day) for 12 weeks in patients (N = 67) with type 1 diabetes mellitus (T1DM). Based on this prospective controlled pilot study, patients were divided into group 1 (N = 23 with CAN) and group 2 (N = 44 without CAN). At baseline, group 1 had higher systolic BP (SBP) during sleep (115 ± 14 vs. 107 ± 12 mmHg, p = 0.04) and lower nocturnal dipping (3 ± 5 vs. 8 ± 6%, p = 0.009). Among those with loss of nocturnal dipping, 45.4% (20/44) had CAN, while in normal nocturnal dipping group it occurred only in 13% (3/23) (p = 0.007). Non-dipper group had worse CAN parameters when compared to dipper group [Very low frequency (VLF) (2.5 ± 0.5vs.2.8 ± 0.4 s, p = 0.01), total power (TP) (2.9 ± 0.6 vs. 3.3 ± 0.4 s, p = 0.01), Valsalva coefficient (1.5 ± 0.4 vs. 1.8 ± 0.6, p = 0.06)]. After VD, only group 1 improved CAN parameters [TP (2.5 ± 0.4 vs. 2.8 ± 0.6, p = 0.01) and VLF (2.2 ± 0.4 vs. 2.4 ± 0.5, p = 0.03). Group 1 presented a reduction in morning SBP (120 ± 20 vs. 114 ± 17 mmHg, p = 0.038) and in morning SBP surge (13 ± 13 vs. 5 ± 14, p = 0.04). High-dose VD was associated with improved CAN parameters and reduced awake SBP and morning SBP surge. These findings suggest that VD may benefit patients with cardiovascular autonomic neuropathy. ISRCTN32601947, registration date: 31/07/2017.

Vitamin D insufficiency in infants with increased risk of developing type 1 diabetes: a secondary analysis of the POInT Study.

BACKGROUND: Vitamin D insufficiency (VDI) may be a factor in the development of type 1 diabetes (T1D). The aim of this study is to investigate the presence and persistence of VDI in a large cohort of infants with increased risk of developing T1D, in light of the differences in local supplementation guidelines. METHODS: In the POInT Study, a multicentre primary prevention study between February 2018 and March 2021 in Germany, Poland, Belgium, England and Sweden, including infants aged 4-7 months at high genetic risk of developing ß-cell autoantibodies, vitamin D levels were analysed at each study visit from inclusion (4-7 months) until 3 years, with an interval of 2 months (first three visits) or 4-6 months (visits 4-8). The protocol actively promotes vitamin D sufficiency to optimise immune tolerance. VDI was defined as a concentration below 30 ng/mL and was treated according to local guidelines of participating centres. Recovery from VDI was defined as a concentration above or equal to 30 ng/mL on the subsequent visit after VDI. RESULTS: 1050 infants were included, of which 5937 vitamin D levels were available for analyses. VDI was observed in 1464 (24.7%) visits and 507 (46.1%) of these were not resolved at the next visit. The risk of having VDI was independently associated with season (higher in winter), weight (higher with increased weight), age (higher with increased age) and country (higher in England). The risk of not recovering from VDI was independently associated with the season of the previously determined VDI, which was higher if VDI was identified in winter. CONCLUSIONS: VDI is frequent in infants with increased risk of developing T1D. Treatment guidelines for VDI do not seem effective. Increasing supplementation dosages in this patient population seems warranted, especially during winter, and increasing dosages more aggressively after VDI should be considered.

Peripheral fatigue regulation during knee extensor exercise in type 1 diabetes and consequences on the force-duration relationship.

PURPOSE: This study aimed to examine if peripheral fatigue is adjusted during knee extensor (KE) exercise in order not to surpass a critical threshold patient with type 1 diabetes (T1D) and the consequences of this mechanism on the force-duration relationship. METHODS: Eleven T1D individuals randomly performed two different sessions in which they performed 60 maximum voluntary contractions (MVC; 3 s contraction, 2 s relaxation). One trial was performed in the non-fatigued state (CTRL) and another after fatiguing neuromuscular stimulation of the KE (FNMES). Peripheral and central fatigue were quantified by the difference between pre and post exercise in quadriceps voluntary activation (ΔVA) and potentiated twitch (ΔPtw). Critical torque (CT) was determined as the average force of the last 12 contractions, whereas W' was calculated as the area above the CT. RESULTS: Although FNMES led to a significant decrease in potentiated twitch (Ptw) before performing the 60-MVCs protocol (p < 0.05), ΔVA (∼ -7.5%), ΔPtw (∼ -39%), and CT (∼816 N) post-MVCs were similar between the two conditions. The difference in W' between CTRL and FNMES was correlated with the level of pre-fatigue induced in FNMES (r2 = 0.60). In addition, W' was correlated with ΔPtw (r2 = 0.62) in the CTRL session. CONCLUSION: Correlative results in the present study indicate that regulating peripheral fatigue mechanisms at a critical threshold limit W'. Additionally, peripheral fatigue during KE exercise is limited to an individual threshold in T1D patients.

Ayurveda for a Type 1 Diabetes Patient with Peripheral Arterial Occlusive Disease: A Case Report.

INTRODUCTION: The effect of Ayurvedic therapy in type 2 diabetes (T2D) is well documented. For people with type 1 diabetes (T1D), there is little evidence on the applicability of Ayurvedic therapy. This case illustrates the course of Ayurvedic treatment in a person with T1D accompanied by peripheral arterial occlusive disease (PAOD). CASE PRESENTATION: The patient had insulin-dependent T1D since the age of 6 years. At 39 years of age, he developed progressive bilateral PAOD of the femoral arteries. He presented claudication symptoms at a walking distance of 150 m. Ten surgical interventions for recanalization have been performed. The PAOD put heavy psychological strains on the patient. He developed moderate depression with anxiety and complained of tinnitus and sleep disturbances. Through an initial outpatient Ayurvedic treatment mainly focused on dietary, lifestyle changes and phytotherapeutics, and a subsequent 6-week inpatient Ayurvedic treatment in India, a weight reduction of 12 kg, a reduction in insulin requirement to 65% of baseline, as well as a walking performance without restriction at a medium load could be achieved. The depression and inner tension retreated, and one-sided tinnitus and existing sleep disturbances dissolved completely. The lasting effect was still perceptible 5 months after the inpatient stay. CONCLUSIONS: For this person with T1D with PAOD, outpatient and inpatient Ayurvedic therapy could generate a significant improvement of his situation. The case demonstrates that people with T1D can benefit from using individualized Ayurvedic therapy. This case motivates to invest in Ayurvedic research for people with T1D and complications.Die Wirkung der ayurvedischen Therapie bei Typ-2-Diabetes (T2D) ist gut dokumentiert. Für Menschen mit Typ-1-Diabetes (T1D) gibt es kaum Belege für die Anwendbarkeit der ayurvedischen Therapie. Dieser Fall veranschaulicht den Verlauf einer ayurvedischen Behandlung bei einer Person mit T1D, begleitet von einer peripheren arteriellen Verschlusskrankheit (pAVK).Der Patient hatte seit seinem 6. Lebensjahr einen insulinabhängigen 'T1D'. Im Alter von 39 Jahren entwickelte er eine fortschreitende bilaterale periphere arterielle Verschlusskrankheit (pAVK) der Oberschenkelarterien. Bei einer Gehstrecke von 150 m zeigte er Claudicatio-Symptome. Es wurden 10 chirurgische Eingriffe zur Rekanalisation durchgeführt. Die pAVK stellte für den Patienten eine starke psychische Belastung dar. Er entwickelte eine mittelschwere Depression mit Angstzuständen und klagte über Tinnitus und Schlafstörungen. Durch eine erste ambulante ayurvedische Behandlung, die sich hauptsächlich auf Ernährungs-, Lebensstiländerungen und Phytotherapeutika konzentrierte, und eine anschließende 6-wöchige stationäre ayurvedische Behandlung in Indien wurde eine Gewichtsreduktion um 12 kg, eine Reduzierung des Insulinbedarfs auf 65% des Ausgangswerts sowie eine bedeutende Verbesserung der Gehstrecke erreicht. Die Depression und die innere Anspannung verschwanden, und der einseitige Tinnitus und bestehende Schlafstörungen lösten sich vollständig auf. Der nachhaltige Effekt war noch 5 Monate nach dem stationären Aufenthalt spürbar.Für diese Person mit T1D mit pAVK konnte eine ambulante und stationäre ayurvedische Therapie eine deutliche Verbesserung der Situation bewirken. Der Fall zeigt, dass Menschen mit T1D von einer individualisierten ayurvedischen Therapie profitieren können. Dieser Fall motiviert dazu, in die ayurvedische Forschung für Menschen mit T1D und Komplikationen zu investieren.

The protective effects of icariin against testicular dysfunction in type 1 diabetic mice Via AMPK-mediated Nrf2 activation and NF-κB p65 inhibition.

BACKGROUND: Owing to the early suffering age and the rising incidence of type 1 diabetes (T1D), the resulting male reproductive dysfunction and fertility decline have become a disturbing reality worldwide, with no effective strategy being available. Icariin (ICA), a flavonoid extracted from Herba Epimedium, has been proved its promising application in improving diabetes-related complications including diabetic nephropathy, endothelial dysfunction and erectile dysfunction. Ensuring the future reproductive health of children and adolescents with T1D is crucial to improve global fertility. However, its roles in the treatment of T1D-induced testicular dysfunction and the potential mechanisms remain elusive. PURPOSE: The purpose of this present study was to investigate whether ICA ameliorates T1D-induced testicular dysfunction as well as its potential mechanisms. METHODS: T1D murine model was established by intraperitoneal injection of STZ with or without treated with ICA for eleven weeks. Morphological, pathological and serological experiments were used to determine the efficacy of ICA on male reproductive function of T1D mice. Western blotting, Immunohistochemistry analysis, qRT-PCR and kit determination were performed to investigated the underlying mechanisms. RESULTS: We found that replenishment of ICA alleviated testicular damage, promoted testosterone production and spermatogenesis, ameliorated apoptosis and blood testis barrier impairment in streptozotocin-induced T1D mice. Functionally, ICA treatment triggered adenosine monophosphate protein kinase (AMPK) activation, which in turn inhibited the nuclear translocation of nuclear factor kappa B p65 (NF-κB p65) to reduce inflammatory responses in the testis and activated nuclear factor erythroid 2-related factor 2(Nrf2), thereby enhancing testicular antioxidant capacity. Further studies revealed that supplementation with the AMPK antagonist Compound C or depletion of Nrf2 weakened the beneficial effects of ICA on testicular dysfunction of T1D mice. CONCLUSION: Collectively, these results demonstrate the feasibility of ICA in the treatment of T1D-induced testicular dysfunction, and reveal the important role of AMPK-mediated Nrf2 activation and NF-κB p65 inhibition in ICA-associated testicular protection during T1D.

Virtual reality's impact on children with type 1 diabetes: a proof-of-concept randomized cross-over trial on anxiety, pain, adherence, and glycemic control.

AIMS:  Assess the effectiveness of virtual reality (VR) technology, in reducing pain and anxiety, and improving adherence and glycemic control among children with type 1 diabetes (T1D). METHODS: Children with T1D, managed with continuous glucose monitoring and insulin pumps, were recruited for a randomized cross-over trial. Children were randomized to one of two interventions for diabetes management: group 1 used VR glasses first and group 2 listened to vocal-guided affective imagery first (audio). After 1 month, the interventions were crossed over. The outcome measures included pain and anxiety assessment, adherence, glycemic control, and patient-reported outcome measures (PROMs) of VR satisfaction and effectiveness. RESULTS:  Forty children, mean age 11.4 ± 1.8 years, were participated. During the VR part, the monthly mean pain score compared to the baseline improved in both groups by 30% (p = 0.03). A 14% reduction in the state anxiety score was observed from baseline to 1 month in both groups (p = 0.009). Glycemic control measures including time in range, time above range, and glucose management indicator improved in both groups during VR part (p < 0.004 for all), compared to audio part. After one month, the patient-reported outcome measure (PROM) of satisfaction and effectiveness was sixfold higher after 1 month in group 1 compared to group 2 (p = 0.002). Adherence improved for both groups. CONCLUSIONS: VR was shown to be effective in reducing pain and anxiety, improving adherence, PROM, and glycemic control among children with T1D. We suggest incorporating VR technology in pediatric diabetes clinics to facilitate and improve coping and management of diabetes. TRIAL REGISTRATION: Trial registration number and date of registration for prospectively registered trials:ClinicalTrials.gov Identifier: NCT05883267, May 10th, 2023.

What are the childbearing experiences of women with type 1 diabetes? A scoping review of qualitative literature.

PROBLEM: Type 1 diabetes is associated with the risk of adverse outcomes for mother and baby. BACKGROUND: How pregnant people adapt to the challenges of type 1 diabetes and engage with healthcare professionals can affect how likely they will be to maintain good glycaemic control. Therefore, it is important to understand the childbearing and care experiences of women with type 1 diabetes. AIM: To examine contemporary literature describing the childbearing experiences of women with type 1 diabetes over the last decade. METHOD: The review follows 5 stages of Arksey and O'Malley's scoping review framework. Four databases were searched for English language publications 2012-2023 using indexed terms and Boolean operators. 64 studies were retrieved, 10 included in the review. Braun and Clarke's thematic synthesis process was used to collate findings. FINDINGS: Five key themes emerged: 1. Glycaemic control dominates the childbearing journey, 2. Emphasis on risk, 3. Importance of social and peer support, 4. Care organisation, systems, and communication, 5. The impact of technology on the childbearing experience. CONCLUSION: Based on lived experiences, women with type 1 diabetes value being treated as partners in their care by health professionals providing medical and midwifery services. Peer and social support from family, friends and the diabetes community can bring comfort and reassurance in a perceived 'medicalised' childbearing journey. Further research is needed on the impact of the use of type 1 diabetes technologies on childbearing experiences and how peer support can be incorporated into current care provision.

Trabecular bone score in type 1 diabetes: a meta-analysis of cross-sectional studies.

BACKGROUND: Bone fragility is a recognized complication of type 1 diabetes (T1D). Thus, lower trabecular bone score (TBS) measurements in T1D patients can be predicted. However, the results of current studies on TBS in patients with T1D are inconsistent. In this context, the present study aimed to test the hypothesis that T1D is associated with lower TBS through a meta-analysis. METHODS: An electronic search of the literature was conducted using PubMed, Embase and Web of science databases to identify studies related to TBS and T1D, supplemented by an additional manual check of the reference list of relevant original and review articles. All data was analyzed using a random effects model. Results were compared using standardized mean differences (SMD) and 95% confidence intervals (CI). P ≤ 0.05 was considered statistically significant. Review Manager 5.4 software and Stata 17.0 software were used for statistical analysis. RESULTS: Seven cross-sectional studies involving 848 participants were included. TBS was lower in T1D patients than in healthy controls on random effects analysis, with no heterogeneity (SMD = - 0.39, 95% CI [- 0.53, - 0.24], P < 0.001; I2 = 0%). In addition, by subgroup analysis, T1D patients were strongly associated with reduced TBS in different regions and age groups, and the results were independent of covariate adjustment. CONCLUSION: This study showed that TBS was lower in patients with T1D than in healthy individuals with normal blood glucose levels, suggesting that TBS may be a useful measure to assess fracture risk in T1D.

Omega-3 fatty acids supplementation improves early-stage diabetic nephropathy and subclinical atherosclerosis in pediatric patients with type 1 diabetes: A randomized controlled trial.

BACKGROUND: Numerous studies have evaluated the beneficial effects of omega-3 fatty acids on inflammatory, autoimmune and renal diseases. However, data about the effects of omega-3 fatty acids on diabetic kidney disease in type 1 diabetes mellitus (T1DM) are lacking. OBJECTIVES: This randomized-controlled trial assessed the effect of oral omega-3 supplementation on glycemic control, lipid profile, albuminuria level, kidney injury molecule-1 (KIM-1) and carotid intima media thickness (CIMT) in pediatric patients with T1DM and diabetic nephropathy. METHODS: Seventy T1DM patients and diabetic nephropathy were enrolled with a mean age 15.2 ± 1.96 years and median disease duration 7 years. Patients were randomly assigned into two groups; intervention group which received oral omega-3 fatty acids capsules (1 g daily). The other group received a matching placebo and served as a control group. Both groups were followed-up for 6 months with assessment of fasting blood glucose (FBG), HbA1c, fasting lipids, urinary albumin creatinine ratio (UACR), KIM-1 and CIMT. RESULTS: After 6 months, omega-3 fatty acids adjuvant therapy for the intervention group resulted in a significant decrease in FBG, HbA1c, triglycerides, total cholesterol, LDL-cholesterol, UACR, KIM-1 and CIMT, whereas, HDL-cholesterol was significantly higher post-therapy compared with baseline levels and compared with the control group (p < 0.05). Baseline KIM-1 levels were positively correlated to HbA1c, UACR and CIMT. Supplementation with omega-3 fatty acids was safe and well-tolerated. CONCLUSIONS: Omega-3 fatty acids as an adjuvant therapy in pediatric T1DM patients with diabetic nephropathy improved glycemic control, dyslipidemia and delayed disease progression and subclinical atherosclerosis among those patients. This trial was registered under ClinicalTrials.gov Identifier no. NCT05980026.

The Role of Vitamin D and Its Molecular Bases in Insulin Resistance, Diabetes, Metabolic Syndrome, and Cardiovascular Disease: State of the Art.

In the last decade, an increasing awareness was directed to the role of Vitamin D in non-skeletal and preventive roles for chronic diseases. Vitamin D is an essential hormone in regulating calcium/phosphorous balance and in the pathogenesis of inflammation, insulin resistance, and obesity. The main forms of vitamin D, Cholecalciferol (Vitamin D3) and Ergocalciferol (Vitamin D2) are converted into the active form (1,25-dihydroxyvitamin D) thanks to two hydroxylations in the liver, kidney, pancreas, and immune cells. Some anti-inflammatory cytokines are produced at higher levels by vitamin D, while some pro-inflammatory cytokines are released at lower levels. Toll-Like Receptor (TLR) expression is increased, and a pro-inflammatory state is also linked to low levels of vitamin D. Regardless of how it affects inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body may change the ratio of pro- to anti-inflammatory cytokines, which would impact insulin action, lipid metabolism, and the development and function of adipose tissue. Many studies have demonstrated an inverse relationship between vitamin D concentrations and pro-inflammatory markers, insulin resistance, glucose intolerance, metabolic syndrome, obesity, and cardiovascular disease. It is interesting to note that several long-term studies also revealed an inverse correlation between vitamin D levels and the occurrence of diabetes mellitus. Vitamin D supplementation in people has controversial effects. While some studies demonstrated improvements in insulin sensitivity, glucose, and lipid metabolism, others revealed no significant effect on glycemic homeostasis and inflammation. This review aims to provide insight into the molecular basis of the relationship between vitamin D, insulin resistance, metabolic syndrome, type 1 and 2 diabetes, gestational diabetes, and cardiovascular diseases.

Autoimmune gastritis as an unexpected cause of diarrhea in a young adult with type I diabetes: a case report.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a lifelong diagnosis that involves immune-mediated damage of pancreatic beta cells and subsequent hyperglycemia, manifesting as: polyuria, polydipsia, polyphagia, and weight loss. Treatment of type 1 diabetes centers on insulin administration to replace or supplement the body's own insulin with the goal of achieving euglycemia and preventing or minimizing complications. Patients with T1DM are at risk for developing other autoimmune conditions, most commonly thyroid or celiac disease. CASE PRESENTATION: A 20-year-old African American female with T1DM was referred by her endocrinologist to pediatric gastroenterology for 2 months of nocturnal, non-bloody diarrhea, left lower quadrant pain, and nausea; she was also being followed by neurology for complaints of lower extremity paresthesias and pain. The patient's initial lab-workup was remarkable for a low total Immunoglobulin A (IgA) level of < 6.7 mg/dL. As IgA deficiency is associated with an increased risk of celiac disease, the patient underwent upper and lower endoscopy, which was grossly unremarkable; however, histology revealed a pattern consistent with autoimmune gastritis. Subsequent serum evaluation was remarkable for an elevated fasting gastrin level and an elevated parietal cell antibody level without macrocytic anemia, iron deficiency, or vitamin B12 depletion. The patient was diagnosed with autoimmune gastritis (AIG) and subsequently initiated on parenteral B12 supplementation therapy with improvement in her neurologic and gastrointestinal symptoms. CONCLUSION: This case illustrates the importance of recognition of red flag findings in a patient with known autoimmune disease. Following well-established health maintenance recommendations for individuals with T1DM ensures that common comorbidities will be detected. Autoimmune gastritis, while a rarer pathology in the pediatric population, deserves consideration in patients with pre-existing autoimmune conditions and new gastrointestinal or neurologic symptoms, as AIG can be associated with poor outcomes and risk of malignancy. Initial lab findings associated with an eventual diagnosis of AIG typically include anemia, iron deficiency, or Vitamin B12 deficiency. However, as demonstrated in this case, symptoms of AIG can rarely present before anemia or Vitamin B12 deficiency develops. To prevent permanent neurological damage, parenteral Vitamin B12 therapy must be considered even in the absence of Vitamin B12 deficiency, especially in those patients already experiencing neurological symptoms.

N-acetylcysteine alleviates oxidative stress and apoptosis and prevents skeletal muscle atrophy in type 1 diabetes mellitus through the NRF2/HO-1 pathway.

AIMS: Type 1 diabetes mellitus (T1DM) has been linked to the occurrence of skeletal muscle atrophy. Insulin monotherapy may lead to excessive blood glucose fluctuations. N-acetylcysteine (NAC), a clinically employed antioxidant, possesses cytoprotective, anti-inflammatory, and antioxidant properties. The objective of our study was to evaluate the viability of NAC as a supplementary treatment for T1DM, specifically regarding its therapeutic and preventative impacts on skeletal muscle. MAIN METHODS: Here, we used beagles as T1DM model for 120d to explore the mechanism of NRF2/HO-1-mediated skeletal muscle oxidative stress and apoptosis and the therapeutic effects of NAC. Oxidative stress and apoptosis related factors were analyzed by immunohistochemistry, immunofluorescence, western blotting, and RT-qPCR assay. KEY FINDINGS: The findings indicated that the co-administration of NAC and insulin led to a reduction in creatine kinase levels, preventing weight loss and skeletal muscle atrophy. Improvement in the reduction of muscle fiber cross-sectional area. The expression of Atrogin-1, MuRF-1 and MyoD1 was downregulated, while Myh2 and MyoG were upregulated. In addition, CAT and GSH-Px levels were increased, MDA levels were decreased, and redox was maintained at a steady state. The decreased of key factors in the NRF2/HO-1 pathway, including NRF2, HO-1, NQO1, and SOD1, while KEAP1 increased. In addition, the apoptosis key factors Caspase-3, Bax, and Bak1 were found to be downregulated, while Bcl-2, Bcl-2/Bax, and CytC were upregulated. SIGNIFICANCE: Our findings demonstrated that NAC and insulin mitigate oxidative stress and apoptosis in T1DM skeletal muscle and prevent skeletal muscle atrophy by activating the NRF2/HO-1 pathway.

Downregulation of BDNF-TrkB signaling may contribute to the colonic motility disorders in mice with streptozocin-induced diabetes.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) acts as a neuromodulator to regulate gut motility, but the role of BDNF in diabetes-related dysmotility is uncertain. The aim of this study was to investigate the possible involvement of BDNF and its receptor TrkB in the colonic hypomotility of mice with streptozotocin (STZ)-induced diabetes. METHODS: A single intraperitoneal injection of STZ was used to establish a type 1 diabetes model. An organ bath system was applied to observe the contractile activities of colonic muscle strips. Immunofluorescence and western blotting were performed to evaluate the expression of BDNF and TrkB in the colon. ELISA was used to detect BDNF and SP levels in the serum and colon. The patch-clamp technique was applied to record the currents of L-type calcium channels and large conductance Ca2+ -activated K+ channels on smooth muscle cells. KEY RESULTS: Compared with healthy controls, diabetic mice showed attenuated colonic muscle contraction (p < 0.001), which was partly reversed by BDNF supplementation. TrkB protein expression was significantly reduced in diabetic mice (p < 0.05). In addition, both BDNF and substance P (SP) levels were decreased, and exogenous administration of BDNF increased SP levels in diabetic mice (p < 0.05). Both the TrkB antagonist and the TrkB antibody inhibited the spontaneous contraction of colonic muscle strips (p < 0.01). Moreover, the BDNF-TrkB signaling system enhanced SP-induced muscle contraction. CONCLUSIONS: Downregulation of BDNF/TrkB signaling and reduced SP release from the colon may contribute to the colonic hypomotility associated with type 1 diabetes. Brain-derived neurotrophic factor supplementation may have therapeutic potential for diabetes-related constipation.

Prevalence of LDL-hypercholesterolemia and other cardiovascular risk factors in young people with type 1 diabetes.

BACKGROUND: Mortality and morbidity in people with Type 1 diabetes (T1D) is mainly caused by cardiovascular disease (CVD). Early treatment of cardiovascular risk factors (CVRFs) is of great importance. OBJECTIVE: To analyze the prevalence of LDL-hypercholesterolemia and other CVRFs in youth with T1D. METHODS: Clinical and laboratory parameters, and vascular thickness measurement were obtained in youth with T1D (age 6-18 years, T1D duration >1 year) attending a diabetes clinic. LDL-hypercholesterolemia, microalbuminuria and arterial hypertension were defined as CVRFs. RESULTS: A total of 333 youth (48% girls; age: 13.3 years [10.3-15.5], median [interquartile range]) participated in the study. The T1D duration was 5.9 years [3.5-9.4] with HbA1c of 7.4% [6.8-8.0]. Intima media thickness (N=223) was 538.0 µm [470.0-618.0]). LDL-hypercholesterolemia was present in 30 participants (9%; 18 girls; age: 14.3 years [11.2-15.7]). None of the participants had persistent microalbuminuria, although 59 (18.3%) had elevated albumin excretion in a random urine specimen. LDL-hypercholesterolemia was associated with increased blood pressure (p<0.05), insulin requirement (p<0.05), HbA1c (p<0.05), triglyceride (p<0.001) and total cholesterol (p<0.001), and a family history of premature CVD (p<0.001), but negatively correlated with HDL cholesterol levels (p<0.05). Sex, pubertal status, duration of diabetes, type of therapy, and physical activity did not differ between participants with and without LDL- hypercholesterolemia. Arterial hypertension was present in 11 participants (3.3%; 4 girls; age: 14.1 years [11.1-16.1]). CONCLUSION: LDL-hypercholesterolemia affected 9% of youth with T1D in this cohort and was associated with other CVRFs. A holistic therapeutic concept for these young people is essential.

Association Between Diabetes Severity and Risks of COVID-19 Infection and Outcomes.

BACKGROUND: Little is known about whether diabetes increases the risk of COVID-19 infection and whether measures of diabetes severity are related to COVID-19 outcomes. OBJECTIVE: Investigate diabetes severity measures as potential risk factors for COVID-19 infection and COVID-19 outcomes. DESIGN, PARTICIPANTS, MEASURES: In integrated healthcare systems in Colorado, Oregon, and Washington, we identified a cohort of adults on February 29, 2020 (n = 1,086,918) and conducted follow-up through February 28, 2021. Electronic health data and death certificates were used to identify markers of diabetes severity, covariates, and outcomes. Outcomes were COVID-19 infection (positive nucleic acid antigen test, COVID-19 hospitalization, or COVID-19 death) and severe COVID-19 (invasive mechanical ventilation or COVID-19 death). Individuals with diabetes (n = 142,340) and categories of diabetes severity measures were compared with a referent group with no diabetes (n = 944,578), adjusting for demographic variables, neighborhood deprivation index, body mass index, and comorbidities. RESULTS: Of 30,935 patients with COVID-19 infection, 996 met the criteria for severe COVID-19. Type 1 (odds ratio [OR] 1.41, 95% CI 1.27-1.57) and type 2 diabetes (OR 1.27, 95% CI 1.23-1.31) were associated with increased risk of COVID-19 infection. Insulin treatment was associated with greater COVID-19 infection risk (OR 1.43, 95% CI 1.34-1.52) than treatment with non-insulin drugs (OR 1.26, 95% 1.20-1.33) or no treatment (OR 1.24; 1.18-1.29). The relationship between glycemic control and COVID-19 infection risk was dose-dependent: from an OR of 1.21 (95% CI 1.15-1.26) for hemoglobin A1c (HbA1c) < 7% to an OR of 1.62 (95% CI 1.51-1.75) for HbA1c ≥ 9%. Risk factors for severe COVID-19 were type 1 diabetes (OR 2.87; 95% CI 1.99-4.15), type 2 diabetes (OR 1.80; 95% CI 1.55-2.09), insulin treatment (OR 2.65; 95% CI 2.13-3.28), and HbA1c ≥ 9% (OR 2.61; 95% CI 1.94-3.52). CONCLUSIONS: Diabetes and greater diabetes severity were associated with increased risks of COVID-19 infection and worse COVID-19 outcomes.

Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes.

BACKGROUND: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. METHODS: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. RESULTS: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:-0.33, q = 0.01), histidine (r:-0.45, q < 0.001), methionine (r: -0.29, q = 0.02), phenylalanine (r: -0.29, q = 0.01), serine (r: -0.42, q < 0.001), threonine (r: -0.28, q = 0.02), citrate (r: -0.35, q = 0.003), fumarate (r: -0.24, q = 0.04), and malate (r: -0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: -0.28, q = 0.04), phenylalanine (r:-0.3, q = 0.03), fumarate (r: -0.29, q = 0.04), and malate (r: -0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: -0.28, q = 0.02) was correlated with higher mean ACR. CONCLUSIONS: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03618420 and NCT03584217 A higher resolution version of the Graphical abstract is available as Supplementary information.

Pre-pregnancy health of women with pre-existing diabetes or previous gestational diabetes: Analysis of pregnancy risk factors and behavioural data from a digital tool.

AIMS: To examine health behaviours and risk factors in women with pre-existing diabetes or previous gestational diabetes mellitus who are planning pregnancy. METHODS: Health behaviour, risk factor and demographic data obtained from a digital pregnancy planning advisory tool (Tommy's charity UK) were analysed. Descriptive statistical analysis was performed, stratified by diabetes type. RESULTS: Data from 84,359 women, including 668 with type 1 diabetes, 707 with type 2 diabetes and 1785 with previous gestational diabetes obtained over a 12-month period (September 2019-September 2020) were analysed. 65%, 95%CI (61,68%) of women with type 2 diabetes and 46%, 95%CI (43,48%) with previous gestational diabetes were obese (BMI ≥30 kg/m2 ), compared with 26%, 95%CI (26,26%) without diabetes. Use of folic acid supplements was low; 41%, 95%CI (40,41%) of women without diabetes and 42%, 95%CI (40,45%) with previous gestational diabetes reported taking folic acid (any dose) while 47%, 95%CI (43.50%) women with type 1 diabetes and 44%, 95%CI (40,47%) women with type 2 diabetes respectively reported taking the recommended dose (5 mg). More women with type 1 diabetes and type 2 diabetes reported smoking (20%, 95%CI [17,23%] and 23%, 95%CI [20,26%] respectively) and taking illicit/recreational drugs (7%, 95%CI [6,10%] and 9%, 95% CI [7,11%]) compared to women without diabetes (smoking 17%, 95% CI [16,17%], drug use 5%, 95%CI [5,5%]). Alcohol consumption, low levels of physical activity and of fruit and vegetable intake were also evident. CONCLUSIONS: This study highlights the potential of online pregnancy planning advisory tools to reach high-risk women and emphasises the need to improve pre-pregnancy care for women with pre-existing diabetes and previous gestational diabetes, many of whom are actively seeking advice. It is also the first to describe pre-pregnancy health behaviours in women with previous gestational diabetes.

Alterations in Functional Connectivity of Thalamus and Primary Somatosensory Cortex in Painful and Painless Diabetic Peripheral Neuropathy.

OBJECTIVE: In this study we aimed to investigate the functional connectivity of brain regions involved in sensory processing in diabetes with and without painful and painless diabetic peripheral neuropathy (DPN) and the association with peripheral nerve function and pain intensity. RESEARCH DESIGN AND METHODS: In this cross-sectional study we used resting-state functional MRI (fMRI) to investigate functional brain connectivity of 19 individuals with type 1 diabetes and painful DPN, 19 with type 1 diabetes and painless DPN, 18 with type 1 diabetes without DPN, and 20 healthy control subjects. Seed-based connectivity analyses were performed for thalamus, postcentral gyrus, and insula, and the connectivity z scores were correlated with peripheral nerve function measurements and pain scores. RESULTS: Overall, compared with those with painful DPN and healthy control subjects, subjects with type 1 diabetes without DPN showed hyperconnectivity between thalamus and motor areas and between postcentral gyrus and motor areas (all P ≤ 0.029). Poorer peripheral nerve functions and higher pain scores were associated with lower connectivity of the thalamus and postcentral gyrus (all P ≤ 0.043). No connectivity differences were found in insula (all P ≥ 0.071). CONCLUSIONS: Higher functional connectivity of thalamus and postcentral gyrus appeared only in diabetes without neuropathic complications. Thalamic/postcentral gyral connectivity measures demonstrated an association with peripheral nerve functions. Based on thalamic connectivity, it was possible to group the phenotypes of type 1 diabetes with painful/painless DPN and type 1 diabetes without DPN. The results of the current study support that fMRI can be used for phenotyping, and with validation, it may contribute to early detection and prevention of neuropathic complications.