Experimental and Clinical Endocrinology & Diabetes最新文献

The interactions between muscle and bone are noted in the clinical relationships between sarcopenia and osteoporosis. Myokines secreted from the skeletal muscles play roles in muscle-bone interactions related to various physiological and pathophysiological states. Although numerous evidence suggests that growth hormone (GH) influences both muscle and bone, the effects of GH on the muscle-bone interactions have remained unknown. We, therefore, investigated the influences of GH administration for 8 weeks on muscle and bone, including myokine expression, in mice with or without ovariectomy (OVX). GH administration significantly increased muscle mass in the whole body and lower limbs, as well as tissue weights of the extensor digitorum longus (EDL) and soleus muscles in mice with or without OVX. Moreover, it markedly increased grip strength in both mice. As for femurs, GH administration significantly increased cortical thickness and area in mice with or without OVX. Moreover, GH significantly blunted the decrease in the ratio of bone volume to tissue volume at the trabecular bone in mice with OVX. GH administration significantly decreased follistatin mRNA levels in the EDL, but not the soleus, muscles in mice with or without OVX, although it did not affect the other myokines examined. However, GH administration significantly elevated serum follistatin levels in mice. In conclusion, this study indicates that GH administration increases skeletal muscle mass and grip strength and cortical and trabecular bone-related parameters obtained by micro-computed tomography analyses in mice. However, myokine regulation might not be critical for the effects of GH on muscle and bone.

Background: Newborn screening for congenital adrenal hyperplasia (CAH) has benefits with a high adoption rate worldwide. It also has problems of high false positives, which can cause stress to the patient's family with economic losses and unnecessary visits of newborns to hospitals. Therefore, we investigated the influence of birth weight (BW), gestational age (GA), and GA with sampling time on 17-hydroxyprogesterone (17-OHP) concentration and attempted to establish the 17-OHP cutoff values in preterm, low birth weight (LBW), and sick newborns.

Methods: Newborns (n=1,071) born between October 2020 and January 2022 were screened for CAH. Samples from neonates were collected on filter paper with the heel prick method. 17-OHP concentration was measured by time-resolved immunofluorescence with an AutoDELFIA Neonatal 17-hydroxyprogesteron kit and grouped in relation to BW, GA, and GA with sampling time.

Results: The median age of newborns at neonatal sample collection was 6 days. 17-OHP concentration showed a statistically significant negative correlation with BW (r=-0.488, p<0.001) and GA (r=-0.560, p<0.001). Full-term and preterm subgroups had a similar decreasing tendency of 17-OHP concentration with increasing sampling time. Application of newly establishing cutoff criteria significantly reduced recall rates to 1.16%, 0.9%, and 1.75% according to each criterion of BW, GA, and GA with sampling time, respectively.

Conclusions: This study presents new 17-OHP cutoff values for preterm, LBW, and sick newborns. These data in our laboratory can be used as a reference by other laboratories for establishing new cutoff criteria to help lower the high recall rate and reduce unnecessary follow-up tests.

Background: Retinal screening is mandatory to prevent vision loss and blindness due to diabetic retinopathy (DR). The aim of the study was to determine retinopathy screening rates and potential barriers in a German metropolitan diabetes care center.

Methods: Between May and October 2019, 265 patients with diabetes mellitus (95% type 2 diabetes; age 62±13.2 years; diabetes duration 11.1±8.5 years, HbA1c 7.4±1.0%) were referred to an ophthalmologist (referral form with order "Fundoscopy in diabetes mellitus, findings requested," completed documentation form "General practitioner's/diabetologist's report to the ophthalmologist" and prepared documentation form "Ophthalmologist's report"). A structured interview was used to assess the level of compliance with the guidelines and to identify potential barriers to retinopathy screening in a real-world setting, including the quantification of extra payments.

Results: All patients were interviewed at 7.9±2.5 months after the referral for retinopathy screening had been issued. According to patient reporting, fundoscopy was performed in 191 (75%) patients. Ophthalmological reports were obtained from 119/191 (62%) patients (46% of the entire cohort). 10/119 (8%) patients had been previously diagnosed with DR and 6/119 (5%) with new-onset DR. In 158/191 (83%) of patients, the referral had been accepted by the ophthalmology practice, of which 25,1% made a co-payment of 36.2±37.6 €.

Discussion: Despite a high screening performance in a real-world setting, complete screening in compliance with German guidelines, including written reporting, was found in less than half of the cohort. The prevalence and incidence of DR are high. Even when referred according to the regulations, one-quarter of patients made a co-payment. Efficient solutions to current barriers can emerge with mutual time-saving information prior to examination and feedback about the implementation of findings into treatment.

Background: Diabetes is associated with systemic complications. Prevalence of diabetic nephropathy, and retinopathy, in type 1 diabetes mellitus (T1DM) is declining, but it is not known if this is true also for diabetic neuropathy.

Aim: To investigate the relationship between large fibre diabetic neuropathy and other diabetic complications.

Materials and methods: Neuropathy, defined here as large fibre neuropathy, was assessed by measuring vibration perception thresholds at four different frequencies on the sole of the foot, using a standard VibroSense Meter and/or neuropathic symptoms, in 599 individuals with T1DM. Retinopathy status was graded using the International Clinical Disease Severity Scale. Grade of albuminuria and previous history of any macrovascular complications were registered.

Results: Diabetic individuals without retinopathy had similar vibration thresholds as age- and gender-matched control participants without diabetes, whereas those without microalbuminuria had higher thresholds than controls. Two individuals out of 599 (0.3%) had microalbuminuria, but not retinopathy or neuropathy, and 12/134 (9%) without retinopathy had signs of neuropathy. Totally 119/536 (22%) of the patients without microalbuminuria had neuropathy. Vibration thresholds increased with the rising severity of retinopathy and grade of albuminuria. In a multinomial logistic regression analysis, neuropathy was associated with retinopathy (OR 2.96 [1.35-6.49], p=0.007), nephropathy (OR 6.25 [3.21-12.15]; p=6.7×10-8) and macrovascular disease (OR 2.72 [1.50-4.93], p=0.001).

Conclusions: Despite recent changes in the incidence of diabetic complications, the onset of large fibre neuropathy follows that of retinopathy but precedes the onset of nephropathy in T1DM.

Background: Hypochondroplasia is a skeletal dysplasia caused by activating pathologic variants of FGFR3. The N540K variant accounts for 60-70% of reported cases and is associated with severe manifestations. Here, we analyze the clinical manifestations and outcomes of Korean patients with hypochondroplasia harboring the FGFR3 N540K variant.

Methods: Medical records of 20 unrelated patients with genetically confirmed N540K-related hypochondroplasia were retrospectively reviewed. All individuals were diagnosed with hypochondroplasia by Sanger sequencing for FGFR3, or target-panel sequencing for skeletal dysplasia. The effectiveness of growth hormone therapy was analyzed in 16 patients treated with growth hormones.

Results: Among 20 patients (7 men, 13 women), the mean age at first visit was 3.5±1.0 years, and the mean follow-up duration was 6.8±0.6 years. The patients presented with a short stature and/or short limbs. Genu varum, macrocephaly, and developmental delay were observed in 11 (55.0%), 9 (45.0%), and 5 (25.0%) patients, respectively. Of the 12 patients who underwent neuroimaging, five (41.7%) showed abnormal findings (one required operation for obstructive hydrocephalus). Among 16 growth-hormone-treated patients (two were growth-hormone deficient), the increase in height standard deviation scores was significant after a mean 5.4±0.7 years of treatment (+0.6 and+1.8 using growth references for healthy controls and achondroplasia children, respectively). Four patients underwent surgical limb lengthening at a mean age of 8.8±3.3 years.

Conclusions: Neurodevelopmental abnormalities are frequently observed in patients with N540K-related hypochondroplasia. Close monitoring of skeletal manifestations and neurodevelopmental status is necessary for hypochondroplasia.

Introduction: Established scores estimate 10-year fracture risk in osteoporosis to assist with treatment recommendations. This study compared the risk probabilities of major osteoporotic and hip fractures calculated by the FRAX tool with those of the DVO score, established in German-speaking countries.

Material and methods: This seven-year retrospective study analyzed data of 125 male patients (mean age: 59.2±10.7 years) evaluated for osteoporosis. For the DVO score, the therapy threshold of>30% for vertebral and hip fractures suggested by DVO guidelines was implemented. We calculated fracture risks based on FRAX scores with aBMD and applied a common therapy threshold of≥3% for hip fracture and subsequently determined the "DVO-equivalent risk level" for FRAX-based assessment that would identify as many male patients as identified by the DVO score.

Results: Based on DVO score, 60.0% of patients had a 10-year risk of hip and vertebral fractures>30%. The recommendations for individuals based on FRAX scores for hip fracture with aBMD with risk≥3% overlapped with those based on DVO score in 36% of patients. Patients identified for treatment only by DVO score presented a higher percentage of spine fractures (65 vs. 41%). The thresholds for this "DVO-equivalent risk level" for 'FRAX with aBMD' was estimated to be≥6.7% for major osteoporotic fracture and≥2.1% for hip fracture.This study demonstrates that the DVO score was more sensitive than the FRAX score for patients with prevalent spinal fractures. We suggest considering the appropriate score and therapy threshold carefully in the daily care of male patients.

Objectives: To analyze whether prescription use of GLP-1RA and SGLT2i in individuals with type 2 diabetes with cardiovascular disease (CVD) has increased after the ADA/EASD consensus guidelines (2018) in a German Real-World setting and which clinical characteristics are associated with prescription use of these drugs.

Methods: The Disease Analyzer database (IQVIA) comprises a representative panel of 1,373 general practitioners, diabetologists, and cardiologists throughout Germany (01/2015-12/2020: 12.6 million patients). Newly diagnosed type 2 diabetes (n=45,531) was identified by ICD-10 codes (E11). Matching (1:1) on practice specialty, sex, age, and year of diabetes diagnosis was performed for CVD. Logistic regression models were fitted to obtain adjusted odds ratios (OR) for characteristics associated with prescription use (median follow-up: 1.9 years).

Results: Overall, 35% of patients (n=16,006) were treated with glucose-lowering drugs during the first year after type 2 diabetes diagnosis (HbA1c≥7.0%: 80%). GLP-1RA (2.4%) and SGLT2i (8.5%) were rarely prescribed. After the consensus, use of GLP-1RA and SGLT2i increased, however, almost independently of pre-existing CVD (12/2019-11/2020 vs. 12/2017-11/2018: yes, no): GLP-1RA: from 5.7 to 9.2%, 5.2 to 7.6%; SGLT2i: from 13.9 to 20.4%, 12.1 to 16.6%. Among cardiovascular risk factors, the largest OR for GLP-1RA was for obesity (4.5; 95%CI: 3.2-6.3). CVD was moderately related with SGLT2i (1.45; 1.32-1.60) and GLP-1RA (1.35; 1.08-1.69) prescriptions. A weak association was observed between SGLT2i and heart failure (1.18; 95%CI: 1.05-1.32).

Conclusion: National prescription use of GLP-1RA and SGLT2i did not come close to the recommendation in subjects with CVD issued by the 2018 ADA/EASD consensus.

Introduction: Uromodulin is a kidney-specific tubular protein, and its assessment in serum (sUMOD) reveals the potential as a novel marker for function and the integrity of renal parenchymal cells and does not directly depend on the glomerular filtration rate. Early diabetic nephropathy parallels glomerular hyperfiltration, often leading to diagnostic misinterpretation. Moreover, traditional kidney function markers are not able to diagnose structural lesions. Recent data show that sUMOD is linked to glucose intolerance in adults. Thus, we launched to assess the hypothesis that sUMOD is also associated with kidney function, biometric data, and quality of metabolic control in children/adolescents with type 1 diabetes.

Patients and methods: Patients with type 1 diabetes (n=135) and healthy controls (n=69) were recruited to participate in the trial. Clinical, biometrical data, sUMOD, and other laboratory parameters were assessed.

Results: The mean concentrations of sUMOD in diabetic patients and controls were comparable (201.19±103.22 vs. 198.32±84.27 ng/mL, p=0.832). However, in contrast to healthy controls, sUMOD levels in patients with diabetes were associated with serum-creatinine (r=-0.368, p<0.0001), age (r=-0.350, p<0.0001), height (r=-0.379, p<0.0001), body weight (r=-0.394, p<0.0001), Body mass index (r=-0.292, p=0.001), daily insulin dosage (r=-0.300, p<0.0001), HbA1c (%) (r=-0.190, p=0.027), standardized HbA1c/IFCC (mmol/mol) (r=-0.189, p=0.028), and systolic (r=-0.299, p<0.0001) and diastolic (r=-0.235, p=0.006) arterial blood pressure.

Conclusions: Our study shows that children/adolescents with type 1 diabetes disclose similar sUMOD concentrations as healthy controls. Serum UMOD appears to indicate higher risks for kidney tissue remodeling and possibly subsequent cardiovascular alterations. However, further studies are mandatory to settle these findings.

C-peptide is an increasingly used and established marker for beta cell function by assessing endogenous insulin secretion. Accurate and comparable C-peptide measurements are needed in clinical practice and research studies. For example, to calculate HOMA-indices, the C-peptide/glucose ratio, and the classification of recently published novel subgroups of diabetes and prediabetes have used C-peptide measurements. Although the process for standardization of C-peptide measurements is advanced, its full implementation is still missing; therefore, the current status of the comparability of C-peptide measurements using different immunoassays is unclear. Here we compared five widely used C-peptide immunoassays on different analyzers (Abbott ALINITY i, DiaSorin Liaison XL, Roche Cobas e411, Siemens Healthineers ADVIA Centaur XPT, and Immulite 2000 XPi) using serum samples covering the clinically relevant C-peptide concentration range. Although all investigated immunoassays are traceable to the international reference reagent for C-peptide (NIBSC code: 84/510), results of C-peptide measurements showed significant differences between analyzers in the entire concentration range, especially with increasing C-peptide concentrations. The mean bias was largest (36.6%) between results of the immunoassays by Roche and Siemens Healthineers (ADVIA Centaur XPT), and both assays revealed large discrepancies compared to immunoassays by Abbott, DiaSorin, and Siemens Healthineers (Immulite 2000 XPi). In contrast, the three latter assays showed similar C-peptide results (mean bias: 2.3% to 4.2%). Consequently, C-peptide discrepancies might affect clinical diagnosis and the interpretation of study results. Therefore, there is an urgent need to implement and finalize the standardization process of C-peptide measurements to improve patient care and the comparability of research studies.

Objective: The E2F2 transcription factor can accelerate cell proliferation and wound healing. However, its mechanism of action in a diabetic foot ulcer (DFU) remains unclear. Therefore, this study explores the influence of E2F2 on wound healing in DFU by examining cell division cycle-associated 7-like (CDCA7L) expression.

Methods: CDCA7L and E2F2 expression in DFU tissues were analyzed with databases. CDCA7L and E2F2 expression were altered in human umbilical vein endothelial cells (HUVECs) and spontaneously transformed human keratinocyte cell culture (HaCaT) cells. Cell viability, migration, colony formation, and angiogenesis were evaluated. Binding of E2F2 to the CDCA7L promoter was examined. Subsequently, a diabetes mellitus (DM) mouse model was established and treated with full-thickness excision followed by CDCA7L overexpression. Wound healing in these mice was observed and recorded, and vascular endothelial growth factor receptor 2 (VEGFR2) and hematopoietic progenitor cell antigen CD34 (CD34) expression were determined. E2F2 and CDCA7L expression levels in cells and mice were evaluated. The expression of growth factors was tested.

Results: CDCA7L expression was downregulated in DFU tissues and wound tissues from DM mice. Mechanistically, E2F2 bound to the CDCA7L promoter to upregulate CDCA7L expression. E2F2 overexpression enhanced viability, migration, and growth factor expression in HaCaT cells and HUVECs, and augmented HUVEC angiogenesis and HaCaT cell proliferation, which was nullified by silencing CDCA7L. In DM mice, CDCA7L overexpression facilitated wound healing and elevated the expression level of growth factors.

Conclusions: E2F2 facilitated cell proliferation and migration and fostered wound healing in DFU cells through binding to the CDCA7L promoter.