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Abstract Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12 -/- ) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.

Abstract Background Previous studies on magnetic resonance neurography (MRN) found different patterns of structural nerve damage in type 1 diabetes (T1D) and type 2 diabetes (T2D). Magnetization transfer ratio (MTR) is a quantitative technique to analyze the macromolecular tissue composition. We compared MTR values of the sciatic nerve in patients with T1D, T2D, and healthy controls (HC). Methods 3-T MRN of the right sciatic nerve at thigh level was performed in 14 HC, 10 patients with T1D (3 with diabetic neuropathy), and 28 patients with T2D (10 with diabetic neuropathy). Results were subsequently correlated with clinical and electrophysiological data. Results The sciatic nerve’s MTR was lower in patients with T2D (0.211 ± 0.07, mean ± standard deviation) compared to patients with T1D (T1D 0.285 ± 0.03; p = 0.015) and HC (0.269 ± 0.05; p = 0.039). In patients with T1D, sciatic MTR correlated positively with tibial nerve conduction velocity (NCV; r = 0.71; p = 0.021) and negatively with hemoglobin A1c (r = − 0.63; p

IntroductionIncreasing evidence supports chronic psychological stress as a risk factor for the development of type 2 diabetes. Much less is known, however, about the role of chronic stress in established diabetes.MethodsThe aim of the current study was to comprehensively assess chronic stress in a sample of 73 patients with type 2 diabetes and 48 non-diabetic control participants, and to investigate associations with indicators of glycemic control (HbA1c), insulin resistance (HOMA-IR), β-cell functioning (C-peptide), illness duration, and the presence of microvascular complications. Chronic stress was measured using questionnaires [the Perceived Stress Scale (PSS), the Screening Scale of the Trier Inventory of Chronic Stress (SSCS), the Perceived Health Questionnaire (PHQ) as well as the Questionnaire on Stress in Patients with Diabetes—Revised (QSD-R)]; hair cortisol was used as a biological indicator.ResultsWe found that patients with type 2 diabetes had higher levels of hair cortisol in comparison to the control group (F(1,112) = 5.3; p = 0.023). Within the diabetic group, higher hair cortisol was associated with a longer duration of the illness (r = 0.25, p = 0.04). General perceived stress did not show significant associations with metabolic outcomes in type 2 diabetes patients. In contrast, higher diabetes-related distress, as measured with the QSD-R, was associated with lower glycemic control (r = 0.28, p = 0.02), higher insulin resistance (r = 0.26, p = 0.03) and a longer duration of the illness (r = 0.30, p = 0.01).DiscussionOur results corroborate the importance of chronic psychological stress in type 2 diabetes. It appears, however, that once type 2 diabetes has developed, diabetes-specific distress gains in importance over general subjective stress. On a biological level, increased cortisol production could be linked to the course of the illness.

Persistent diabetic complications despite controlled blood glucose levels, known as hyperglycemic memory, remain a poorly understood phenomenon in diabetic kidney disease. Here the authors identify senescence-associated gene p21 as a regulator of hyperglycemic memory, the suppression of which improves hyperglycemic memory and renal function.

Abstract Objectives Clinical and histological studies have found evidence that nerve ischemia is a major contributor to diabetic neuropathy (DN) in type 2 diabetes (T2D). The aim of this study was to investigate peripheral nerve microvascular permeability using dynamic contrast enhanced (DCE) magnetic resonance neurography (MRN) to analyze potential correlations with clinical, electrophysiological, and demographic data. Methods Sixty‐five patients (35/30 with/without DN) and 10 controls matched for age and body mass index (BMI) underwent DCE MRN of the distal sciatic nerve with an axial T1‐weighted sequence. Microvascular permeability (Ktrans), plasma volume fraction (vp), and extravascular extracellular volume fraction (ve) were determined with the extended Tofts model, and subsequently correlated with clinical data. Results Ktrans and ve were lower in T2D patients with DN compared to patients without DN (0.037 min−1 ± 0.010 vs. 0.046 min−1 ± 0.014; p = 0.011, and 2.35% ± 3.87 vs. 5.11% ± 5.53; p = 0.003, respectively). In individuals with T2D, Ktrans correlated positively with tibial, peroneal, and sural NCVs (r = 0.42; 95%CI = 0.18 to 0.61, 0.50; 95%CI = 0.29 to 0.67, and 0.44; 95%CI = 0.19 to 0.63, respectively), with tibial and peroneal CMAPs (r = 0.27; 95%CI = 0.01 to 0.49 and r = 0.32; 95%CI = 0.07 to 0.53), and with the BMI (r = 0.47; 95%CI = 0.25 to 0.64). Negative correlations were found with the neuropathy deficit score (r = −0.40; 95%CI = −0.60 to −0.16) and age (r = −0.51; 95%CI = −0.67 to −0.31). No such correlations were found for vp. Conclusion This study is the first to find associations of MR nerve perfusion parameters with clinical and electrophysiological parameters related to DN in T2D. The results indicate that a decrease in microvascular permeability but not plasma volume may result in nerve ischemia that subsequently causes demyelination.

Background and aimCurrent strategies for preventing diabetic sensorimotor polyneuropathy (DSPN) are limited mainly to glucose control but rapid decrease of glycemia can lead to acute onset or worsening of DSPN. The aim of this study was to examine the effects of periodic fasting on somatosensory nerve function in patients with type 2 diabetes (T2D).Study design and methodsSomatosensory nerve function was assessed in thirty-one patients with T2D (HbA1c 7.8 ± 1.3% [61.4 ± 14.3 mmol/mol]) before and after a six-month fasting-mimicking diet (FMD; n=14) or a control Mediterranean diet (M-diet; n=17). Neuropathy disability score (NDS), neuropathy symptoms score (NSS), nerve conduction velocity and quantitative sensory testing (QST) were analyzed. 6 participants of the M-Diet group and 7 of the FMD group underwent diffusion-weighted high-resolution magnetic resonance neurography (MRN) of the right leg before and after the diet intervention.ResultsClinical neuropathy scores did not differ between study groups at baseline (64% in the M-Diet group and 47% in the FMD group had DSPN) and no change was found after intervention. The differences in sensory NCV and sensory nerve action potential (SNAP) of sural nerve were comparable between study groups. Motor NCV of tibial nerve decreased by 12% in the M-Diet group (P=0.04), but did not change in the FMD group (P=0.39). Compound motor action potential (CMAP) of tibial nerve did not change in M-Diet group (P=0.8) and increased in the FMD group by 18% (P=0.02). Motor NCV and CMAP of peroneal nerve remained unchanged in both groups. In QST M-diet-group showed a decrease by 45% in heat pain threshold (P=0.02), FMD group showed no change (P=0.50). Changes in thermal detection, mechanical detection and mechanical pain did not differ between groups. MRN analysis showed stable fascicular nerve lesions irrespective of the degree of structural pathology. Fractional anisotropy and T2-time did not change in both study groups, while a correlation with the clinical degree of DSPN could be confirmed for both.ConclusionsOur study shows that six-month periodic fasting was safe in preserving nerve function and had no detrimental effects on somatosensory nerve function in T2D patients.Clinical trial registrationhttps://drks.de/search/en/trial/DRKS00014287, identifier DRKS00014287.

BackgroundDiabetic sensorimotor polyneuropathy (DSPN) is one of the most prevalent and poorly understood diabetic microvascular complications. Recent studies have found that fractional anisotropy (FA), a marker for microstructural nerve integrity, is a sensitive parameter for the structural and functional nerve damage in DSPN. The aim of this study was to investigate the significance of proximal sciatic nerve’s FA on different distal nerve fiber deficits of the upper and lower limbs and its correlation with the neuroaxonal biomarker, neurofilament light chain protein (NfL).Materials and methodsSixty-nine patients with type 2 diabetes (T2DM) and 30 healthy controls underwent detailed clinical and electrophysiological assessments, complete quantitative sensory testing (QST), and diffusion-weighted magnetic resonance neurography of the sciatic nerve. NfL was measured in the serum of healthy controls and patients with T2DM. Multivariate models were used to adjust for confounders of microvascular damage.ResultsPatients with DSPN showed a 17% lower sciatic microstructural integrity compared to healthy controls (p

Neurovegetative and autonomic symptoms are common presentations of various diseases, ranging from psychosomatic to severe organic disorders. A 23-year-old man presented with a history of recurrent presyncope, dizziness, and tachycardia. Repeated diagnostic work-up in various clinical settings could not identify any definite cause for approximately eight years. However, the incidental detection of postprandial and exercise-induced hypoglycemia was suggestive of an insulin-related disorder. A 72 h plasma glucose fasting test revealed endogenous hyperinsulinism. Upon imaging studies, no tumor mass potentially indicating insulinoma could be detected. 68Ga-DOTA-Exendin-4 PET/CT showed diffuse tracer enrichment throughout the whole pancreas. A subtotal pancreatectomy was performed, and the diagnosis of diffuse, adult-onset nesidioblastosis was established histopathologically. This corresponds to the clinical findings of a functional β-cell disorder, also known as non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS). After nine months, the symptoms recurred, making complete pancreatectomy necessary. Postoperative laboratory evaluation exhibited no residual endogenous C-peptide production. This case illustrates the diagnostic challenges in patients presenting with unspecific, neurovegetative and autonomic symptoms with a severe and rare underlying cause.

Differential diagnosis of hypoglycemia in the non-diabetic adult patient is complex and comprises various diseases, including endogenous hyperinsulinism caused by functional β-cell disorders. The latter is also designated as nesidioblastosis or non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS). Clinically, this rare disease presents with unspecific adrenergic and neuroglycopenic symptoms and is, therefore, often overlooked. A combination of careful clinical assessment, oral glucose tolerance testing, 72 h fasting, sectional and functional imaging, and invasive insulin measurements can lead to the correct diagnosis. Due to a lack of a pathophysiological understanding of the condition, conservative treatment options are limited and mostly ineffective. Therefore, nearly all patients currently undergo surgical resection of parts or the entire pancreas. Consequently, apart from faster diagnosis, more elaborate and less invasive treatment options are needed to relieve the patients from the dangerous and devastating symptoms. Based on a case of a 23-year-old man presenting with this disease in our department, we performed an extensive review of the medical literature dealing with this condition and herein presented a comprehensive discussion of this interesting disease, including all aspects from epidemiology to therapy.

AimsCardiac transplant recipients often suffer from type 2 diabetes mellitus (T2DM) but its influence on graft failure and post-transplant mortality remains unknown. The aim of this study was to investigate the long-term effects of pre-transplant T2DM in patients after heart transplantation (HTX).MethodsThis study included a total of 376 adult patients who received HTX at Heidelberg Heart Center between 01/01/2000 and 01/10/2016. HTX recipients were stratified by diagnosis of T2DM at the time of HTX. Patients with T2DM were further subdivided by hemoglobin A1c (HbA1c ≥ 7.0%). Analysis included donor and recipient data, immunosuppressive drugs, concomitant medications, post-transplant mortality, and causes of death. Five-year post-transplant mortality was further assessed by multivariate analysis (Cox regression) and Kaplan–Meier estimator.ResultsAbout one-third of all HTX recipients had T2DM (121 of 376 [32.2%]). Patients with T2DM showed an increased 5-year post-transplant mortality (41.3% versus 29.8%; P = 0.027) and had a higher percentage of death due to graft failure (14.9% versus 7.8%; P = 0.035). Multivariate analysis showed T2DM (HR: 1.563; 95% CI: 1.053–2.319; P = 0.027) as an independent risk factor for 5-year mortality after HTX. Kaplan–Meier analysis showed a significantly better 5-year post-transplant survival of patients with T2DM and a HbA1c < 7.0% than patients with T2DM and a HbA1c ≥ 7.0% (68.7% versus 46.3%; P = 0.008) emphasizing the clinical relevance of a well-controlled T2DM in HTX recipients.ConclusionPre-transplant T2DM is associated with higher graft failure and increased 5-year mortality after HTX.

ObjectiveThe pathogenesis of diabetic polyneuropathy (DN) is poorly understood and given the increasing prevalence of DN, there is a need for clinical or imaging biomarkers that quantify structural and functional nerve damage. While clinical studies have found evidence of an association between elevated levels of troponin T (hsTNT) and N-terminal pro brain natriuretic peptide (proBNP) with microvascular compromise in type 2 diabetes (T2D), their implication in mirroring DN nerve perfusion changes remains unclear. The objective of this study was, therefore, to investigate whether hsTNT and proBNP assays are associated with MRI nerve perfusion in T2D.MethodsIn this prospective cross-sectional single-center case-control study, 56 participants (44 with T2D, 12 healthy control subjects) consented to undergo magnetic resonance neurography (MRN) including dynamic contrast-enhanced (DCE) perfusion imaging of the right leg. Using the extended Tofts model, primary outcome parameters that were quantified are the sciatic nerve’s microvascular permeability (Ktrans), the extravascular extracellular volume fraction (ve), and the plasma volume fraction (vp), as well as hsTNT and proBNP values from serological workup. Further secondary outcomes were clinical, serological, and electrophysiological findings.ResultsIn T2D patients, hsTNT was negatively correlated with Ktrans (r=-0.38; p=0.012) and ve (r=-0.30; p=0.048) but not with vp (r=-0.16; p=0.294). HsTNT, Ktrans, and ve were correlated with peroneal nerve conduction velocities (NCVs; r=-0.44; p=0.006, r=0.42; p=0.008, r=0.39; p=0.014), and tibial NCVs (r=-0.38;p=0.022, r=0.33; p=0.048, r=0.37; p=0.025). No such correlations were found for proBNP.ConclusionsThis study is the first to find that hsTNT is correlated with a decrease of microvascular permeability and a reduced extravascular extracellular volume fraction of nerves in patients with T2D. The results indicate that hsTNT may serve as a potential marker for the assessment of nerve perfusion in future studies on DN.

ObjectiveIt is controversially discussed in how far smoking contributes to diabetic polyneuropathy (DPN) in type 2 diabetes (T2D). Diffusion-weighted magnetic resonance neurography (MRN) at 3 Tesla has been shown to provide objective values for structural nerve integrity in patients with T2D. The aim of this study was to investigate the contribution of cigarette smoking on structural nerve integrity in T2D.MethodsThis cross-sectional prospective cohort study investigated the structural integrity of the sciatic nerve in 10 smokers, 40 never-smokers, and 20 ex-smokers with T2D and 10 healthy control subjects, using diffusion tensor imaging MRN at 3 Tesla and semi-automated nerve fiber tracking. Results were correlated with clinical, electrophysiological, and serological data.ResultsThe sciatic nerve’s fractional anisotropy (FA), a parameter for structural nerve integrity, was significantly lower in smokers with T2D when compared to controls (p = 0.002) and never-smokers (p = 0.015), and lower in ex-smokers when compared to controls (p = 0.015). In addition, sciatic nerve radial diffusivity, a marker of myelin damage, was increased in smokers versus controls and never-smokers (p = 0.048, p = 0.049, respectively). Furthermore, FA in T2D patients was negatively correlated with clinical and electrophysiological markers of DPN. FA also showed negative correlations with the pulse wave velocity, a marker of arterial stiffness and associated microangiopathy, in controls (r = −0.70; p = 0.037), never-smokers (r = −0.45; p = 0.004), ex-smokers (r = −0.55; p = 0.009), and a similar trend in smokers (r = −0.63; p = 0.076). Negative correlations were found between FA and skin auto-fluorescence, a marker of tissue advanced glycation end product accumulation and therefore long-term glycemic stress in T2D, in never-smokers (r = −0.39; p = 0.020) and smokers (r = −0.84; p = 0.004), but not in ex-smokers (r = −0.07; p = 0.765).ConclusionThe findings indicate that smoking contributes to sciatic nerve damage in T2D, potentially worsening DPN due to glycemic stress and less microangiopathy-associated myelin damage in active smokers, while angiopathic effects predominate in ex-smokers. To stop smoking may therefore pose a promising preventive measure to slow the progression of DPN in T2D.

BackgroundRecent studies have found that troponin T parallels the structural and functional decay of peripheral nerves at the level of the lower limbs in patients with type 2 diabetes (T2D). The aim of this study was to determine whether this finding can also be reproduced at the level of the upper limbs.MethodsTen patients with fasting glucose levels >100 mg/dl (five with prediabetes and five with T2D) underwent magnetic resonance neurography of the right upper arm comprising T2-weighted and diffusion weighted sequences. The fractional anisotropy (FA), an indicator for the structural integrity of peripheral nerves, was calculated in an automated approach for the median, ulnar, and radial nerve. All participants underwent additional clinical, serological, and electrophysiological assessments.ResultsHigh sensitivity Troponin T (hsTNT) and HbA1c were negatively correlated with the average FA of the median, ulnar and radial nerve (r = −0.84; p = 0.002 and r = −0.68; p = 0.032). Both FA and hsTNT further showed correlations with items of the Michigan Hand Outcome Questionnaire (r = −0.76; p = 0.010 and r = 0.87; p = 0.001, respectively). A negative correlation was found for hsTNT and HbA1c with the total Purdue Pegboard Test Score (r = −0.87; p = 0.001 and r = −0.68; p = 0.031).ConclusionThis study is the first to find that hsTNT and HbA1c are associated with functional and structural parameters of the nerves at the level of the upper limbs in patients with impaired glucose tolerance and T2D. Our results support the hypothesis that hyperglycemia-related microangiopathy, represented by elevated hsTNT levels, is a contributor to nerve damage in diabetic polyneuropathy.

Background Impaired cardiac autonomic control is common among people with type 2 diabetes. The autonomic nervous system and its regulatory influence on the cardiovascular system also play a key role in the physiological response to psychosocial stressors. It is unclear whether the disease-related impairment of cardiac autonomic control in people with type 2 diabetes affects the stress response. The aim of this study was therefore to examine the cardiac autonomic and the psychological stress response of people with type 2 diabetes compared to healthy control participants. Methods We used the trier social stress test to induce stress in n = 51 participants with type 2 diabetes and n = 47 healthy controls. We assessed heart rate (HR) and heart rate variability (HRV) using six ECG samples before, during and after the stress test. We measured participants’ psychological stress response using visual analogue scales. Results Longitudinal multilevel models showed an attenuated HR increase in response to the stress test combined with a slower HR recovery after the stress test, in people with type 2 diabetes. This pattern was accompanied by significantly lower low frequency HRV but no differences in high frequency HRV between the groups. Additionally, people with type 2 diabetes showed an increased level of self-reported psychological tension 45 minutes after the stress test. Conclusions The impairment of the autonomic nervous system found in people with type 2 diabetes is reflected in the HR response to stress—but not in the HRV response—and partially mirrored in the psychological stress response. Our results underline the importance of considering the interplay of psychosocial stress and disease-related changes in the physiological stress response system in research and treatment of type 2 diabetes.

BackgroundImpaired cardiac autonomic control is common among people with type 2 diabetes. The autonomic nervous system and its regulatory influence on the cardiovascular system also play a key role in the physiological response to psychosocial stressors. It is unclear whether the disease-related impairment of cardiac autonomic control in people with type 2 diabetes affects the stress response. The aim of this study was therefore to examine the cardiac autonomic and the psychological stress response of people with type 2 diabetes compared to healthy control participants.MethodsWe used the trier social stress test to induce stress in n = 51 participants with type 2 diabetes and n = 47 healthy controls. We assessed heart rate (HR) and heart rate variability (HRV) using six ECG samples before, during and after the stress test. We measured participants' psychological stress response using visual analogue scales.ResultsLongitudinal multilevel models showed an attenuated HR increase in response to the stress test combined with a slower HR recovery after the stress test, in people with type 2 diabetes. This pattern was accompanied by significantly lower low frequency HRV but no differences in high frequency HRV between the groups. Additionally, people with type 2 diabetes showed an increased level of self-reported psychological tension 45 minutes after the stress test.ConclusionsThe impairment of the autonomic nervous system found in people with type 2 diabetes is reflected in the HR response to stress-but not in the HRV response-and partially mirrored in the psychological stress response. Our results underline the importance of considering the interplay of psychosocial stress and disease-related changes in the physiological stress response system in research and treatment of type 2 diabetes.

Patients with diabetes are over-represented among the total cases reported with “idiopathic” pulmonary fibrosis (IPF). This raises the question, whether this is an association only or whether diabetes itself can cause pulmonary fibrosis. Recent studies in mouse models of type 1 and type 2 diabetes demonstrated that diabetes causes pulmonary fibrosis. Both types of diabetes trigger a cascade, starting with increased DNA damage, an impaired DNA repair, and leading to persistent DNA damage signaling. This response, in turn, induces senescence, a senescence-associated-secretory phenotype (SASP), marked by the release of pro-inflammatory cytokines and growth factors, finally resulting in fibrosis. Restoring DNA repair drives fibrosis into remission, thus proving causality. These data can be translated clinically to patients with type 2 diabetes, characterized by long-term diabetes and albuminuria. Hence there are several arguments, to substitute the term “idiopathic” pulmonary fibrosis (IPF) in patients with diabetes (and exclusion of other causes of lung diseases) by the term “diabetes-induced pulmonary fibrosis” (DiPF). However, future studies are required to establish this term and to study whether patients with diabetes respond to the established therapies similar to non-diabetic patients.

Background: Cross-sectional as well as longitudinal studies have linked childhood maltreatment to type 2 diabetes in adulthood with childhood neglect showing the strongest effect on type 2 diabetes risk. However, the mechanisms that link childhood maltreatment to type 2 diabetes are still unclear. Alterations in the psychological and physiological stress response system, specifically the hypothalamus-pituitary-adrenal (HPA) axis are a common finding in samples with a background of childhood neglect and are associated with type 2 diabetes. In the present study, we investigated the association between childhood neglect and the physiological and psychological stress response in patients with type 2 diabetes and healthy control participants.Method: We assessed emotional and physical childhood neglect in a sample of n = 74 patients with type 2 diabetes and n = 50 healthy control participants. We used the trier social stress test (TSST) to induce a stress response. Blood ACTH and cortisol levels were measured before (T0), directly after (T1) as well as 30 (T2) and 60 (T3) min after the TSST. Participants' subjective experience was assessed via visual analog scales before, directly after as well as at 45 min after the TSST. We used multiple regression analyses to predict the change in self-reported tension between T0 and T1. Multilevel models were applied to predict cortisol and ACTH levels across all measurement points.Results: We found a significant association between moderate to severe childhood neglect and a stronger psychological stress response in patients with type 2 diabetes, that was not present in healthy controls. In type 2 diabetes patients, but not in healthy controls, higher ACTH levels across all measurement points were significantly associated with higher severity of emotional neglect and higher severity of physical neglect was significantly associated with a stronger increase in plasma cortisol from T0 to T1.Conclusions: This is the first study to investigate whether childhood maltreatment in patients with type 2 diabetes could be associated with a dysregulated stress response. Our results show a link between the psychological and physiological stress response and childhood neglect in type 2 diabetes patients. This pathway is thus a possible mechanism connecting type 2 diabetes and childhood neglect.

Objectives: The deficit of Glyoxalase I (Glo1) and the subsequent increase in methylglyoxal (MG) has been reported to be one the five mechanisms by which hyperglycemia causes diabetic late complications. Aldo-keto reductases (AKR) have been shown to metabolize MG; however, the relative contribution of this superfamily to the detoxification of MG in vivo, particularly within the diabetic state, remains unknown. Methods: CRISPR/Cas9-mediated genome editing was used to generate a Glo1 knock-out (Glo1−/−) mouse line. Streptozotocin was then applied to investigate metabolic changes under hyperglycemic conditions. Results: Glo1−/− mice were viable and showed no elevated MG or MG-H1 levels under hyperglycemic conditions. It was subsequently found that the enzymatic efficiency of various oxidoreductases in the liver and kidney towards MG were increased in the Glo1−/− mice. The functional relevance of this was supported by the altered distribution of alternative detoxification products. Furthermore, it was shown that MG-dependent AKR activity is a potentially clinical relevant pathway in human patients suffering from diabetes. Conclusions: These data suggest that in the absence of GLO1, AKR can effectively compensate to prevent the accumulation of MG. The combination of metabolic, enzymatic, and genetic factors, therefore, may provide a better means of identifying patients who are at risk for the development of late complications caused by elevated levels of MG. Keywords: Advanced glycation end products, Glyoxalase 1, Reactive metabolites, Methylglyoxal, Diabetic complications, Aldo-keto reductases

BackgroundNerve damage in diabetic neuropathy (DN) is assumed to begin in the distal legs with a subsequent progression to hands and arms at later stages. In contrast, recent studies have found that lower limb nerve lesions in DN predominate at the proximal sciatic nerve and that, in the upper limb, nerve functions can be impaired at early stages of DN.Materials and MethodsIn this prospective, single-center cross-sectional study, participants underwent diffusion-weighted 3 Tesla magnetic resonance neurography in order to calculate the sciatic nerve’s fractional anisotropy (FA), a surrogate parameter for structural nerve integrity. Results were correlated with clinical and electrophysiological assessments of the lower limb and an examination of hand function derived from the Purdue Pegboard Test.ResultsOverall, 71 patients with diabetes, 11 patients with prediabetes and 25 age-matched control subjects took part in this study. In patients with diabetes, the sciatic nerve’s FA showed positive correlations with tibial and peroneal nerve conduction velocities (r = 0.62; p < 0.001 and r = 0.56; p < 0.001, respectively), and tibial and peroneal nerve compound motor action potentials (r = 0.62; p < 0.001 and r = 0.63; p < 0.001, respectively). Moreover, the sciatic nerve’s FA was correlated with the Pegboard Test results in patients with diabetes (r = 0.52; p < 0.001), prediabetes (r = 0.76; p < 0.001) and in controls (r = 0.79; p = 0.007).ConclusionThis study is the first to show that the sciatic nerve’s FA is a surrogate marker for functional and electrophysiological parameters of both upper and lower limbs in patients with diabetes and prediabetes, suggesting that nerve damage in these patients is not restricted to the level of the symptomatic limbs but rather affects the entire peripheral nervous system.

Increased methylglyoxal (MG) formation is associated with diabetes and its complications. In zebrafish, knockout of the main MG detoxifying system Glyoxalase 1, led to limited MG elevation but significantly elevated aldehyde dehydrogenases (ALDH) activity and aldh3a1 expression, suggesting the compensatory role of Aldh3a1 in diabetes. To evaluate the function of Aldh3a1 in glucose homeostasis and diabetes, aldh3a1−/− zebrafish mutants were generated using CRISPR-Cas9. Vasculature and pancreas morphology were analysed by zebrafish transgenic reporter lines. Corresponding reactive carbonyl species (RCS), glucose, transcriptome and metabolomics screenings were performed and ALDH activity was measured for further verification. Aldh3a1−/− zebrafish larvae displayed retinal vasodilatory alterations, impaired glucose homeostasis, which can be aggravated via pdx1 silencing induced hyperglycaemia. Unexpectedly, MG was not altered, but 4-hydroxynonenal (4-HNE), another prominent lipid peroxidation RCS exhibited high affinity with Aldh3a1, was increased in aldh3a1 mutants. 4-HNE was responsible for the retinal phenotype via pancreas disruption induced hyperglycaemia and can be rescued via l-Carnosine treatment. Furthermore, in type 2 diabetic patients, serum 4-HNE was increased and correlated with disease progression. Thus, our data suggest impaired 4-HNE detoxification and elevated 4-HNE concentration as biomarkers but also the possible inducers for diabetes, from genetic susceptibility to the pathological progression.

Diabetic neuropathy (DPN) is one of the most severe and yet most poorly understood complications of diabetes mellitus. In vivo imaging of dorsal root ganglia (DRG), a key structure for the understanding of DPN, has been restricted to animal studies. These have shown a correlation of decreased DRG volume with neuropathic symptom severity. Our objective was to investigate correlations of DRG morphology and signal characteristics at 3 Tesla (3T) magnetic resonance neurography (MRN) with clinical and serological data in diabetic patients with and without DPN. In this cross-sectional study, participants underwent 3T MRN of both L5 DRG using an isotropic 3D T2-weighted, fat-suppressed sequence with subsequent segmentation of DRG volume and analysis of normalized signal properties. Overall, 55 diabetes patients (66 ± 9 years; 32 men; 30 with DPN) took part in this study. DRG volume was smaller in patients with severe DPN when compared to patients with mild or moderate DPN (134.7 ± 21.86 vs 170.1 ± 49.22; p = 0.040). In DPN patients, DRG volume was negatively correlated with the neuropathy disability score (r = −0.43; 95%CI = −0.66 to −0.14; p = 0.02), a measure of neuropathy severity. DRG volume showed negative correlations with triglycerides (r = −0.40; 95%CI = −0.57 to −0.19; p = 0.006), and LDL cholesterol (r = −0.33; 95%CI = −0.51 to −0.11; p = 0.04). There was a strong positive correlation of normalized MR signal intensity (SI) with the neuropathy symptom score in the subgroup of patients with painful DPN (r = 0.80; 95%CI = 0.46 to 0.93; p = 0.005). DRG SI was positively correlated with HbA1c levels (r = 0.30; 95%CI = 0.09 to 0.50; p = 0.03) and the triglyceride/HDL ratio (r = 0.40; 95%CI = 0.19 to 0.57; p = 0.007). In this first in vivo study, we found DRG morphological degeneration and signal increase in correlation with neuropathy severity. This elucidates the potential importance of MR-based DRG assessments in studying structural and functional changes in DPN.

The number of diabetic patients in Europe and world-wide is growing. Diabetes confers a 2-fold higher risk for vascular disease. Lack of insulin production (Type 1 diabetes, T1D) or lack of insulin responsiveness (Type 2 diabetes, T2D) causes systemic metabolic changes such as hyperglycemia (HG) which contribute to the pathology of diabetes. Monocytes and macrophages are key innate immune cells that control inflammatory reactions associated with diabetic vascular complications. Inflammatory programming of macrophages is regulated and maintained by epigenetic mechanisms, in particular histone modifications. The aim of our study was to identify the epigenetic mechanisms involved in the hyperglycemia-mediated macrophage activation. Using Affymetrix microarray profiling and RT-qPCR we identified that hyperglycemia increased the expression of S100A9 and S100A12 in primary human macrophages. Expression of S100A12 was sustained after glucose levels were normalized. Glucose augmented the response of macrophages to Toll-like receptor (TLR)-ligands Palmatic acid (PA) and Lipopolysaccharide (LPS) i.e., pro-inflammatory stimulation. The abundance of activating histone Histone 3 Lysine 4 methylation marks (H3K4me1, H3K4me3) and general acetylation on histone 3 (AceH3) with the promoters of these genes was analyzed by chromatin immunoprecipitation. Hyperglycemia increased acetylation of histones bound to the promoters of S100A9 and S100A12 in M1 macrophages. In contrast, hyperglycemia caused a reduction in total H3 which correlated with the increased expression of both S100 genes. The inhibition of histone methyltransferases SET domain-containing protein (SET)7/9 and SET and MYND domain-containing protein (SMYD)3 showed that these specifically regulated S100A12 expression. We conclude that hyperglycemia upregulates expression of S100A9, S100A12 via epigenetic regulation and induces an activating histone code on the respective gene promoters in M1 macrophages. Mechanistically, this regulation relies on action of histone methyltransferases SMYD3 and SET7/9. The results define an important role for epigenetic regulation in macrophage mediated inflammation in diabetic conditions.

Asprosin is a counter-regulatory hormone to insulin which plays a role in fasting. It may therefore also play a role in hypoglycaemia unawareness, which has been subsequently examined in this pilot study. Intravenous glucose tolerance test was used to induce controlled hyperglycemia whereas a hyperinsulinemic clamp test was used to induce a controlled hypoglycaemia in 15 patients with diabetes type 1, with and without hypoglycaemia unawareness. Changes in asprosin plasma levels did not differ between patients with and without hypoglycaemia unawareness. However, nine patients with insulin resistance as well as higher liver stiffness values and low-density lipoprotein but lower high-density lipoprotein levels did not show the expected increase in asprosin plasma levels during hypoglycemia. Therefore, insulin resistance and alterations in liver structure, most likely early stages of non-alcoholic fatty liver disease, seem to be relevant in type 1 diabetes and do not only lead to elevated plasma levels of asprosin, but also to a blunted asprosin response in hypoglycemia.

The protein hormone adiponectin promotes metabolic and psychological health. The aim of the study was to track changes in adiponectin levels in response to weight gain and to assess associations between adiponectin and psychological aspects in patients with anorexia nervosa (AN).To investigate if adiponectin levels depend on AN severity, data were assessed from 11 inpatients with a very low body mass index (BMI) and a high chronicity (high severity group; HSS), and nine with less severe symptoms (LSS). During the course of treatment, serum adiponectin concentrations were assessed on a weekly basis along with BMI. Psychological variables (i.e., depression, anxiety, stress, and AN-specific symptoms) were obtained by means of electronic diaries. Longitudinal regressions and correlations were calculated to evaluate the temporal course of adiponectin and its relationship with psychological self-ratings.At the beginning adiponectin was not increased in HSS patients (p = .56), and only marginally elevated in LSS patients (p = 0.07) compared with controls. In HSS patients, adiponectin increased along with BMI during the first treatment phase (i.e., when the BMI of patients was below 16 kg/m2) and thereafter decreased with further weight gain. In LSS patients, adiponectin was not associated with BMI increase. Furthermore, adiponectin was strongly negatively correlated with psychological self-ratings when the BMI of patients was above 16 kg/m2, i.e., higher levels of adiponectin were related to lower ratings of depression, anxiety, and AN-specific symptoms.The study connects previous varying results by indicating that the course of adiponectin is dependent on BMI and symptom severity. Similarly, associations of adiponectin and psychological health depended on BMI.

Leptin, a hormone secreted by adipose tissue, appears to play a major role in the homeostasis of body weight and psychobiological processes associated with anorexia nervosa (AN). However, there is scarce data on its exact influence on this disorder, in particular data over time.The present study addresses whether leptin changes during inpatient treatment play a role for treatment outcome and psychological factors in underweight AN patients.In order to understand whether leptin's role differs in relation to AN severity, data were assessed from 11 patients with a very low BMI and a higher chronicity (high severity group; HSS; mean BMI at the beginning of the study = 13.6; mean duration of illness = 5.1 years) vs. nine with less severe symptoms (LSS; mean BMI = 16.2; mean duration of illness = 3.7 years). During the course of treatment, serum leptin concentrations were assessed weekly while weight (BMI) was assessed twice per week. Concomitantly, psychological variables were obtained by means of electronic diaries. Unconditional linear growth models were calculated to evaluate the temporal course of leptin in relation to BMI. For HSS patients, two phases of treatment (BMI < 16 and BMI ≥ 16 kg/m2) were investigated.Leptin increased significantly with BMI in both groups of patients. For HSS patients, the increase of leptin in the first treatment phase did not predict later increases in BMI. Furthermore, the relationship of leptin and psychological factors was modulated by symptom severity. In HSS patients, higher leptin levels were associated with greater feelings of depression, anxiety, and stress whereas in LSS patients a higher leptin level showed the trend to be associated with lower psychological symptom burden.Our results suggest that leptin changes are differently associated with weight gain and psychological symptoms depending on the severity of starvation.

Bacterial toxin–antitoxin (TA) systems are genetic elements, which are encoded by plasmid as well as chromosomal loci. They mediate plasmid and genomic island maintenance through post-segregational killing mechanisms but may also have milder effects, acting as mobile stress response systems that help certain cells of a population in persisting adverse growth conditions. Very few cyanobacterial TA system have been characterized thus far. In this work, we focus on the cyanobacterium Synechocystis 6803, a widely used model organism. We expand the number of putative Type II TA systems from 36 to 69 plus seven stand-alone components. Forty-seven TA pairs are located on the chromosome and 22 are plasmid-located. Different types of toxins are associated with various antitoxins in a mix and match principle. According to protein domains and experimental data, 81% of all toxins in Synechocystis 6803 likely exhibit RNase activity, suggesting extensive potential for toxicity-related RNA degradation and toxin-mediated transcriptome remodeling. Of particular interest is the Ssr8013–Slr8014 system encoded on plasmid pSYSG, which is part of a larger defense island or the pSYSX system Slr6056–Slr6057, which is linked to a bacterial ubiquitin-like system. Consequently, Synechocystis 6803 is one of the most prolific sources of new information about these genetic elements.