Management of pasireotide-induced hyperglycemia in patients with acromegaly: An experts' consensus statement.

Pasireotide is a somatostatin analogue for the treatment of acromegaly, a chronic condition caused by excess growth hormone. Despite the therapeutic benefits of pasireotide as a second-line treatment for inadequately controlled acromegaly, a major concern is its hyperglycemic side-effect. Here, we provide guidance on how to select appropriate patients with acromegaly for treatment with pasireotide. We summarize baseline characteristics of patients at high risk for pasireotide-associated hyperglycemia and recommend a monitoring strategy based on the risk profile. Self-monitoring of blood glucose levels (SMBG), measurements of fasting plasma glucose (FPG), postprandial plasma glucose (PPG) and regular HbA1c measurements are the foundation of our proposed monitoring approach. The pathophysiology of pasireotide-induced hyperglycemia involves decreased secretion of the incretin hormones GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). Our expert recommendations address the specific pathophysiology of pasireotide-induced hyperglycemia by recommending the incretin-based therapeutics dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in all appropriate patients as an alternative to first-line monotherapy with metformin. Furthermore, we emphasize the importance of adequate control of acromegaly, excellent diabetes education, nutrition and lifestyle guidance and advise to consult expert diabetologists in case of uncertainty in the management of patients with hyperglycemia under pasireotide.

Diabetic neuropathy is a generalized phenomenon with impact on hand functional performance and quality of life.

BACKGROUND AND PURPOSE: Diabetic sensorimotor peripheral neuropathy is usually considered to affect predominantly the lower limbs (LL-N), whereas the impact of upper limb neuropathy (UL-N) on hand functional performance and quality of life (QoL) has not been evaluated systematically. This study aims to investigate the prevalence and characteristics of UL-N and its functional and psychosocial consequences in type 2 diabetes. METHODS: Individuals with type 2 diabetes (n = 141) and an age- and sex-matched control group (n = 73) underwent comprehensive assessment of neuropathy, hand functional performance, and psychosocial status. RESULTS: The prevalence of UL-N was 30.5% in patients with diabetes and that of LL-N was 49.6%, with 25.5% exhibiting both. Patients with diabetes showed similar sensory phenotype regarding both large and small fiber functions in hands and feet. Patients with UL-N showed reduced manual dexterity, but normal hand grip force. Additionally, there was a correlation between reduced dexterity and sensory deficits. Patients with UL-N had reduced estimates of psychosocial health including health-related QoL compared to control subjects and patients without UL-N. UL-N correlated with the severity of LL-N, but not with duration of diabetes, glycemia, age, or sex. CONCLUSIONS: This study points to a substantial prevalence of UL-N in type 2 diabetes. The sensory phenotype of patients with UL-N was similar to LL-N and was characterized by loss of sensory function. Our study demonstrated an association of UL-N with impaired manual dexterity and reduced health-related QoL. Thus, upper limb sensorimotor functions should be assessed early in patients with diabetes.

Neuron-specific biomarkers predict hypo- and hyperalgesia in individuals with diabetic peripheral neuropathy.

AIMS/HYPOTHESIS: The individual risk of progression of diabetic peripheral neuropathy is difficult to predict for each individual. Mutations in proteins that are responsible for the process of myelination are known to cause neurodegeneration and display alteration in experimental models of diabetic neuropathy. In a prospective observational human pilot study, we investigated myelin-specific circulating mRNA targets, which have been identified in vitro, for their capacity in the diagnosis and prediction of diabetic neuropathy. The most promising candidate was tested against the recently established biomarker of neural damage, neurofilament light chain protein. METHODS: Schwann cells were cultured under high-glucose conditions and mRNAs of various myelin-specific genes were screened intra- and extracellularly. Ninety-two participants with type 2 diabetes and 30 control participants were enrolled and evaluated for peripheral neuropathy using neuropathy deficit scores, neuropathy symptom scores and nerve conduction studies as well as quantitative sensory testing at baseline and after 12/24 months of a follow-up period. Magnetic resonance neurography of the sciatic nerve was performed in 37 individuals. Neurofilament light chain protein and four myelin-specific mRNA transcripts derived from in vitro screenings were measured in the serum of all participants. The results were tested for associations with specific neuropathic deficits, fractional anisotropy and the progression of neuropathic deficits at baseline and after 12 and 24 months. RESULTS: In neuronal Schwann cells and human nerve sections, myelin protein zero was identified as the strongest candidate for a biomarker study. Circulating mRNA of myelin protein zero was decreased significantly in participants with diabetic neuropathy (p < 0.001), whereas neurofilament light chain protein showed increased levels in participants with diabetic neuropathy (p < 0.05). Both variables were linked to altered electrophysiology, fractional anisotropy and quantitative sensory testing. In a receiver-operating characteristic curve analysis myelin protein zero improved the diagnostic performance significantly in combination with a standard model (diabetes duration, age, BMI, HbA1c) from an AUC of 0.681 to 0.836 for the detection of diabetic peripheral neuropathy. A follow-up study revealed that increased neurofilament light chain was associated with the development of a hyperalgesic phenotype (p < 0.05), whereas decreased myelin protein zero predicted hypoalgesia (p < 0.001) and progressive loss of nerve function 24 months in advance (HR of 6.519). CONCLUSIONS/INTERPRETATION: This study introduces a dynamic and non-invasive assessment strategy for the underlying pathogenesis of diabetic peripheral neuropathy. The diagnosis of axonal degeneration, associated with hyperalgesia, and demyelination, linked to hypoalgesia, could benefit from the usage of neurofilament light chain protein and circulating mRNA of myelin protein zero as potential biomarkers.

Diffusion Tensor Imaging of the Sciatic Nerve as a Surrogate Marker for Nerve Functionality of the Upper and Lower Limb in Patients With Diabetes and Prediabetes.

BACKGROUND: Nerve 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 METHODS: In 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. RESULTS: Overall, 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). CONCLUSION: This 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.

Magnetic Resonance Neurography Reveals Smoking-Associated Decrease in Sciatic Nerve Structural Integrity in Type 2 Diabetes.

OBJECTIVE: It 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. METHODS: This 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. RESULTS: The 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). CONCLUSION: The 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.

Diabetic Polyneuropathy Is Associated With Pathomorphological Changes in Human Dorsal Root Ganglia: A Study Using 3T MR Neurography.

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.

Troponin T Parallels Structural Nerve Damage in Type 2 Diabetes: A Cross-sectional Study Using Magnetic Resonance Neurography.

Clinical studies have suggested that changes in peripheral nerve microcirculation may contribute to nerve damage in diabetic polyneuropathy (DN). High-sensitivity troponin T (hsTNT) assays have been recently shown to provide predictive values for both cardiac and peripheral microangiopathy in type 2 diabetes (T2D). This study investigated the association of sciatic nerve structural damage in 3 Tesla (3T) magnetic resonance neurography (MRN) with hsTNT and N-terminal pro-brain natriuretic peptide serum levels in patients with T2D. MRN at 3T was performed in 51 patients with T2D (23 without DN, 28 with DN) and 10 control subjects without diabetes. The sciatic nerve's fractional anisotropy (FA), a marker of structural nerve integrity, was correlated with clinical, electrophysiological, and serological data. In patients with T2D, hsTNT showed a negative correlation with the sciatic nerve's FA (r = -0.52, P < 0.001), with a closer correlation in DN patients (r = -0.66, P < 0.001). hsTNT further correlated positively with the neuropathy disability score (r = 0.39, P = 0.005). Negative correlations were found with sural nerve conduction velocities (NCVs) (r = -0.65, P < 0.001) and tibial NCVs (r = -0.44, P = 0.002) and amplitudes (r = -0.53, P < 0.001). This study is the first to show that hsTNT is a potential indicator for structural nerve damage in T2D. Our results indirectly support the hypothesis that microangiopathy contributes to structural nerve damage in T2D.

Structural Nerve Remodeling at 3-T MR Neurography Differs between Painful and Painless Diabetic Polyneuropathy in Type 1 or 2 Diabetes.

Background The pathophysiologic mechanisms underlying painful symptoms in diabetic polyneuropathy (DPN) are poorly understood. They may be associated with MRI characteristics, which have not yet been investigated. Purpose To investigate correlations between nerve structure, load and spatial distribution of nerve lesions, and pain in patients with DPN. Materials and Methods In this prospective single-center cross-sectional study, participants with type 1 or 2 diabetes volunteered between June 2015 and March 2018. Participants underwent 3-T MR neurography of the sciatic nerve with a T2-weighed fat-suppressed sequence, which was preceded by clinical and electrophysiologic tests. For group comparisons, analysis of variance or the Kruskal-Wallis test was performed depending on Gaussian or non-Gaussian distribution of data. Spearman correlation coefficients were calculated for correlation analysis. Results A total of 131 participants (mean age, 62 years ± 11 [standard deviation]; 82 men) with either type 1 (n = 45) or type 2 (n = 86) diabetes were evaluated with painful (n = 64), painless (n = 37), or no (n = 30) DPN. Participants who had painful diabetic neuropathy had a higher percentage of nerve lesions in the full nerve volume (15.2% ± 1.6) than did participants with nonpainful DPN (10.4% ± 1.7, P = .03) or no DPN (8.3% ± 1.7; P < .001). The amount and extension of T2-weighted hyperintense nerve lesions correlated positively with the neuropathy disability score (r = 0.37; 95% confidence interval [CI]: 0.21, 0.52; r = 0.37; 95% CI: 0.20, 0.52, respectively) and the neuropathy symptom score (r = 0.41; 95% CI: 0.25, 0.55; r = 0.34; 95% CI: 0.17, 0.49, respectively). Negative correlations were found for the tibial nerve conduction velocity (r = -0.23; 95% CI: -0.44, -0.01; r = -0.37; 95% CI: -0.55, -0.15, respectively). The cross-sectional area of the nerve was positively correlated with the neuropathy disability score (r = 0.23; 95% CI: 0.03, 0.36). Negative correlations were found for the tibial nerve conduction velocity (r = -0.24; 95% CI: -0.45, -0.01). Conclusion The amount and extension of T2-weighted hyperintense fascicular nerve lesions were greater in patients with painful diabetic neuropathy than in those with painless diabetic neuropathy. These results suggest that proximal fascicular damage is associated with the evolution of painful sensory symptoms in diabetic polyneuropathy. © RSNA, 2019 Online supplemental material is available for this article.

Understanding Diabetic Neuropathy-From Subclinical Nerve Lesions to Severe Nerve Fiber Deficits: A Cross-Sectional Study in Patients With Type 2 Diabetes and Healthy Control Subjects.

Studies on magnetic resonance neurography (MRN) in diabetic polyneuropathy (DPN) have found proximal sciatic nerve lesions. The aim of this study was to evaluate the functional relevance of sciatic nerve lesions in DPN, with the expectation of correlations with the impairment of large-fiber function. Sixty-one patients with type 2 diabetes (48 with and 13 without DPN) and 12 control subjects were enrolled and underwent MRN, quantitative sensory testing, and electrophysiological examinations. There were differences in mechanical detection (Aß fibers) and mechanical pain (Aδ fibers) but not in thermal pain and thermal detection clusters (C fibers) among the groups. Lesion load correlated with lower Aα-, Aß-, and Aδ-fiber but not with C-fiber function in all participants. Patients with lower function showed a higher load of nerve lesions than patients with elevated function or no measurable deficit despite apparent DPN. Longer diabetes duration was associated with higher lesion load in patients with DPN, suggesting that nerve lesions in DPN may accumulate over time and become clinically relevant once a critical amount of nerve fascicles is affected. Moreover, MRN is an objective method for determining lower function mainly in medium and large fibers in DPN.

Association of Serum Cholesterol Levels With Peripheral Nerve Damage in Patients With Type 2 Diabetes.

Importance: Lowering serum cholesterol levels is a well-established treatment for dyslipidemia in patients with type 2 diabetes (T2D). However, nerve lesions in patients with T2D increase with lower serum cholesterol levels, suggesting that lowering serum cholesterol levels is associated with diabetic polyneuropathy (DPN) in patients with T2D. Objective: To investigate whether there is an association between serum cholesterol levels and peripheral nerve lesions in patients with T2D with and without DPN. Design, Setting, and Participants: This single-center, cross-sectional, prospective cohort study was performed from June 1, 2015, to March 31, 2018. Observers were blinded to clinical data. A total of 256 participants were approached, of whom 156 were excluded. A total of 100 participants consented to undergo magnetic resonance neurography of the right leg at the Department of Neuroradiology and clinical, serologic, and electrophysiologic assessment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. Exposures: Quantification of the nerve's diameter and lipid equivalent lesion (LEL) load with a subsequent analysis of all acquired clinical and serologic data with use of 3.0-T magnetic resonance neurography of the right leg with 3-dimensional reconstruction of the sciatic nerve. Main Outcomes and Measures: The primary outcome was lesion load and extension. Secondary outcomes were clinical, serologic, and electrophysiologic findings. Results: A total of 100 participants with T2D (mean [SD] age, 64.6 [0.9] years; 68 [68.0%] male) participated in the study. The LEL load correlated positively with the nerve's mean cross-sectional area (r = 0.44; P < .001) and the maximum length of a lesion (r = 0.71; P < .001). The LEL load was negatively associated with total serum cholesterol level (r = -0.41; P < .001), high-density lipoprotein cholesterol level (r = -0.30; P = .006), low-density lipoprotein cholesterol level (r = -0.33; P = .003), nerve conduction velocities of the tibial (r = -0.33; P = .01) and peroneal (r = -0.51; P < .001) nerves, and nerve conduction amplitudes of the tibial (r = -0.31; P = .02) and peroneal (r = -0.28; P = .03) nerves. Conclusions and Relevance: The findings suggest that lowering serum cholesterol levels in patients with T2D and DPN is associated with a higher amount of nerve lesions and declining nerve conduction velocities and amplitudes. These findings may be relevant to emerging therapies that promote an aggressive lowering of serum cholesterol levels in patients with T2D.

Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism - What We Know in Mammals and What We Can Learn From Yeast.

Levels of reactive metabolites such as reactive carbonyl and oxygen species are increased in patients with diabetes mellitus. The most important reactive dicarbonyl species, methylglyoxal (MG), formed as by-product during glucose metabolism, is more and more recognized as a trigger for the development and progression of diabetic complications. Although it is clear that MG provokes toxic effects, it is currently not well understood what cellular changes MG induces on a molecular level that may lead to pathophysiological conditions found in long-term diabetic complications. Here we review the current knowledge about the molecular effects that MG can induce in a cell. Within the mammalian system, we will focus mostly on the metabolic effects MG exerts when applied systemically to rodents or when applied in vitro to pancreatic ß-cells and adipocytes. Due to the common limitations associated with complex model organisms, we then summarize how yeast as a very simple model organism can help to gain valuable comprehensive information on general defence pathways cells exert in response to MG stress. Pioneering studies in additional rather simple eukaryotic model organisms suggest that many cellular reactions in response to MG are highly conserved throughout evolution.

Deep phenotyping neuropathy: An underestimated complication in patients with pre-diabetes and type 2 diabetes associated with albuminuria.

AIMS: The aim of the study was to assess whether quantitative-sensory-testing could be used to evaluate prevalence and predictors of diabetic neuropathy (DPNP) in patients with pre-diabetes and type 2 diabetes. METHODS: Twenty-eight pre-diabetics and 108 patients with type 2 diabetes were evaluated using neuropathy-deficit-score (NDS), neuropathy-symptom-score (NSS), nerve-conduction-studies (NCS), short-QST-protocol to examine small fibers and the comprehensive QST-battery (long-QST) according to the German Research Network on Neuropathic Pain protocol. RESULTS: Long-QST revealed a DPNP-prevalence of 71% in pre-diabetics and 95% in patients with type 2 diabetes, while according to NDS it was only 11% and 63%, and NCS missed 58% of patients with DPNP. Small and medium fibers were similarly affected in both groups, while large fiber deficits were significantly more common in type 2 diabetes (p < 0.01). Complete loss of function in all fibers was significantly higher in patients with type 2 diabetes than in pre-diabetics (26% vs. 11%, p < 0.05). Hyperalgesia was slightly increased in pre-diabetes than in type 2 diabetes (57% vs. 43%, p = n.s.). However, NSS only showed significant associations with large fiber deficits. Logistic regression analyses revealed that age (OR 1.14[1.05/1.24]) and albuminuria (OR 12.8[1.52/107.3]) were independent predictors for the presence of DPNP. CONCLUSIONS: DPNP is much more prevalent in patients with pre-diabetes and type 2 diabetes and clinical routine tests may miss the majority of affected patients. Age and albuminuria, but not HbA1c, appear to be significantly associated with DPNP. CLINICAL TRIAL REGISTRATION: NCT03022721.

Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes mellitus is a significant comorbidity of interstitial lung disease (ILD). OBJECTIVES: The aim of this study was to investigate the incidence of restrictive lung disease (RLD) and ILD in patients with prediabetes and type 2 diabetes (T2D). METHODS: Forty-eight nondiabetics, 68 patients with prediabetes, 29 newly diagnosed T2D, and 110 patients with long-term T2D were examined for metabolic control, diabetes-related complications, breathlessness, and lung function. Five participants with T2D, breathlessness, and RLD underwent multidetector computed tomography (MDCT) and a Six-Minute Walk Test (6MWT). Lung tissue from 4 patients without diabetes and from 3 patients with T2D was histologically examined for presence of pulmonary fibrosis. RESULTS: Breathlessness in combination with RLD was significantly increased in patients with prediabetes and T2D (p < 0.01). RLD was found in 9% of patients with prediabetes, in 20% of patients with newly diagnosed T2D, and in 27% of patients with long-term T2D. Thus, patients with long-term T2D had an increased risk of RLD (OR 5.82 [95% CI 1.71-20.5], p < 0.01). RLD was significantly associated with glucose metabolism and albuminuria (p < 0.01); furthermore, presence of nephropathy increased the risk of RLD (OR 8.57 [95% CI 3.4-21.9], p < 0.01) compared to nondiabetics. MDCT revealed ILD in 4 patients, the 6MWT correlated with the extent of ILD, and histological analysis showed fibrosing ILD in patients with T2D. CONCLUSIONS: This study demonstrates increased breathlessness and a high prevalence of RLD in patients with T2D, indicating an association between diabetes and fibrosing ILD.

Urine levels of 5-aminoimidazole-4-carboxamide riboside (AICAR) in patients with type 2 diabetes.

AIMS: 5-Aminoimidazole-4-carboxamide riboside (AICAR) is an endogenous activator of AMPK, a central regulator of energy homeostasis. Loss and/or reduction of AMPK signaling plays an important role in the development of insulin resistance in type 2 diabetes. The loss of AMPK in diabetes could be due to a loss of AICAR. The aim of this study was to characterize urine levels of AICAR in diabetes and determine whether an association exists with respect to late complications, e.g., retinopathy, nephropathy and neuropathy. METHODS: Urine AICAR was measured by liquid chromatography tandem mass spectrometry in 223 patients consisting of 5 healthy controls, 63 patients with pre-diabetes, 29 patients with newly diagnosed type 2 diabetes and 126 patients with long-standing type 2 diabetes. For statistical analyses, nonparametric Kruskal-Wallis test, one-way ANOVA and multivariate regression analysis were performed to investigate the associations of urinary AICAR excretion within different groups and different clinical parameters. RESULTS: The mean urine AICAR for all 223 patients was 694.7 ± 641.1 ng/ml. There was no significant difference in urine AICAR between the control and patients with diabetes (592.3 ± 345.1 vs. 697.1 ± 646.5 ng/ml). No association between any of the biochemical and/or clinical parameters measured and urine AICAR was found, with the exception of age of patient (R = - 0.34; p < 0.01) and estimated glomerular filtration rate (R = 0.19; p = 0.039). These results were confirmed additionally by linear regression analysis. CONCLUSIONS: Clinical diabetes is not associated with a change in endogenous AICAR levels. Loss of AICAR may therefore not be a mechanism by which AMPK signaling is reduced in diabetes.

Diabetic neuropathy differs between type 1 and type 2 diabetes: Insights from magnetic resonance neurography.

OBJECTIVE: To visualize and quantify differences of microstructural nerve damage in distal symmetric diabetic neuropathy (DPN) between type 1 diabetes (T1D) and type 2 diabetes (T2D), and to detect correlations between neuropathic symptoms and serological risk factors. METHODS: Three-tesla magnetic resonance neurography of the sciatic nerve was performed in 120 patients (T1D, n = 35; T2D, n = 85) with either DPN (n = 84) or no DPN (n = 36). Results were subsequently correlated with clinical, serological, and electrophysiological patient data. RESULTS: T2-weighted (T2w)-hyperintense lesions correlated negatively with tibial compound motor action potential (r = -0.58, p < 0.0001) and peroneal nerve conduction (r = 0.51, p = 0.0002), and positively with neuropathy disability score (NDS; r = -0.54, p < 0.0001), neuropathy symptom score (NSS; r = 0.52, p < 0.0001), and HbA1c level (r = 0.23, p = 0.014). T2w-hypointense lesions correlated positively with NDS (r = 0.28, p = 0.002), NSS (r = 0.36, p < 0.0001), and serum triglycerides (r = 0.34, p = 0.0003), and negatively with serum high-density lipoprotein (HDL; r = -0.48, p < 0.0001). For DPN in T1D, elevated values of T2w-hyperintense lesions (19.67 ± 4.13% vs 12.49 ± 1.23%, p = 0.027) and HbA1c (8.74 ± 0.29% vs 7.11 ± 0.16%, p < 0.0001) were found when compared to T2D. For DPN in T2D, elevated T2w-hypointense lesions (23.41 ± 2.69mm3 vs 11.43 ± 1.74mm3 , p = 0.046) and triglycerides (220.70 ± 23.70mg/dl vs 106.60 ± 14.51mg/dl, p < 0.0001), and lower serum HDL (51.29 ± 3.02mg/dl vs 70.79 ± 4.65mg/dl, p < 0.0001) were found when compared to T1D. INTERPRETATION: The predominant type of nerve lesion in DPN differs between T1D and T2D. Correlations found between lesion type and serological parameters indicate that predominant nerve lesions in T1D are associated with poor glycemic control and loss of nerve conduction, whereas predominant lesions in T2D are associated with changes in lipid metabolism. These findings may be helpful for future studies on the underlying pathophysiological pathways and possible treatments for DPN in T1D and T2D. Ann Neurol 2018;83:588-598.

An 8-week diet high in cereal fiber and coffee but free of red meat does not improve beta-cell function in patients with type 2 diabetes mellitus: a randomized controlled trial.

BACKGROUND: Higher dietary intake of fibers and coffee, but lower red meat intake is associated with reduced risk for type 2 diabetes in epidemiological studies. We hypothesized that a calorie-restricted diet, which is high in fiber and coffee, but free of red meat, improves beta-cell function in patients with T2D. METHODS: In a randomized parallel-group pilot trial, obese type 2 diabetes patients were randomly allocated to consume either a diet high in cereal fiber and coffee, but free of red meat (n = 17) (L-RISK) or a diet low in fiber, free of coffee but high in red meat (n = 20) (H-RISK) for 8 weeks. Insulin secretion was assessed from glucagon stimulation tests (GST) and mixed-meal tolerance tests (MMTT) before and after dietary intervention. RESULTS: Both diets resulted in comparable reduction of fasting concentrations of insulin (H-RISK -28% vs. L-RISK -32%, both p < 0.01), C-peptide (H-RISK -26% vs. L-RISK -30%, both p < 0.01) and blood glucose (H-RISK -6.8%, p < 0.05 vs. L-RISK -10%, p < 0.01). Gastric inhibitory peptide (GIP) secretion increased by 24% after 8 weeks in the L-RISK only (p < 0.01). However, GST and MMTT showed no differences in insulin secretion after intervention. CONCLUSIONS: Calorie restriction independent of the intake of fiber, coffee or meat failed to improve beta-cell function, but improved GIP secretion in obese patients with type 2 diabetes. TRIAL REGISTRATION: Registration at Clinicaltrials.gov, Identifier number: NCT01409330, Registered 4 August 2011 - Retrospectively registered.

Electrical Muscle Stimulation Induces an Increase of VEGFR2 on Circulating Hematopoietic Stem Cells in Patients With Diabetes.

PURPOSE: External electric muscle stimulation (EMS) of the thigh muscles was found to reduce pain resulting from diabetic neuropathy (DN), a vascular complication of diabetes. This study investigated circulating hematopoietic stem cells (HSCs) after EMS treatment. Impaired function of HSCs and the subpopulation endothelial progenitor cells (EPCs), important for neovascularization and endothelial repair, has been associated with DN. METHODS: Twenty-four patients with painful DN were treated 3 times with EMS over a period of 1 week. Blood samples were collected before and after the first EMS treatment. Before a fourth treatment, neuropathic pain was evaluated and a third blood sample was collected. Cells were used for flow cytometry. FINDINGS: Patients with painful DN reported that the pain decreased after 3 times of 1-hour treatments with EMS (Neuropathy Symptom Score: from 8 to 6, P = 0.001; Neuropathy Disability Score: from 5.5 to 5, P = 0.027, n = 24). At the end of the study, diastolic blood pressure had decreased from 80 to 70 mm Hg (P = 0.043), and plasma adrenaline and noradrenaline metabolites metanephrine and normetanephrine were reduced (both P ≤ 0.01; n = 21). A single EMS treatment caused an immediate and transient decrease in the frequency of CD34+ HSCs in circulation (-20%; P < 0.001; n = 27). In 9 of the patients with DN, the proportion of HSCs expressing vascular endothelial growth factor receptor 2 (VEGFR2; defining the HSCs as EPCs) increased by 36% (P = 0.011) after EMS treatment. Proteins required for binding to endothelium (junctional adhesion molecule A and CD31), homing toward hypoxic tissue (C-X-C chemokine receptor type 4), and endothelial differentiation (CD31) were increased on HSCs immediately after EMS treatment. An increased frequency of VEGFR2 expression was also observed on HSCs of 6 healthy control volunteers (34%; P = 0.046) after EMS treatment, but not after sham treatment. IMPLICATIONS: Three EMS treatments decreased symptoms of pain caused by DN and reduced diastolic blood pressure and biomarkers of stress. A single EMS treatment increased molecules mediating attachment and differentiation on the surface of HSCs in circulation. We hypothesize that the EMS-induced increase in surface attachment molecules on the HSCs caused the HSCs to leave circulation and that EMS treatment improves the function of HSCs and EPCs in vivo.

Shedding light into the black box: A prospective longitudinal study identifying the CanMEDS roles of final year medical students' on-ward activities.

INTRODUCTION: To our best knowledge, a rigorous prospective analysis of final year medical students' (FY medical students) activity profiles during workplace learning is lacking. The present study investigated the CanMEDS characteristics of all on-ward activities performed by internal medicine FY medical students. We tested the hypotheses that during FY medical student workplace training (I) routine activities are predominantly performed, while supervised, more complex activities are underrepresented with (II) FY medical students performing an insufficient number of autonomous activities and that (III) the CanMEDS roles of the Communicator and the Professional prevail. METHODS: During the second and the sixth week of their final year trimester at the University of Heidelberg Medical Hospital, N = 34 FY medical students (73% female; mean age 26.4 ± 2.4) were asked to keep a detailed record of all their on-ward activities and to document the duration, mode of action (active versus passive; independent versus supervised), estimated relevance for later practice, and difficulty-level in specially designed activity logbooks. CanMEDS roles were assigned to the documented activities via post-hoc expert consensus. RESULTS: About 4308 activities lasting a total of 2211.4 h were documented. Drawing blood (20.8%) was the most frequently documented medical activity followed by full admission procedures (9.6%). About 14.9% of the time was spent with non-medical activities. About 82.1% of all medical activities performed went unsupervised. The Communicator (42%), the Professional (38%), and the Collaborator (7%) were assigned as the top three CanMEDS roles. CONCLUSIONS: The results call for increased efforts in creating more authentic learning experiences for FY medical students shifting towards more complex, supervised tasks, and improved team integration.