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Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.

The article takes stock of the main issues concerning the studies on the linguistic coding of space, movement and manner and introduces the papers in the volume.

OBJECTIVE In the Italian Diabetes and Exercise Study_2 (IDES_2), behavioral counseling promoted a sustained increase in physical activity (PA) volume (+3.3 MET h ⋅ week−1), moderate- to vigorous-intensity PA (MVPA) (+6.4 min ⋅ day−1), and light-intensity PA (LPA) (+0.8 h ⋅ day−1) and decrease in sedentary time (SED-time) (−0.8 h ⋅ day−1). Here, we investigated the relationships of changes in PA/SED-time with changes in physical fitness and cardiometabolic risk profile in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS In this 3-year randomized clinical trial, 300 physically inactive and sedentary patients were randomized 1:1 to receive 1-month theoretical and practical counseling once a year or standard care. Changes in physical fitness and cardiovascular risk factors/scores according to quartiles of accelerometer-measured changes in PA/SED-time were assessed, together with univariate and multivariable associations between these parameters, in the whole cohort and by study arm. RESULTS Physical fitness increased and HbA1c and coronary heart disease 10-year risk scores decreased with quartiles of MVPA and SED-time change. In quartile IV of MVPA increase and SED-time decrease, cardiorespiratory fitness increased by 5.23 and 4.49 mL ⋅ min−1 ⋅ kg−1 and HbA1c decreased by 0.73 and 0.85%, respectively. Univariate correlations confirmed these relationships, and mean changes in both MPVA and SED-time predicted changes in physical fitness and cardiovascular risk factors/scores independently of one another and of other confounders. Similar findings were observed with LPA and PA volume and in each group separately. CONCLUSIONS Even modest increments in MVPA may have a clinically meaningful impact, and reallocating SED-time to LPA may also contribute to improved outcomes, possibly by increasing total energy expenditure.

Molti lettori ci pongono domande sul verbo supportare: “esiste” nella nostra lingua? O lo dobbiamo all’inglese? Altri pongono le stesse domande a proposito di supportivo; un lettore in particolare chiede se non sia preferibile usare supportevole.

Simple Summary Diabetic people have an increased risk of developing several types of cancers, particularly pancreatic cancer. The higher availability of glucose and/or lipids that characterizes diabetes and obesity is responsible for the increased production of highly reactive carbonyl compounds, a condition referred to as “carbonyl stress”. Also known as glycotoxins and lipotoxins, these compounds react quickly and damage various molecules in cells forming final products termed AGEs (advanced glycation end-products). AGEs were shown to markedly accelerate tumor development in an experimental model of pancreatic cancer and AGE inhibition prevented the tumor-promoting effect of diabetes. In humans, carbonyl stress has been associated with the risk of pancreatic cancer and recognized as a possible contributor to other cancers, including breast and colorectal cancer. These findings suggest that carbonyl stress is involved in cancer development and growth and may be the mechanistic link between diabetes and pancreatic cancer, thus representing a potential drug target. Abstract Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals.

Adiposopathy is a pathological adipose tissue (AT) response to overfeeding characterized by reduced AT expandability due to impaired adipogenesis, which favors inflammation, insulin resistance (IR), and abnormal glucose regulation. However, it is unclear whether defective adipogenesis causes metabolic derangement also independently of an increased demand for fat storage. As galectin-3 has been implicated in both adipocyte differentiation and glucose homeostasis, we tested this hypothesis in galectin-3 knockout (Lgal3−/−) mice fed a standard chow. In vitro, Lgal3−/− adipocyte precursors showed impaired terminal differentiation (maturation). Two-month-old Lgal3−/− mice showed impaired AT maturation, with reduced adipocyte size and expression of adipogenic genes, but unchanged fat mass and no sign of adipocyte degeneration/death or ectopic fat accumulation. AT immaturity was associated with AT and whole-body inflammation and IR, glucose intolerance, and hyperglycemia. Five-month-old Lgal3−/− mice exhibited a more mature AT phenotype, with no difference in insulin sensitivity and expression of inflammatory cytokines versus WT animals, though abnormal glucose homeostasis persisted and was associated with reduced β-cell function. These data show that adipogenesis capacity per se affects AT function, insulin sensitivity, and glucose homeostasis independently of increased fat intake, accumulation and redistribution, thus uncovering a direct link between defective adipogenesis, IR and susceptibility to diabetes.

Diversi lettori dichiarano perplessità sulla correttezza dell’impiego del verbo sversare e del suo derivato sversamento.

Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.

Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.

Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.

The term parasynthesis is mainly used in modern theoretical linguistics in the meaning introduced by Arsène Darmesteter (1874) to refer to denominal or deadjectival prefixed verbs of the Romance languages (Fr. embarquer ‘to load, to board’) in which the non-prefixed verb (barquer) is not an actual word, and the co-radical nominal form (embarqu-) is not well formed. The Romance parasynthetic verb is characterized with reference to its nominal or adjectival base as the result of the co-occurrence of both a prefix and a suffix (typically of a conversion process, i.e., non-overt derivational marking). The co-occurrence or simultaneity of the two processes has been seen by some scholars as a circumfixation phenomenon, whereby two elements act in combination. The peculiar relationship existing between base and parasynthetic verb is particularly problematic for an Item and Process theoretical perspective since this approach entails the application of one process at a time. Conversely, a Word and Paradigm framework deals more easily with parasynthetic patterns, as parasynthetic verbs are put in relation with prefixed verbs and verbs formed by conversion, without being undermined neither by gaps in derivational patterns nor by the possible concomitant addition of prefixes and suffixes. Due to their peculiar structure, parasynthetic verbs have been matter of investigation even for non-specialists of Romance languages, especially from synchronic (or, better said, achronic) point of view. Attention has been also placed on their diachronic development in that, despite being characteristic of the Romance languages, parasynthetic verbs were already present, although to a lesser extent, in Latin. The diachronic development of parasynthetic verbs is strictly connected with that of spatial verb prefixes from Latin to the Romance languages, with particular reference to their loss of productivity in the encoding of spatial meanings and their grammaticalization into actionality markers. Parasynthetic verbs have been in the Romance languages since their earliest stages and have shown constant productivity and diffusion in all the Romance varieties, thus differing from spatial prefixes, which underwent a strong reduction in productivity in combination with verbs. The term parasynthetic is sometimes also used to refer to nouns and adjectives derived from compounds or in which both a prefix and a suffix are attached to a lexical base. In the case of nominal and adjectival formation, there is much less consensus among scholars on the need to use this term, as well as on which processes should fall under this label. The common denominator of such cases consists either in the non-attestation of presumed intermediate stages (Sp. corchotaponero ‘relative to the industry of cork plugs’) or in the non-correspondence between sense and structure of the morphologically complex word (Fr. surnaturel ‘supernatural’).

The need of cumulability of data and replicability of resultus in motion event description has led to the construction of a prototype of an annotation tool named Modeg (Motion DEcoding Grid). This classification grid allows to encode the most relevant formal and semantic elements implied in the linguistic expression of motion events. Modeg identifies a set of comparative concepts and their possible values that can be annotated with respect to their expression in four loci (satellite, adnominal, verb, noun) as well as to their distribution in the sentence. The software on which Modeg is tested should be considered not a final product, but rather as a tool developed to demostrate the applicability of the criteria we have identified. The results that can be obtained with Modeg are shown with examples mostly relates to parallel corpora analysis.

Background Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. The recent finding that PaC incidence increases linearly with increasing fasting glucose levels supports a central role for hyperglycaemia, which is known to cause carbonyl stress and advanced glycation end-product (AGE) accumulation through increased glycolytic activity and non-enzymatic reactions. This study investigated the impact of hyperglycaemia on invasive tumour development and the underlying mechanisms involved. Methods Pdx1-Cre;LSL-KrasG12D/+ mice were interbred with mitosis luciferase reporter mice, rendered diabetic with streptozotocin and treated or not with carnosinol (FL-926-16), a selective scavenger of reactive carbonyl species (RCS) and, as such, an inhibitor of AGE formation. Mice were monitored for tumour development by in vivo bioluminescence imaging. At the end of the study, pancreatic tissue was collected for histology/immunohistochemistry and molecular analyses. Mechanistic studies were performed in pancreatic ductal adenocarcinoma cell lines challenged with high glucose, glycolysis- and glycoxidation-derived RCS, their protein adducts AGEs and sera from diabetic patients. Results Cumulative incidence of invasive PaC at 22 weeks of age was 75% in untreated diabetic vs 25% in FL-926-16-gtreated diabetic and 8.3% in non-diabetic mice. FL-926-16 treatment suppressed systemic and pancreatic carbonyl stress, extracellular signal-regulated kinases (ERK) 1/2 activation, and nuclear translocation of Yes-associated protein (YAP) in pancreas. In vitro, RCS scavenging and AGE elimination completely inhibited cell proliferation stimulated by high glucose, and YAP proved essential in mediating the effects of both glucose-derived RCS and their protein adducts AGEs. However, RCS and AGEs induced YAP activity through distinct pathways, causing reduction of Large Tumour Suppressor Kinase 1 and activation of the Epidermal Growth Factor Receptor/ERK signalling pathway, respectively. Conclusions An RCS scavenger and AGE inhibitor prevented the accelerating effect of diabetes on PainINs progression to invasive PaC, showing that hyperglycaemia promotes PaC mainly through increased carbonyl stress. In vitro experiments demonstrated that both circulating RCS/AGEs and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by YAP activation, hence providing a molecular mechanism underlying the link between diabetes and PaC (and cancer in general).

Additional file 1. Supplementary Table S1. Antibodies used in Western blot and IHC studies. Supplementary Table S2. Silencer select Validated/Predesigned siRNAs and related TaqMan assays. Supplementary Table S3. TaqMan Gene Expression assays. Supplementary Fig. S1. Color digital photo (A), ex vivo BLI (B) and histological analysis (C) of the lung (left) and the liver (right) of a Diab KCM mice with metastatic PaC. Supplementary Fig. S2. Effect of RCS, AGE and FL-926-16 on YAP activity. Supplementary Fig. S3. Effect of EGFR silencing on KRAS activity and p-ERK 1/2 levels in human PDA cells exposed to CML.