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Increased circulating sclerostin levels and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D). Recent data from our group have shown that T2D affects the expression of genes controlling bone formation (SOST and RUNX2) and that accumulation of AGEs is associated with impaired bone microarchitecture. Whether the expression of the Wnt beta-catenin target genes is altered in T2D, and whether AGEs accumulation it is associated with type 1 Collagen (COL1A1) alteration is still unknown. We hypothesized that increased SOST gene expression leads to downregulation of Wnt β- catenin target genes (TCF/LEF1) and AGEs accumulation is related to a downregulation of COL1A1 in bones from subjects with T2D. We analyzed bone tissue from femoral heads of 14 T2D postmenopausal women (mean HbA1c 6.5%) and 21 age- and BMI-comparable nondiabetic women undergoing hip replacement surgery. We found that TCF-LEF1 was significantly lower in T2D compared to non- diabetic subjects (p=0.0092). Dickkopf -1 (DKK-1), the other inhibitor of beta-catenin-dependent Wnt signalling besides sclerostin, was not different between groups (p=0.1083). However, analysis of correlation showed that DKK-1 increases with age (r2=0.038; p=0.043) and HbA1c (r2=0.503; p=0.048) in T2D subjects. COL1A1 gene expression was lower in T2D compared to controls although significance was not fully reached (p=0.0564). Importantly, AGEs bone content was significantly higher in T2D compared to nondiabetics (1.5 fold increase; p In conclusion, our data show that even in patients with relatively good glycemic control, T2D affects the expression of collagen and Wnt beta-catenin target genes. We also found that accumulation of AGEs is possibly associated with alteration in collagen gene expression. We provide novel insights that may help understand the mechanisms underlying bone fragility in T2D. Disclosure G. Leanza: None. F. Tramontana: None. F. Cannata: None. A. Piccoli: None. M. Faraj: None. V. Viola: None. R. Strollo: None. N. Napoli: None. P. Pozzilli: None. Funding Campus Bio-Medico University

In this study, a novel approach was developed to quantify endocannabinoids (eCBs), and was based on the liquid biosensor BIONOTE. This device is composed of a probe that can be immersed in a solution, and an electronic interface that can record a current related to the oxy-reductive reactions occurring in the sample. The two most representative members of eCBs have been analysed in vitro by BIONOTE: anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG). Bovine serum albumin was used to functionalize the probe and improve the sensibility of the whole analytical system. We show that BIONOTE is able to detect both AEA and 2-AG at concentrations in the low nanomolar range, and to discriminate between these eCBs and their moieties arachidonic acid, ethanolamine and glycerol. Notably, BIONOTE distinguished these five different molecules, and it was also able to quantify AEA in human plasma. Although this is just a proof-of-concept study, we suggest BIONOTE as a cheap and user-friendly prototype sensor for high throughput quantitation of eCB content in biological matrices, with an apparent diagnostic potential for tomorrow’s medicine.

Fatty acid amide hydrolase (FAAH) is a membrane-bound enzyme, that inactivates endogenous signaling lipids of the fatty acid amide family, including the endocannabinoid anandamide (This review reports the latest advances in the development of new single targeted and dual-targeted FAAH inhibitors over the past 5 years.In recent years, several FAAH inhibitors have been synthesized and investigated, yet to date none of them has reached the market as a systemic drug. Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases.

Increased circulating sclerostin and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D). Whether the expression of the sclerostin-encoding SOST gene is altered in T2D, and whether it is associated with AGEs accumulation or regulation of other bone formation-related genes is unknown. We hypothesized that AGEs accumulate and SOST gene expression is upregulated in bones from subjects with T2D, leading to downregulation of bone forming genes (RUNX2 and osteocalcin) and impaired bone microarchitecture and strength. We obtained bone tissue from femoral heads of 19 T2D postmenopausal women (mean glycated hemoglobin [HbA1c] 6.5%) and 73 age- and BMI-comparable nondiabetic women undergoing hip replacement surgery. Despite similar bone mineral density (BMD) and biomechanical properties, we found a significantly higher SOST (p = .006) and a parallel lower RUNX2 (p = .025) expression in T2D compared with non-diabetic subjects. Osteocalcin gene expression did not differ between T2D and non-diabetic subjects, as well as circulating osteocalcin and sclerostin levels. We found a 1.5-fold increase in total bone AGEs content in T2D compared with non-diabetic women (364.8 ± 78.2 versus 209.9 ± 34.4 μg quinine/g collagen, respectively; p < .001). AGEs bone content correlated with worse bone microarchitecture, including lower volumetric BMD (r = -0.633; p = .02), BV/TV (r = -0.59; p = .033) and increased trabecular separation/spacing (r = 0.624; p = .023). In conclusion, our data show that even in patients with good glycemic control, T2D affects the expression of genes controlling bone formation (SOST and RUNX2). We also found that accumulation of AGEs is associated with impaired bone microarchitecture. We provide novel insights that may help understand the mechanisms underlying bone fragility in T2D. © 2020 American Society for Bone and Mineral Research (ASBMR).

AIM To compare a Mediterranean diet (MED) with a high-fibre vegetarian diet (HFV) in terms of hunger-satiety perception through post-prandial assessment of appetite-related hormones glucagon-like peptide 1 (GLP-1) and oxyntomodulin, as well as self-rated visual analogue scale (VAS) quantification, in overweight/obese subjects with type 2 diabetes (T2D). MATERIALS AND METHODS Twelve T2D subjects (Male to female ratio = 7:5), mean age 63 ± 8.5 years, were enrolled in a randomized, controlled, crossover study. Participants consumed an MED meal as well as an isocaloric meal rich in complex carbohydrate as well as an isocaloric MED meal in two different visits with a 1-week washout period between the two visits. Appetite ratings, glucose/insulin, and gastrointestinal hormone concentrations were measured at fasting and every 30' until 210' following meal consumption. RESULTS GLP-1 and oxyntomodulin levels were significantly higher following MED meal compared with HFV meals (210' area under the curve, p < 0.022 and p < 0.023, respectively). Both MED and HFV meal resulted in a biphasic pattern of GLP-1 and oxyntomodulin, although MED meal was related to a delayed, significantly higher second GLP-1 peak at 150' compared with that of HFV meal (p < 0.05). MED meal was related to lower glucose profile compared with HFV meal (p < 0.039), whereas we did not observe significant changes in terms of self-reported VAS scores and insulin trend. CONCLUSIONS In T2D overweight/obese subjects, an MED meal is more effective than a HFV meal in terms of post-prandial plasma glucose homoeostasis and GLP-1 and oxyntomodulin release. These changes were not confirmed by VAS appetite self-assessment over a 210' period.