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Diabetes is not a single and homogeneous disease, but a cluster of metabolic diseases characterized by the common feature of hyperglycemia. The pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D) (and all other intermediate forms of diabetes) involves the immune system, in terms of inflammation and autoimmunity. The past decades have seen an increase in all types of diabetes, accompanied by changes in eating habits and consequently a structural evolution of gut microbiota. It is likely that all these events could be related and that gut microbiota alterations might be involved in the immunomodulation of diabetes. Thus, gut microbiota seems to have a direct, even causative role in mediating connections between the environment, food intake, and chronic disease. As many conditions that increase the risk of diabetes modulate gut microbiota composition, it is likely that immune-mediated reactions, induced by alterations in the composition of the microbiota, can act as facilitators for the onset of diabetes in predisposed subjects. In this review, we summarize recent evidence in the field of gut microbiota and the role of the latter in modulating the immune reactions involved in the pathogenesis of diabetes.

Sotagliflozin is a dual sodium-glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 (T1D) and type 2 diabetes (T2D). Sotagliflozin inhibits renal sodium-glucose co-transporter 2 (determining significant excretion of glucose in the urine, in the same way as other, already available SGLT-2 selective inhibitors) and intestinal SGLT-1, delaying glucose absorption and therefore reducing post prandial glucose. Well-designed clinical trials, have shown that sotagliflozin (as monotherapy or add-on therapy to other anti-hyperglycemic agents) improves glycated hemoglobin in adults with T2D, with beneficial effects on bodyweight and blood pressure. Similar results have been obtained in adults with T1D treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections, even after insulin optimization. A still ongoing phase 3 study is currently evaluating the effect of sotagliflozin on cardiovascular outcomes (ClinicalTrials.gov NCT03315143). In this review we illustrate the advantages and disadvantages of dual SGLT 2/1 inhibition, in order to better characterize and investigate its mechanisms of action and potentialities.

OBJECTIVE: changes in bile flow after bariatric surgery may beneficially modulate secretion of insulin and incretins leading to diabetes remission. However, the exact mechanism(s) involved are still unclear. We here propose an alternative method to investigate the relation between alterations in physiological bile flow and insulin and incretin secretion by studying the changes in gut-pancreatic function in extrahepatic cholestasis in non-diabetic humans. METHODS: to pursue this aim, 58 non-diabetic patients with recent diagnosis of periampullary tumors underwent an OGTT, and a subgroup of 16 patients also underwent 4-hour mixed meal tests and hyperinsulinemic euglycemic clamps. RESULTS: The analysis of the entire cohort revealed strong inverse correlation between total bilirubin levels and insulinogenic index. When subjects were divided on the basis of bilirubin levels, used as marker of altered bile flow, subjects with high bilirubin levels displayed inferior glucose control and decreased insulin secretion during OGTT. Altered bile flow elicited a markedly greater increase in glucagon and GLP-1 secretion at fasting state and following the meal both glucagon and GLP-1 levels remained increased over time. Conversely, GIP levels were comparable at the fasting state, while the increase following meal ingestion was significantly blunted in H-Bil. We revealed strong correlations between total bilirubin and glucagon and GLP-1 levels. CONCLUSIONS: Our findings suggest that acute extrahepatic cholestasis determines a significant impairment in the entero-endocrine gut-pancreatic secretory function. The altered bile flow might determine a direct deleterious effect on beta cell function perhaps mediated by the impairment of incretin hormone function.

Introduction: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been shown to have beneficial effects on various cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) in primary prevention and in those with a high CV risk profile. However, the mechanism(s) responsible for these CV benefits remain elusive and unexplained. The aim of the DAPAHEART study will be to demonstrate that treatment with SGLT-2 inhibitors is associated with greater myocardial insulin sensitivity in patients with T2D, and to determine whether this improvement can be attributed to a decrease in whole-body (and tissue-specific) insulin resistance and to increased myocardial perfusion and/or glucose uptake. We will also determine whether there is an appreciable degree of improvement in myocardial-wall conditions subtended by affected and non-affected coronary vessels, and if this relates to changes in left ventricular function. Methods: The DAPAHEART trial will be a phase III, single-center, randomized, two-arm, parallel-group, double-blind, placebo-controlled study. A cohort of 52 T2D patients with stable coronary artery disease (without any previous history of myocardial infarction, with or without previous percutaneous coronary intervention), with suboptimal glycemic control (glycated hemoglobin [HbA1c] 7–8.5%) on their current standard of care anti-hyperglycemic regimen, will be randomized in a 1:1 ratio to dapagliflozin or placebo. The primary outcome is to detect changes in myocardial glucose uptake from baseline to 4 weeks after treatment initiation. The main secondary outcome will be changes in myocardial blood flow, as measured by 13N-ammonia positron emission tomography/computed tomography (PET/CT). Other outcomes include cardiac function, glucose uptake in skeletal muscle, adipose tissue, liver, brain and kidney, as assessed by fluorodeoxyglucose (FDG) PET-CT imaging during hyperinsulinemic-euglycemic clamp; pericardial, subcutaneous and visceral fat, and brown

Aims/hypothesis: Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the “disappearance” of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. Methods: Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. Results: The islets of diabetic subjects were 3 times more innervated than controls (0.91 ± 0.21 vs 0.32 ± 0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = −0.84; p = 0.01), incremental second-phase insulin secretion (r = −0.84, p = 0.03) and arginine-stimulated insulin secretion (r = −0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). Conclusions/interpretation: Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.

Increased proinsulin secretion, which characterizes type 2 diabetes and insulin resistance, may be due to an intrinsic, primitive defect in proinsulin processing or be secondary to increased demand on b-cells (hyperinsulinemia secondary to insulin resistance). An alternative way to investigate the relation between relative hyperproinsulinemia and increased secretory demand is to study the dynamic changes in the proinsulin-to-insulin ratio after partial pancreatectomy, a model of acute increased b-cell workload on the remaining pancreas. To pursue this aim, patients without diabetes, scheduled for partial pancreatectomy, underwent 4-h mixed-meal tests and hyperinsulinemic-euglycemic clamps before and after surgery. After acute b-cell mass reduction, no changes were observed in the fasting proinsulin-to-insulin ratio, whereas the fold change in the proinsulin-to-insulin ratio significantly increased over time after the meal. Further, our data demonstrate that whole-body insulin resistance is associated with underlying defects in proinsulin secretion, which become detectable only in the presence of increased insulin secretion demand.

Objective: The aim was to investigate whether vitamin D supplementation, combined with a hypocaloric diet, could have an independent effect on insulin sensitivity in subjects with both overweight and hypovitaminosis D. Changes from baseline in anthropometric parameters, body composition, glucose tolerance, and insulin secretion were considered as secondary outcomes. Methods: Eighteen volunteers who were nondiabetic and vitamin D deficient and had BMI>25 kg/m2 were randomized (1:1) in a double-blind manner to a hypocaloric diet1either oral cholecalciferol at 25,000 IU/wk or placebo for 3 months. Hyperinsulinemic-euglycemic clamp to measure insulin sensitivity was performed at baseline and after intervention. Results: Body weight in both groups decreased significantly (27.5% in the vitamin D group and 210% in the placebo group; P<0.05 for both), with no between-group differences. Serum 25-hydroxyvitamin D levels in the vitamin D group increased considerably (from 36.7613.2 nmol/L to 74.8618.7 nmol/L; P<0.001). Insulin sensitivity in the vitamin D group improved (from 4.662.0 to 6.963.3mgkg21min21; P<0.001), whereas no changes were observed in the placebo group (from 4.961.1 to 5.160.3mgkg21min21; P50.84). Conclusions: Cholecalciferol supplementation, combined with a weight loss program, significantly improves insulin sensitivity in healthy subjects with obesity and might represent a personalized approach for insulin-resistant subjects with obesity.

A methodology for a comprehensive probabilistic tsunami hazard analysis is presented for the major sources of tsunamis (seismic events, landslides, and volcanic activity) and preliminarily applied in the Gulf of Naples (Italy). The methodology uses both a modular procedure to evaluate the tsunami hazard and a Bayesian analysis to include the historical information of the past tsunami events. In the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0001 the submarine earthquakes and the submarine mass failures are initially identified in a gridded domain and defined by a set of parameters, producing the sea floor deformations and the corresponding initial tsunami waves. Differently volcanic tsunamis generate sea surface waves caused by pyroclastic density currents from Somma‐Vesuvius. In the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0002 the tsunami waves are simulated and propagated in the deep sea by a numerical model that solves the shallow water equations. In the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0003 the tsunami wave heights are estimated at the coast using the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0004's amplification law. The selected tsunami intensity is the wave height. In the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0005 the probabilistic tsunami analysis computes the long‐term comprehensive Bayesian probabilistic tsunami hazard analysis. In the prior analysis the probabilities from the scenarios in which the tsunami parameter overcomes the selected threshold levels are combined with the spatial, temporal, and frequency‐size probabilities of occurrence of the tsunamigenic sources. The urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0006 probability density functions are integrated with the urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0007 derived from the historical information based on past tsunami data. The urn:x-wiley:jgrc:media:jgrc23818:jgrc23818-math-0008 probability density functions are evaluated to produce the

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest therapeutic strategy in the treatment of type 2 diabetes mellitus (T2DM). Using an insulin-independent mechanism (glycosuria), they reduce glucose toxicity and improve insulin sensitivity and Î2-cell function. The promising results obtained in clinical trials show that SGLT2 significantly improves glycemic control and provides greater cardiovascular protection, combined with a reduction in body weight and blood pressure (BP). This review focuses on ertugliflozin, a new, highly selective, and reversible SGLT2 inhibitor. Clinical trials published to date show that ertugliflozin, both as a monotherapy and as an add-on to oral antidiabetic agents, is safe and effective in reducing glycosylated hemoglobin (HbA1c), body weight, and BP in T2DM patients.

Purpose: Recent evidence indicates that people with normal glucose tolerance (NGT) but 1-h post-load plasma glucose (1-h OGTT) ≥ 155 mg/dl have an increased risk for developing Type 2 diabetes mellitus (T2DM), determining a new risk category with deeper metabolic impairment. The aim of this study was to identify, among women with gestational diabetes (GDM), which alterations at OGTT during pregnancy are more frequently associated with 1-h OGTT ≥ 155 mg/dl at post-partum examination. Methods: Among 297 women affected by GDM, we retrospectively evaluated 244 resulted NGT after delivery. Based on post-partum glucose levels at 1-h OGTT, these people were divided into 188 cases (77.0%) with 1-h OGTT < 155 mg/dl (L-NGT) and 56 (23.0%) with 1-h OGTT ≥ 155 mg/dl (H-NGT). Results: Abnormal glucose levels at 1-h OGTT during pregnancy (≥ 180 mg/dl) were more frequent in H-NGT than in L-NGT (39.3 vs. 24.6%, odds ratio 3.7 [95% CI 1.4–9.6]; p = 0.016). Moreover, H-NGT showed more frequently the simultaneous alteration of all three OGTT plasma glucose values during pregnancy (10.7 vs. 2.1%, odds ratio 4.5 [95% CI 1.5–20.3]; p = 0.038) and less frequently the alteration of fasting plasma glucose alone (14.3 vs. 30.8%, odds ratio 0.4 [95% CI 0.1–0.7]; p = 0.028). Conclusions: Abnormal 1-h OGTT during pregnancy predicts an increased risk for post-partum 1-h OGTT ≥ 155 mg/dl in women with previous GDM. Even if NGT after delivery, these women may require a closer long-term post-partum follow-up, being at higher risk to develop future glucose intolerance.