Metformin acts in the gut and induces gut-liver crosstalk.

Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP.

Hyperglycemia impairs EAAT2 glutamate transporter trafficking and glutamate clearance in islets of Langerhans: implications for type 2 diabetes pathogenesis and treatment.

Pancreatic endocrine cells employ a sophisticated system of paracrine and autocrine signals to synchronize their activities, including glutamate, which controls hormone release and ß-cell viability by acting on glutamate receptors expressed by endocrine cells. We here investigate whether alteration of the excitatory amino acid transporter 2 (EAAT2), the major glutamate clearance system in the islet, may occur in type 2 diabetes mellitus and contribute to ß-cell dysfunction. Increased EAAT2 intracellular localization was evident in islets of Langerhans from T2DM subjects as compared with healthy control subjects, despite similar expression levels. Chronic treatment of islets from healthy donors with high-glucose concentrations led to the transporter internalization in vesicular compartments and reduced [H3]-d-glutamate uptake (65 ± 5% inhibition), phenocopying the findings in T2DM pancreatic sections. The transporter relocalization was associated with decreased Akt phosphorylation protein levels, suggesting an involvement of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the process. In line with this, PI3K inhibition by a 100-µM LY294002 treatment in human and clonal ß-cells caused the transporter relocalization in intracellular compartments and significantly reduced the glutamate uptake compared to control conditions, suggesting that hyperglycemia changes the trafficking of the transporter to the plasma membrane. Upregulation of the glutamate transporter upon treatment with the antibiotic ceftriaxone rescued hyperglycemia-induced ß-cells dysfunction and death. Our data underscore the significance of EAAT2 in regulating islet physiology and provide a rationale for potential therapeutic targeting of this transporter to preserve ß-cell survival and function in diabetes.NEW & NOTEWORTHY The glutamate transporter SLC1A2/excitatory amino acid transporter 2 (EAAT2) is expressed on the plasma membrane of pancreatic ß-cells and controls islet glutamate clearance and ß-cells survival. We found that the EAAT2 membrane expression is lost in the islets of Langerhans from type 2 diabetes mellitus (T2DM) patients due to hyperglycemia-induced downregulation of the phosphoinositide 3-kinase/Akt pathway and modification of its intracellular trafficking. Pharmacological rescue of EAAT2 expression prevents ß-cell dysfunction and death, suggesting EAAT2 as a new potential target of intervention in T2DM.

Type 2 diabetes mellitus pharmacological remission with dapagliflozin plus oral semaglutide.

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor and semaglutide, a glucagon-like peptide 1 receptor agonist, have both demonstrated efficacy in glycemic control, reducing blood pressure, body weight, risk of renal and heart failure in type 2 diabetes mellitus. In this observational, real-world, study we aimed to investigate the efficacy of the combination therapy with those two agents over glycemic control. We thus obtained the data of 1335 patients with type 2 diabetes followed by 11 Diabetes centers in Lombardia, Italy. A group of 443 patients was treated with dapagliflozin alone, the other group of 892 patients was treated with the combination therapy of dapagliflozin plus oral semaglutide. We analyzed changes in glycated hemoglobin from baseline to 6 months of follow-up, as well as changes in fasting glycemia, body weight, body mass index, systolic and diastolic pressure, heart rate, creatinine, estimated glomerular filtration rate and albuminuria. Both groups of patients showed an improvement of glycometabolic control after 6 months of treatment; indeed, the treatment with dapagliflozin plus oral semaglutide showed a reduction of glycated hemoglobin of 1.2% as compared to the 0.5% reduction observed in the dapagliflozin alone group. Significant changes were observed in body mass index, fasting plasmatic glucose, blood pressure, total cholesterol, LDL and albumin to creatinine ratio, with a high rate (55%) of near-normalization of glycated hemoglobin. Our real world data confirmed the potential of the oral combination therapy dapagliflozin with semaglutide in inducing pharmacological remission of type 2 diabetes mellitus.

Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.

Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.

Time-dependent effect of GLP-1 receptor agonists on cardiovascular benefits: a real-world study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in cardiovascular outcome trials in type 2 diabetes mellitus. However, the most convincing evidence was obtained in subjects with established cardiovascular (CV) disease. We analyzed the determinants of GLP-1 RA-mediated CV protection in a real-world population of persons with type 2 diabetes with and without a history of CV events with long-term follow-up. METHODS: Retrospective cohort study of 550 individuals with type 2 diabetes (395 in primary CV prevention, 155 in secondary CV prevention), followed at a single center after the first prescription of a GLP-1 RA between 2009 and 2019. CV and metabolic outcomes were assessed. RESULTS: Median duration of follow-up was 5.0 years (0.25-10.8) in primary prevention and 3.6 years (0-10.3) in secondary prevention, with a median duration of treatment of 3.2 years (0-10.8) and 2.5 years (0-10.3) respectively. In the multivariable Cox regression model considering GLP-1 RA treatment as a time-dependent covariate, in the primary prevention group, changes in BMI and glycated hemoglobin did not have an impact on MACE risk, while age at the time of GLP-1 initiation (HR 1.08, 95% CI 1.03-1.14, p = 0.001) and GLP-1 RA cessation by time (HR 3.40, 95% CI 1.82-6.32, p < 0.001) increased the risk of MACE. Regarding the secondary prevention group, only GLP-1 RA cessation by time (HR 2.71, 95% CI 1.46-5.01, p = 0.002) increased the risk of MACE. With respect to those who withdrew treatment, subjects who continued the GLP-1 RA had significantly greater weight loss and lower glycated hemoglobin levels during follow-up. CONCLUSIONS: In this real-world type 2 diabetes population, discontinuation of GLP-1 RA treatment was associated to a higher risk of major cardiovascular events, in both subjects with and without a history of CV events.

Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.

Autoantibodies against the glial glutamate transporter GLT1/EAAT2 in Type 1 diabetes mellitus-Clues to novel immunological and non-immunological therapies.

Islet cell surface autoantibodies were previously found in subjects with type 1 diabetes mellitus (T1DM), but their target antigens and pathogenic mechanisms remain elusive. The glutamate transporter solute carrier family 1, member 2 (GLT1/EAAT2) is expressed on the membrane of pancreatic ß-cells and physiologically controls extracellular glutamate concentrations thus preventing glutamate-induced ß-cell death. We hypothesized that GLT1 could be an immunological target in T1DM and that autoantibodies against GLT1 could be pathogenic. Immunoprecipitation and ELISA experiments showed that sera from T1DM subjects recognized GLT1 expressed in brain, pancreatic islets, and GLT1-transfected COS7-cell extracts. We validated these findings in two cohorts of T1DM patients by quantitative immunofluorescence assays. Analysis of the combined data sets indicated the presence of autoantibodies against GLT1 in 32 of the 87 (37%) T1DM subjects and in none of healthy controls (n = 64) (p < 0.0001). Exposure of pancreatic ßTC3 cells and human islets to purified IgGs from anti-GLT1 positive sera supplemented with complement resulted in plasma membrane ruffling, cell lysis and death. The cytotoxic effect was prevented when sera were depleted from IgGs. Furthermore, in the absence of complement, 6 out of 16 (37%) anti-GLT1 positive sera markedly reduced GLT1 transport activity in ßTC3 cells by inducing GLT1 internalization, also resulting in ß-cell death. In conclusion, we provide evidence that GLT1 is a novel T1DM autoantigen and that anti-GLT1 autoantibodies cause ß-cell death through complement-dependent and independent mechanisms. GLT1 seems an attractive novel therapeutic target for the prevention of ß-cell death in individuals with diabetes and prediabetes.

SGLT2-inhibitors are effective and safe in the elderly: The SOLD study.

BACKGROUND AND AIMS: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) may have important benefits for the elderly with type 2 diabetes (T2D), however some safety concerns still limit their use in patients over 70 years of age. The SOLD study (SGLT2i in Older Diabetic patients) is a multicenter study, aimed to evaluate the effectiveness and safety of SGLT2i in the older diabetic patients in a real-life setting. MATERIALS AND METHODS: We analyzed a population of 739 adults (mean age 75.4 ± 3.9 years, M/F 420/319) with T2D, which started a SGLT2i-based treatment after the age of 70, with at least one year of follow-up. Data were collected at baseline, at 6 and 12 months of follow-up. RESULTS: SGLT2i (37.5% Empagliflozin, 35.7% Dapagliflozin, 26.1% Canagliflozin, 0.7% Ertugliflozin) were an add-on therapy to Metformin in 88.6%, to basal insulin in 36.1% and to other antidiabetic drugs in 29.6% of cases. 565 subjects completed the follow up, while 174 (23.5%) discontinued treatment due to adverse events which were SGLT2i related. A statistically significant reduction of glycated hemoglobin (baseline vs 12 months: 7.8 ± 1.1 vs 7.1 ± 0.8%, p < 0.001) and body mass index values (baseline vs 12 months: 29.2 ± 4.7 vs 28.1 ± 4.5 kg/m2, p < 0.001) were evident during follow-up. Overall, estimated glomerular filtration rate remained stable over time, with significant reduction of urinary albumin excretion. In the subgroup of patients which were ≥ 80 years, a significant improvement in glycated hemoglobin values without renal function alterations was evident. Overall discontinuation rate during the follow-up period was different across age groups, being urinary tract infections and worsening of renal function the most common cause. CONCLUSION: SGLT2i are well-tolerated and safe in the elderly and appear as an effective therapeutic option, though some caution is also suggested, especially in more fragile subjects.

Dapagliflozin acutely improves kidney function in type 2 diabetes mellitus. The PRECARE study.

Dapagliflozin has been demonstrated to improve glycemic control, blood pressure, and body weight in type 2 diabetes mellitus (T2D); indeed, it can also reduce the risk of progression to renal failure, of hospitalization for heart failure and of cardiovascular death. We aim to investigate the acute effect of Dapagliflozin on kidney function in the common clinical practice in T2D. This is a study including 1402 patients with T2D recruited from 11 centers in Lombardia, Italy, who were evaluated at baseline and after 6 months of treatment with Dapagliflozin 10 mg per day. The primary outcome of the study was the change in HbA1c, while the secondary outcomes were modification of weight, BMI, systolic and diastolic pressure, creatinine, eGFR and albuminuria status. After 24 weeks of treatment with Dapagliflozin, a reduction in Hb1Ac was observed (-0.6 ± 1.8%) as well as in BMI (-1.5 ± 5.2 kg/m2). Statistically significant changes were also found for systolic and diastolic blood pressure, cholesterol and triglycerides. Interestingly, a statistically significant acute improvement of kidney function was evident. Our analyses confirm the beneficial effects of dapagliflozin after 6 months of therapy, with improvements of glycemic and lipid profiles, blood pressure, BMI. Finally, an acute positive effect on albuminuria and KIDGO classes was observed during a 6 months treatment with dapagliflozin in patients with T2D.

Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling.

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.

High plasma renin activity associates with obesity-related diabetes and arterial hypertension, and predicts persistent hypertension after bariatric surgery.

BACKGROUND: Information about the renin-angiotensin-aldosterone system (RAAS) in obese individuals before and after bariatric surgery is scarce. Aim of this study was to analyze the RAAS in severely obese subjects, in relation to anthropometric and metabolic variables, with special reference to glucose tolerance. METHODS: 239 subjects were evaluated at baseline, and 181 one year after bariatric surgery [laparoscopic gastric banding (LAGB)]. RESULTS: At baseline, renin (plasma renin activity, PRA) was increased from normal to glucose tolerance and more in diabetes, also correlating with ferritin. After LAGB, the decrease of PRA and aldosterone was significant in hypertensive, but not in normotensive subjects, and correlatied with decrease of ferritin. PRA and glucose levels were predictive of persistent hypertension 1 year after LAGB. CONCLUSIONS: These data support the role of RAAS in the pathophysiology of glucose homeostasis, and in the regulation of blood pressure in obesity. Ferritin, as a proxy of subclinical inflammation, could be another factor contributing to the cross-talk between RAAS and glucose metabolism.

Physical activity as a proxy to ameliorate inflammation in patients with type 2 diabetes and periodontal disease at high cardiovascular risk.

While the beneficial impact of physical activity has been ascertained in a variety of pathological scenarios, including diabetes and low-grade systemic inflammation, its potential remains still putative for periodontal health. Periodontal disease has been associated with inflammatory systemic alterations, which share a common denominator with type 2 diabetes mellitus and cardiovascular disease. Physical exercise, along with nutritional counseling, is a cornerstone in the treatment and prevention of type 2 diabetes, also able to reduce the prevalence of periodontal disease and cardiovascular risk. In addition, considering the higher incidence of periodontitis in patients with type 2 diabetes compared to healthy controls, the fascinating research question would be whether physical activity could relieve the inflammatory pressure exerted by the combination of these two diseases. This multi-disciplinary viewpoint discusses available literature in order to argument the hypothesis of a "three-way relationship" linking diabetes, periodontitis, and physical activity.

CA.ME.LI.A. An epidemiological study on the prevalence of CArdiovascular, MEtabolic, LIver and Autoimmune diseases in Northern Italy.

BACKGROUND AND AIMS: CA.ME.LI.A (CArdiovascular risks, MEtabolic syndrome, LIver and Autoimmune disease) is a cross-sectional, epidemiological study performed between 2009-2011 in Abbiategrasso (Milan, Italy) to estimate the prevalence of cardiovascular risk factors, metabolic syndrome, liver and autoimmune diseases in the general adult population. This report focuses on the description and presentation of baseline characteristics of the population. METHODS AND RESULTS: Citizens were randomly selected from the city electoral registers (n = 30903), yielding a sample of 2554 subjects (M = 1257, F = 1297; age, 47 ± 15 yrs; range 18-77 yrs). Men had higher prevalence of overweight or obesity (60.8% vs 41.6%; p < 0.0001) and greater thickness of visceral adipose tissue (40 ± 19 vs 27 ± 17 mm; p < 0.0001); no gender difference was found in subcutaneous adipose tissue thickness. Men also showed higher levels of serum triglycerides, γ-GT, fasting blood glucose, insulin and Homa-IR Index, while HDL, CRP, and prevalence of elevated (>5.0 mg/L) CRP were lower. Compared to normal weight men, risk-ratio (RR) of CRP elevation was 1.32 (ns) in overweight and 2.68 (p < 0.0001) in obese subjects. The corresponding figures in females were 2.68 (p < 0.0001) and 5.18 (p < 0.0001). Metabolic syndrome was more frequent in men (32.7% vs 14.5%; RR: 2.24, p < 0.0001). Interadventitia common carotid artery diameter was higher in men and increased with age and BMI. CONCLUSIONS: The present study reports on the overall characteristics of a large population from Northern Italy. It aims to identify the associations among cardiovascular risk factors to prevent their development and progression, improve healthy lifestyle and identify subjects liable to pharmacological interventions.

Early varicocelectomy by percutaneous scleroembolization improves seminiferous tubules spermatozoa release in the adolescent phase of testicular growth.

Varicocele is a rather common andrological condition in adolescents, which can adversely affect testicular growth and seminal parameters, leading to infertility in about 20% of adults. The aim of this study was to investigate if treating varicocele before the age of 18 is a beneficial option to improve testicular hypotrophy and seminal parameters and if minimally invasive techniques could be an appropriate treatment choice for adolescent varicocele associated with spermatic vein reflux. A percutaneous scleroembolization was performed in sixty-four consecutive young patients (13-19 years old) with left varicocele, preceded by a fluoroscopy. In thirty-four of them, semen samples were also collected. We examined semen samples and testicles dimensions before and after percutaneous varicocelectomy, compared to a nonoperated control group, with a six-month follow-up. Total sperm count and sperm morphology were significantly increased in the intervention group. Left testicular volume significantly increased in both groups, while only correction of varicocele improved spermatozoa release per unit of testis volume. We conclude that early varicocelectomy by percutaneous scleroembolization significantly ameliorates seminiferous tubules activity in the critical adolescent phase of testicular growth. It is suggested that adolescents should be; offered varicocele repair as soon as possible in order to improve reproductive potential.

A 23-year study of mortality and development of co-morbidities in patients with obesity undergoing bariatric surgery (laparoscopic gastric banding) in comparison with medical treatment of obesity.

BACKGROUND AND AIM: Several studies have shown that bariatric surgery reduces long term mortality compared to medical weight loss therapy. In a previous study we have demonstrated that gastric banding (LAGB) is associated with reduced mortality in patients with and without diabetes, and with reduced incidence of obesity co-morbidities (cardiovascular disease, diabetes, and cancer) at a 17 year follow-up. The aim of this study was to verify at a longer time interval (23 years) mortality and incidence of co-morbidities in patients undergoing LAGB or medical weight loss therapy. PATIENTS AND METHODS: As reported in the previous shorter-time study, medical records of obese patients [body mass index (BMI) > 35 kg/m2 undergoing LAGB (n = 385; 52 with diabetes) or medical treatment (controls, n = 681; 127 with diabetes), during the period 1995-2001 (visit 1)] were collected. Patients were matched for age, sex, BMI, and blood pressure. Identification codes of patients were entered in the Italian National Health System Lumbardy database, that contains life status, causes of death, as well as exemptions, prescriptions, and hospital admissions (proxies of diseases) from visit 1 to June 2018. Survival was compared across LAGB patients and matched controls using Kaplan-Meier plots adjusted Cox regression analyses. RESULTS: Final observation period was 19.5 ± 1.87 years (13.4-23.5). Compared to controls, LAGB was associated with reduced mortality [HR = 0.52, 95% CI 0.33-0.80, p = 0.003], significant in patients with diabetes [HR = 0.46, 95% CI 0.22-0.94, p = 0.034], borderline significant in patients without diabetes [HR = 0.61, 95% CI = 0.35-1.05, p = 0.076]. LAGB was associated with lower incidence of diabetes (15 vs 75 cases, p = 0.001), of CV diseases (61 vs 226 cases, p = 0.009), of cancer (10 vs 35, p = 0.01), and of renal diseases (0 vs 35, p = 0.001), and of hospital admissions (92 vs 377, p = 0.001). CONCLUSION: The preventive effect of LAGB on mortality is maintained up to 23 years, even with a decreased efficacy compared with the shorter-time study, while the preventive effect of LAGB on co-morbidities and on hospital admissions increases with time.

Multiple target tissue effects of GLP-1 analogues on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Accumulating experimental and clinical evidences over the last decade indicate that GLP-1 analogues have a series of central nervous system and peripheral target tissues actions which are able to significantly influence the liver metabolism. GLP-1 analogues pleiotropic effects proved to be efficacious in T2DM subjects not only reducing liver steatosis and ameliorating NAFLD and NASH, but also in lowering plasma glucose and liver inflammation, improving cardiac function and protecting from kidney dysfunction. While the experimental and clinical data are robust, the precise mechanisms of action potentially involved in these protective multi-target effects need further investigation. Here we present a systematic review of the most recent literature data on the multi-target effects of GLP-1 analogues on the liver, on adipose and muscular tissue and on the nervous system, all capable of influencing significant aspects of the fatty liver disease physiopathology. From this analysis, we can conclude that the multi-target beneficial action of the GLP-1 analogues could explain the positive effects observed in animal and human models on progression of NAFLD to NASH.

Helminth infection in mice improves insulin sensitivity via modulation of gut microbiota and fatty acid metabolism.

Intestinal helminths are prevalent in individuals who live in rural areas of developing countries, where obesity, type 2 diabetes, and metabolic syndrome are rare. In the present study, we analyzed the modulation of the gut microbiota in mice infected with the helminth Strongyloides venezuelensis, and fed either a standard rodent chow diet or high-fat diet (HFD). To investigate the effects of the microbiota modulation on the metabolism, we analyzed the expression of tight-junction proteins present in the gut epithelium, inflammatory markers in the serum and tissue and quantified glucose tolerance and insulin sensitivity and resistance. Additionally, the levels of lipids related to inflammation were evaluated in the feces and serum. Our results show that infection with Strongyloides venezuelensis results in a modification of the gut microbiota, most notably by increasing Lactobacillus spp. These modifications in the microbiota alter the host metabolism by increasing the levels of anti-inflammatory cytokines, switching macrophages from a M1 to M2 pattern in the adipose tissue, increasing the expression of tight junction proteins in the intestinal cells (thereby reducing the permeability) and decreasing LPS in the serum. Taken together, these changes correlate with improved insulin signaling and sensitivity, which could also be achieved with HFD mice treated with probiotics. Additionally, helminth infected mice produce higher levels of oleic acid, which participates in anti-inflammatory pathways. These results suggest that modulation of the microbiota by helminth infection or probiotic treatment causes a reduction in subclinical inflammation, which has a positive effect on the glucose metabolism of the host.

Pancreatic islet of Langerhans' cytoarchitecture and ultrastructure in normal glucose tolerance and in type 2 diabetes mellitus.

While a number of structural and cellular abnormalities occur in the islet of Langerhans in diabetes, and in particular in type 2 diabetes, the focus has been mostly on the insulin producing ß-cells and only more recently on glucagon producing α- and δ-cells. There is ample evidence that in type 2 diabetes mellitus (T2DM), in addition to a progressive decline in ß-cell function and associated insulin resistance in a number of insulin-sensitive tissues, alterations in glucagon secretion are also present and may play an important role in the pathogenesis of hyperglycemia both in the fasting and in the postprandial state. Recently, a number of studies have showed that there are also functional and structural alterations in glucagon-producing α-cells and somatostatin-producing δ-cells. Thus, it is becoming increasingly clear that multiple cellular alterations of multiple cell types occur, which adds even more complexity to our understanding of the pathophysiology of this common and severe disease. We believe that persistent efforts to increase the understanding of the pathophysiology of hormone secretion in the islets of Langerhans will also improve our capability to better prevent and treat diabetes mellitus.

Papio spp. Colon microbiome and its link to obesity in pregnancy.

INTRODUCTION: Gut microbial communities are critical players in the pathogenesis of obesity. Pregnancy is associated with increased bacterial load and changes in gut bacterial diversity. Sparse data exist regarding composition of gut microbial communities in obesity combined with pregnancy. MATERIAL AND METHODS: Banked tissues were collected under sterile conditions during necropsy, from three non-obese (nOb) and four obese (Ob) near-term pregnant baboons. Sequences were assigned taxonomy using the Ribosomal Database Project classifier. Microbiome abundance and its difference between distinct groups were assessed by a nonparametric test. RESULTS: Three families predominated in both the nOb and Ob colonic microbiome: Prevotellaceae (25.98% and 32.71% respectively), Ruminococcaceae (12.96% and 7.48%), and Lachnospiraceae (8.78% and 11.74%). Seven families of the colon microbiome displayed differences between Ob and nOb groups. CONCLUSION: Changes in gut microbiome in pregnant obese animals open the venue for dietary manipulation in pregnancy.

Vitamin D, sub-inflammation and insulin resistance. A window on a potential role for the interaction between bone and glucose metabolism.

Vitamin D is a key hormone involved in the regulation of calcium/phosphorous balance and recently it has been implicated in the pathogenesis of sub-inflammation, insulin resistance and obesity. The two main forms of vitamin D are cholecalciferol (Vitamin D3) and ergocalciferol (Vitamin D2): the active form (1,25-dihydroxyvitamin D) is the result of two hydroxylations that take place in liver, kidney, pancreas and immune cells. Vitamin D increases the production of some anti-inflammatory cytokines and reduces the release of some pro-inflammatory cytokines. Low levels of Vitamin D are also associated with an up-regulation of TLRs expression and a pro-inflammatory state. Regardless of the effect on inflammation, Vitamin D seems to directly increase insulin sensitivity and secretion, through different mechanisms. Considering the importance of low grade chronic inflammation in metabolic syndrome, obesity and diabetes, many authors hypothesized the involvement of this nutrient/hormone in the pathogenesis of these diseases. Vitamin D status could alter the balance between pro and anti-inflammatory cytokines and thus affect insulin action, lipid metabolism and adipose tissue function and structure. Numerous studies have shown that Vitamin D concentrations are inversely associated with pro-inflammatory markers, insulin resistance, glucose intolerance and obesity. Interestingly, some longitudinal trials suggested also an inverse association between vitamin D status and incident type 2 diabetes mellitus. However, vitamin D supplementation in humans showed controversial effects: with some studies demonstrating improvements in insulin sensitivity, glucose and lipid metabolism while others showing no beneficial effect on glycemic control and on inflammation. In conclusion, although the evidences of a significant role of Vitamin D on inflammation, insulin resistance and insulin secretion in the pathogenesis of obesity, metabolic syndrome and type 2 diabetes, its potential function in treatment and prevention of type 2 diabetes mellitus is unclear. Encouraging results have emerged from Vitamin D supplementation trials on patients at risk of developing diabetes and further studies are needed to fully explore and understand its clinical applications.