Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2 diabetes.

AIMS/HYPOTHESIS: Progressive decline in functional beta cell mass is central to the development of type 2 diabetes. Elevated serum levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) are associated with beta cell failure in type 2 diabetes and eNAMPT immuno-neutralisation improves glucose tolerance in mouse models of diabetes. Despite this, the effects of eNAMPT on functional beta cell mass are poorly elucidated, with some studies having separately reported beta cell-protective effects of eNAMPT. eNAMPT exists in structurally and functionally distinct monomeric and dimeric forms. Dimerisation is essential for the NAD-biosynthetic capacity of NAMPT. Monomeric eNAMPT does not possess NAD-biosynthetic capacity and may exert distinct NAD-independent effects. This study aimed to fully characterise the structure-functional effects of eNAMPT on pancreatic beta cell functional mass and to relate these to beta cell failure in type 2 diabetes. METHODS: CD-1 mice and serum from obese humans who were without diabetes, with impaired fasting glucose (IFG) or with type 2 diabetes (from the Body Fat, Surgery and Hormone [BodyFatS&H] study) or with or at risk of developing type 2 diabetes (from the VaSera trial) were used in this study. We generated recombinant wild-type and monomeric eNAMPT to explore the effects of eNAMPT on functional beta cell mass in isolated mouse and human islets. Beta cell function was determined by static and dynamic insulin secretion and intracellular calcium microfluorimetry. NAD-biosynthetic capacity of eNAMPT was assessed by colorimetric and fluorescent assays and by native mass spectrometry. Islet cell number was determined by immunohistochemical staining for insulin, glucagon and somatostatin, with islet apoptosis determined by caspase 3/7 activity. Markers of inflammation and beta cell identity were determined by quantitative reverse transcription PCR. Total, monomeric and dimeric eNAMPT and nicotinamide mononucleotide (NMN) were evaluated by ELISA, western blot and fluorometric assay using serum from non-diabetic, glucose intolerant and type 2 diabetic individuals. RESULTS: eNAMPT exerts bimodal and concentration- and structure-functional-dependent effects on beta cell functional mass. At low physiological concentrations (~1 ng/ml), as seen in serum from humans without diabetes, eNAMPT enhances beta cell function through NAD-dependent mechanisms, consistent with eNAMPT being present as a dimer. However, as eNAMPT concentrations rise to ~5 ng/ml, as in type 2 diabetes, eNAMPT begins to adopt a monomeric form and mediates beta cell dysfunction, reduced beta cell identity and number, increased alpha cell number and increased apoptosis, through NAD-independent proinflammatory mechanisms. CONCLUSIONS/INTERPRETATION: We have characterised a novel mechanism of beta cell dysfunction in type 2 diabetes. At low physiological levels, eNAMPT exists in dimer form and maintains beta cell function and identity through NAD-dependent mechanisms. However, as eNAMPT levels rise, as in type 2 diabetes, structure-functional changes occur resulting in marked elevation of monomeric eNAMPT, which induces a diabetic phenotype in pancreatic islets. Strategies to selectively target monomeric eNAMPT could represent promising therapeutic strategies for the treatment of type 2 diabetes.

Plasma Somatostatin in Advanced Heart Failure: Association with Cardiac Filling Pressures and Outcome.

BACKGROUND: Somatostatin inhibits intestinal motility and hormonal secretion and is a potent arterial vasoconstrictor of the splanchnic blood flow. It is unknown if somatostatin concentrations are associated with central hemodynamic measurements in patients with advanced heart failure (HF). METHODS: A prospective study of HF patients with a left ventricular ejection fraction (LVEF) <45% referred to right heart catheterization (RHC) for evaluation for heart transplantation (HTX) or left ventricular assist device (LVAD). RESULTS: Fifty-three patients were included with mean LVEF 18 ± 8% and majority in NYHA-class III-IV (79%). Median plasma somatostatin concentration was 18 pmol/L. In univariable regression analysis, log(somatostatin) was associated with increased central venous pressure (CVP; r2 = 0.14, p = 0.003) and a reduced cardiac index (CI; r2 = 0.15, p = 0.004). When adjusted for selected clinical variables (age, gender, LVEF, eGFR and BMI), log(somatostatin) remained a significant predictor of CVP (p = 0.044). Increased somatostatin concentrations predicted mortality in multivariable models (hazard ratio: 5.2 [1.2-22.2], p = 0.026) but not the combined endpoint of death, LVAD implantation or HTX. CONCLUSIONS: Somatostatin concentrations were associated with CVP and CI in patients with HF. The pathophysiological mechanism may be related to congestion and/or hypoperfusion of the intestine. Somatostatin was an independent predictor of mortality in advanced HF.

Glucagon receptor antagonism increases mouse pancreatic δ-cell mass through cell proliferation and duct-derived neogenesis.

Pancreatic δ-cells, which produce somatostatin, play an indispensable role in glucose homeostasis by inhibiting glucagon and insulin secretion in a paracrine manner. Recent studies have shown that δ-cells are couple with ß-cells to suppress α-cell activity. Under certain circumstances, δ-cells could also be trans-differentiated into insulin-producing ß-cells. Thus, pancreatic islet may benefit from δ-cell hyperplasia. However, an effective way to increase δ-cell mass has been rarely reported. Here, we found that REMD 2.59, a human monoclonal antibody and competitive antagonist of the glucagon receptor, massively boosted δ-cell number and increased plasma somatostatin level in both normoglycemic and type 1 diabetic (T1D) mice. The increased δ-cells were due to both δ-cell proliferation and derivation of duct lining cells. Notably, the enlarged δ-cell mass could reduce ß-cell burdens by inducing FoxO1 nuclear translocation in normoglycemic mice. Moreover, some somatostatin-positive cells were co-localized with C-peptide in T1D mice, suggesting that δ-cells might be a source of the newborn ß-cells. Collectively, these observations suggest that treatment with the glucagon receptor monoclonal antibody can increase pancreatic δ-cell mass by promoting self-replication and inducing duct-derived neogenesis both in normoglycemia and diabetic mice.

[The influence of chronic intermittent hypoxia on hypothalamic-somatotropic axis in rats].

Objective: To investigate the effects of chronic intermittent hypoxia on somatotropic axis hormone levels in rats. Methods: Mature male Wistar rats were exposed to air or intermittent hypoxia randomly.The serum levels of growth hormone-releasing hormone (GHRH), growth hormone (GH) and somatostatin (SS) were measured before exposure, at the 4th, 8th, and 12th week after exposure. Different hormone levels in two groups were compared and analyzed. Results: Compared with the control group, GHRH levels in chronic intermittent hypoxic group showed a significant decline at the 4th week [(732.77±46.99)pg/ml vs. (893.59±40.00) pg/ml, P<0.05], while SS levels at the 8th week [(30.71±2.27) pg/ml vs. (44.69±3.36) pg/ml, P<0.05] and GH levels at the 12th week [(1.20±0.29) ng/ml vs. (2.06±0.13) ng/ml, P<0.05] were similarly reduced. As the duration of intermittent hypoxia was prolonged, the GHRH levels did not decrease further [4th week (732.77±46.99) pg/ml vs. 8th week (607.54±131.61) pg/ml vs. 12th week (730.05±40.63) pg/ml, P>0.05].However, the serum SS levels decreased further from the 8th week to the 12th week [(30.71±2.27) pg/ml vs. (24.41±4.06) pg/ml, P<0.05]. Conclusion: Chronic intermittent hypoxia might inhibit the function of somatotropic axis. Hypothalamic hormones are the earlyonesto be influenced, thereafter the entire axis.

Relationship between somatostatin and interleukin-6: A cross-sectional study in patients with acute pancreatitis.

OBJECTIVES: The aim of the analysis is to determine dynamic changes in somatostatin (SS) and interleukin-6 (IL-6) concentrations during in acute pancreatitis (AP). METHODS: The influence of tobacco smoking on IL-6 and SS levels in the serum of non-smoking (n = 10) and smoking (n = 27) patients with diagnosed AP and control group: non-smoking (n = 44), smoking (n = 42) and passive smoking (n = 29) healthy persons was proved. The concentration of IL-6 and SS was determined by means of ELISA. Differences between the groups analyzed were tested using the U Mann Whitney test. The Spearman rank correlation analysis was used to evaluate the correlations. RESULTS: The concentrations of IL-6 and SS were significantly higher in smoking patients with AP and healthy persons when compared with non-smoking population on every day (1 day: p = 0.0002, p = 0.015; 3 day: p = 0.005, p = 0.001 and 7 day: p = 0.025, p = 0.038). Dynamic changes in concentrations of IL-6 and SS in the serum of patients with AP were demonstrated in the ensuing days of the disease. In case of non-smoking and smoking patients, significant positive correlations between IL-6 and SS was observed. CONCLUSIONS: These findings suggest that some of the antiinflammatory effects of SS against acute pancreatitis may be mediated by reducing the local proinflammatory cytokine secretion in the pancreas.

Association of plasma somatostatin with disease severity and progression in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Somatostatin (SST) inhibits intracellular cyclic adenosine monophosphate (cAMP) production and thus may modify cyst formation in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether endogenous plasma SST concentration is associated with disease severity and progression in patients with ADPKD, and whether plasma SST concentrations change during treatment with a vasopressin V2 receptor antagonist or SST analogue. METHODS: In this observational study, fasting concentrations of SST were measured in 127 ADPKD patients (diagnosed upon the revised Ravine criteria) by ELISA. cAMP was measured in 24 h urine by Radio Immuno Assay. Kidney function was measured (mGFR) as 125I-iothalamate clearance, and total kidney volume was measured by MRI volumetry and adjusted for height (htTKV). Disease progression was expressed as annual change in mGFR and htTKV. Additionally, baseline versus follow-up SST concentrations were compared in ADPKD patients during vasopressin V2 receptor antagonist (tolvaptan) (n = 27) or SST analogue (lanreotide) treatment (n = 25). RESULTS: In 127 ADPKD patients, 41 ± 11 years, 44% female, eGFR 73 ± 32 ml/min/1.73m2, mGFR 75 ± 32 ml/min/1.73m2 and htTKV 826 (521-1297) ml/m, SST concentration was 48.5 (34.3-77.8) pg/ml. At baseline, SST was associated with urinary cAMP, mGFR and htTKV (p = 0.02, p = 0.004 and p = 0.02, respectively), but these associations lost significance after adjustment for age and sex or protein intake (p = 0.09, p = 0.06 and p = 0.15 respectively). Baseline SST was not associated with annual change in mGFR, or htTKV during follow-up (st. ß = - 0.02, p = 0.87 and st. ß = - 0.07, p = 0.54 respectively). During treatment with tolvaptan SST levels remained stable 38.2 (23.8-70.7) pg/mL vs. 39.8 (31.2-58.5) pg/mL, p = 0.85), whereas SST levels decreased significantly during treatment with lanreotide (42.5 (33.2-55.0) pg/ml vs. 29.3 (24.8-37.6), p = 0.008). CONCLUSIONS: Fasting plasma SST concentration is not associated with disease severity or progression in patients with ADPKD. Treatment with lanreotide caused a decrease in SST concentration. These data suggest that plasma SST cannot be used as a biomarker to assess prognosis in ADPKD, but leave the possibility open that change in SST concentration during lanreotide treatment may reflect therapy efficacy.

Preventive Effect of Lactobacillus fermentum CQPC03 on Activated Carbon-Induced Constipation in ICR Mice.

Background and objectives: Paocai (pickled cabbage), which is fermented by lactic acid bacteria, is a traditional Chinese food. The microorganisms of Paocai were isolated and identified, and the constipation inhibition effect of one of the isolated Lactobacillus was investigated. Materials and Methods: The 16S rDNA technology was used for microbial identification. A mouse constipation model was established using activated carbon. After intragastric administration of Lactobacillus (108 CFU/mL), the mice were dissected to prepare pathological sections of the small intestine. Serum indicators were detected using kits, and the expression of small intestine-related mRNAs was detected by qPCR assay. Results: One strain of Lactobacillus was identified and named Lactobacillus fermentum CQPC03 (LF-CQPC03). Body weight and activated carbon propulsion rate were all higher in mice intragastrically administered with LF-CQPC03 compared with the control group, while the time to the first black stool in treated mice was lower than that in the control group. Serum assays showed that gastrin (Gas), endothelin (ET), and acetylcholinesterase (AchE) levels were significantly higher in the LF-CQPC03-treated mice than in the control group, while somatostatin (SS) levels were significantly lower than in the control mice. Mouse small intestine tissue showed that c-Kit, stem cell factor (SCF), and glial cell-derived neurotrophic factor (GDNF) mRNA expression levels were significantly higher in the LF-CQPC03 treated mice than in control mice, while transient receptor potential cation channel subfamily V member 1 (TRPV1) and inducible nitric oxide synthase (iNOS) expression levels were significantly lower in the LF-CQPC03 treated mice than in control mice. Conclusions: There is a better effect with high-dose LF-CQPC03, compared to the lower dose (LF-CQPC03-L), showing good probiotic potential, as well as development and application value.

Plasma N-terminal Prosomatostatin and Risk of Incident Cardiovascular Disease and All-Cause Mortality in a Prospective Observational Cohort: the PREVEND Study.

BACKGROUND: Somatostatin is a component of the well-known insulin-like growth factor-1/growth hormone (GH) longevity axis. There is observational evidence that increased GH is associated with an increased risk of cardiovascular disease (CVD). We aimed to investigate the potential association of plasma N-terminal fragment prosomatostatin (NT-proSST) with incident CVD and all-cause mortality in apparently healthy adults. METHODS: We studied 8134 participants without history of CVD (aged 28-75 years; women, 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, the Netherlands. Plasma NT-proSST was measured in baseline samples. Outcomes were incidence of CVD and all-cause mortality. RESULTS: In cross-sectional analyses, NT-proSST [mean (SD), 384.0 (169.3) pmol/L] was positively associated with male sex and age (both P < 0.001). During a median follow-up of 10.5 (Q1-Q3: 9.9-10.8) years, 708 (8.7%) participants developed CVD and 517 (6.4%) participants died. In univariable analyses, NT-proSST was associated with an increased risk of incident CVD and all-cause mortality (both P < 0.001). In multivariable analyses, these associations were independent of the Framingham risk factors, with hazard ratios (95% CI) per doubling of NT-proSST of 1.17 (1.03-1.34; P = 0.02) for incident CVD and of 1.28 (1.09-1.49; P = 0.002) for all-cause mortality. Addition of NT-proSST to the updated Framingham Risk Score improved reclassification (integrated discrimination improvement (P < 0.001); net reclassification improvement was 2.5% (P = 0.04)). CONCLUSIONS: Plasma NT-proSST is positively associated with increased risk of future CVD and all-cause mortality, partly independent of traditional CVD risk factors. Further research is needed to address the nature of associations.

Phase II study of lanreotide autogel in Japanese patients with unresectable or metastatic well-differentiated neuroendocrine tumors.

Background Lanreotide is a long-acting somatostatin analog with demonstrated efficacy against enteropancreatic neuroendocrine tumor (NET) in the phase III (CLARINET) study. Materials and Methods In this single-arm study, Japanese patients with grade (G) 1/G2 NET received lanreotide (120 mg/4 weeks) for 48 weeks. Those who completed the study were enrolled in a long-term extension study. The primary endpoint was the clinical benefit rate (CBR) defined as a complete response, partial response (PR), or stable disease (SD) over 24-weeks. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and pharmacokinetics. Results Thirty-two patients were recruited at 10 sites. The full analysis set (FAS) comprised 28 patients. Primary tumors were located in pancreas (12 patients), foregut (non-pancreas, lung; 1), midgut (2), hindgut (8), and unknown (5). Four patients had gastrinoma of the functional NET, and 3 had multiple endocrine neoplasia type 1. In the FAS, 39.3% had progressive disease at baseline. The CBR at 24 weeks was 64.3% (95% confidence interval; CI: 44.1-81.4), and median PFS was 36.3 weeks (95% CI: 24.1-53.1). PR was confirmed in 1 patient at 60 weeks during the extension study (ORR: 3.6%). Frequent adverse events related to lanreotide included injection site induration (28.1%), faeces pale (18.8%), flatulence (12.5%), and diabetes mellitus (12.5%). Conclusions The efficacy and safety of lanreotide in this study indicated its usefulness as a treatment option for Japanese NET patients. TRIAL REGISTRATION: JapicCTI-132,375, JapicCTI-142,698.

N-Terminal Prosomatostatin and Risk of Vascular Dementia.

BACKGROUND: Increased somatostatin plasma concentration has been found in patients with vascular dementia. However, it is unknown whether or not somatostatin levels may predict dementia development in the general population. To this end, we sought to assess the association of circulating N-terminal prosomatostatin (NT-proSST) with incident dementia among community-dwelling older adults. METHODS: In the prospective population-based Malmö Preventive Project, 5,347 study participants (mean age: 69 ± 6years; 70% men) provided plasma for the determination of NT-proSST concentration. Of these, 373 participants (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) during a follow-up period of 4.6 ± 1.3 years. The association of NT-proSST with the risk of dementia and its subtypes was studied using multivariable-adjusted Cox regression models controlling for age, gender, body mass index, systolic blood pressure, antihypertensive treatment, smoking, diabetes, lipid levels and prevalent stroke. RESULTS: Higher levels of NT-proSST were significantly associated with an increased risk of vascular dementia (hazard ratio [HR] per 1 SD: 1.29; 95% CI 1.05-1.59; p = 0.016), whereas no association was observed with Alzheimer's disease (HR per 1 SD: 0.99; 95% CI 0.81-1.20; p = 0.91), all-cause dementia (HR per 1 SD: 1.04; 95% CI 0.94-1.16; p = 0.44), and mixed dementia (HR per 1 SD: 0.98; 95% CI 0.79-1.21; p = 0.84). Levels of NT-proSST above 563 pmol/L (highest quartile) conferred distinctly increased risk of vascular dementia (HR 1.66; 95% CI 1.05-2.63; p = 0.029) compared with lower values. CONCLUSIONS: Higher levels of circulating N-terminal-prosomatostatin are associated with increased incidence of vascular dementia. Our findings might be of importance for the understanding of dementia development in older adults.

Gastric Activity and Gut Peptides in Patients With Functional Dyspepsia: Postprandial Distress Syndrome Versus Epigastric Pain Syndrome.

GOALS: The goals of the study were to investigate in both postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) the gastric electrical activity and the gastric emptying (GE) time together with the circulating concentrations of motilin, somatostatin, corticotrophin-releasing factor, and neurotensin, and to establish whether the genetic variability in the neurotensin system genes differs between these 2 categories of functional dyspepsia (FD). BACKGROUND: The current FD classification is based on symptoms and it has been proven not to be completely satisfying because of a high degree of symptom overlap between subgroups. STUDY: Gastric electrical activity was evaluated by cutaneous electrogastrography: the GE time by C-octanoic acid breast test. Circulating concentrations of gut peptides were measured by a radioimmunoassay. NTS 479 A/G and NTSR1 rs6090453 SNPs were evaluated by PCR and endonuclease digestion. RESULTS: Fifty-four FD patients (50 female/4 male) were studied. Using a symptom questionnaire, 42 patients were classified as PDS and 12 as EPS, although an overlap between the symptom profiles of the 2 subgroups was recorded. The electrogastrographic parameters (the postprandial instability coefficient of dominant frequency, the dominant power, and the power ratio) were significantly different between the subgroups, whereas the GE time did not differ significantly. In addition, EPS was characterized by a different gut peptide profile compared with PDS. Finally, neurotensin polymorphism was shown to be associated with neurotensin levels. This evidence deserves further studies in consideration of an analgesic role of neurotensin. CONCLUSIONS: Analysis of gut peptide profiles could represent an interesting tool to enhance FD diagnosis and overcome limitations due to a distinction based solely on symptoms.

Relationship between pancreatic hormones and glucose metabolism: A cross-sectional study in patients after acute pancreatitis.

Abnormal glucose metabolism is present in almost 40% of patients after acute pancreatitis, but its pathophysiology has been poorly investigated. Pancreatic hormone derangements have been sparingly studied to date, and their relationship with abnormal glucose metabolism is largely unknown. The aim was to investigate the associations between pancreatic hormones and glucose metabolism after acute pancreatitis, including the effect of potential confounders. This was a cross-sectional study of 83 adult patients after acute pancreatitis. Fasting venous blood was collected from all patients and used for analysis of insulin, glucagon, pancreatic polypeptide, amylin, somatostatin, C-peptide, glucose, and hemoglobin A1c. Statistical analyses were conducted using the modified Poisson regression, multivariable linear regression, and Spearman's correlation. Age, sex, body mass index, recurrence of acute pancreatitis, duration from first attack, severity, and etiology were adjusted for. Increased insulin was significantly associated with abnormal glucose metabolism after acute pancreatitis, in both unadjusted (P = 0.038) and adjusted (P = 0.001) analyses. Patients with abnormal glucose metabolism also had significantly decreased pancreatic polypeptide (P = 0.001) and increased amylin (P = 0.047) in adjusted analyses. Somatostatin, C-peptide, and glucagon were not changed significantly in both unadjusted and adjusted analyses. Increased insulin resistance and reduced insulin clearance may be important components of hyperinsulinemic compensation in patients after acute pancreatitis. Increased amylin and reduced pancreatic polypeptide fasting levels characterize impaired glucose homeostasis. Clinical studies investigating islet-cell hormonal responses to mixed-nutrient meal testing and euglycemic-hyperinsulinemic clamps are now warranted for further insights into the role of pancreatic hormones in glucose metabolism derangements secondary to pancreatic diseases.

Differential Mobility Spectrometry Coupled with Multiple Ion Monitoring in Regulated LC-MS/MS Bioanalysis of a Therapeutic Cyclic Peptide in Human Plasma.

A differential mobility spectrometry (DMS) in combination with a multiple ion monitoring (MIM) method was developed and validated for quantitative LC-MS/MS bioanalysis of pasireotide (SOM230) in human plasma. Pasireotide, a therapeutic cyclic peptide, exhibits poor collision-induced dissociation (CID) efficiency for multiple reaction monitoring (MRM) detection. Therefore, in an effort to increase the overall sensitivity of the assay, a DMS-MIM approach was explored. By selecting the most abundant doubly charged precursor ion in both the Q1 and Q3 of the mass analyzer in MIM and combining the DMS capability to significantly reduce the high matrix/chemical background noise, this new LC-DMS-MIM method overcomes the sensitivity challenge in the typical MRM method due to poor CID fragmentation of the analyte. Human plasma was spiked with pasireotide with concentrations in the range 0.01-50 ng/mL. Weak cation-exchange solid-phase extraction was employed for sample preparation. The sample extracts were analyzed with a SCIEX QTRAP 6500 system equipped with an ESI source and DMS device. The separation voltage and compensation voltage of the DMS and other parameters of the MS system were optimized to maximize signal responses. The performance of the LC-DMS-MIM assay for quantitative analysis of pasireotide in human plasma was evaluated and compared to those obtained via LC-MRM and LC-MIM without DMS. Overall, the assay sensitivity with DMS-MIM was approximately 5-fold better than that observed in MRM or MIM without DMS. The assay was validated with accuracy (% bias) and precision (% CV) of the QC results at eight concentration levels (0.01, 0.02, 0.05, 0.15, 0.3, 1.5, 15, and 37.5 ng/mL) evaluated ranging from -4.8 to 5.0% bias and 0.7 to 8.6% CV for the intraday and interday runs. The current LC-DMS-MIM workflow can be expanded to quantitative analysis of other molecules that have poor fragmentation efficiency in CID.

Effect of Diabetes on Circulating Pancreatic Hormones in Pregnant Rats and Their Offspring.

The aim of the study was to investigate the role of diabetic intrauterine environment on circulating insulin, glucagon, and somatostatin levels in pregnant rats, fetuses, and offspring. Diabetes was induced in female Wistar rats by streptozotocin at birth or as adult and the animals were assigned into: control (C); mildly diabetic (MD); and severely diabetic (SD). The rats were mated and distributed into 2 subgroups: euthanasia at day 21 of pregnancy and at day 10 postpartum. Both MD and SD dams showed impaired oral glucose tolerance. SD dams had lower body weight and insulin levels compared to C and MD dams. SD fetuses presented hyperglycemia and reduction of insulin and glucagon levels compared to C and MD fetuses. SD newborns had diminished total pancreatic insulin and plasma somatostatin compared to the other groups. MD dams and fetuses had lower glucagon and somatostatin levels compared to C dams. MD offspring had maintained lower somatostatin levels to neonatal period. Diabetes causes alterations in circulating levels of pancreatic hormones in the mother and offspring.

The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1.

The importance of vagal efferent signaling for the insulinotropic and glucagonostatic effects of glucagon-like peptide-1 (GLP-1) was investigated in a randomized single-blinded study. Healthy male participants (n = 10) received atropine to block vagal cholinergic transmission or saline infusions on separate occasions. At t = 15 min, plasma glucose was clamped at 6 mmol/l. GLP-1 was infused at a low dose (0.3 pmol·kg(-1)·min(-1)) from t = 45-95 min and at a higher dose (1 pmol·kg(-1)·min(-1)) from t = 95-145 min. Atropine blocked muscarinic, cholinergic transmission, as evidenced by an increase in heart rate [peak: 70 ± 2 (saline) vs. 90 ± 2 (atropine) beats/min, P < 0.002] and suppression of pancreatic polypeptide levels [area under the curve during the GLP-1 infusions (AUC45-145): 492 ± 85 (saline) vs. 247 ± 59 (atropine) pmol/l × min, P < 0.0001]. More glucose was needed to maintain the clamp during the high-dose GLP-1 infusion steady-state period on the atropine day [6.4 ± 0.9 (saline) vs. 8.7 ± 0.8 (atropine) mg·kg(-1)·min(-1), P < 0.0023]. GLP-1 dose-dependently increased insulin secretion on both days. The insulinotropic effect of GLP-1 was not impaired by atropine [C-peptide AUCs45-145: 99 ± 8 (saline) vs. 113 ± 13 (atropine) nmol/l × min, P = 0.19]. Atropine suppressed glucagon levels additively with GLP-1 [AUC45-145: 469 ± 70 (saline) vs. 265 ± 50 (atropine) pmol/l × min, P = 0.018], resulting in hypoglycemia when infusions were suspended [3.6 ± 0.2 (saline) vs. 2.7 ± 0.2 (atropine) mmol/l, P < 0.0001]. To ascertain whether atropine could independently suppress glucagon levels, control experiments (n = 5) were carried out without GLP-1 infusions [AUC45-145: 558 ± 103 (saline) vs. 382 ± 76 (atropine) pmol/l × min, P = 0.06]. Our results suggest that efferent muscarinic activity is not required for the insulinotropic effect of exogenous GLP-1 but that blocking efferent muscarinic activity independently suppresses glucagon secretion. In combination, GLP-1 and muscarinic blockade strongly affect glucose turnover.

The relationship between N-terminal prosomatostatin, all-cause and cardiovascular mortality in patients with type 2 diabetes mellitus (ZODIAC-35).

BACKGROUND: The hormone somatostatin inhibits growth hormone release from the pituitary gland and is theoretically linked to diabetes and diabetes related complications. This study aimed to investigate the relationship between levels of the stable somatostatin precursor, N-terminal prosomatostatin (NT-proSST), with mortality in type 2 diabetes (T2DM) patients. METHODS: In 1,326 T2DM outpatients, participating in this ZODIAC prospective cohort study, Cox proportional hazards models were used to investigate the independent relationship between plasma NT-proSST concentrations with all-cause and cardiovascular mortality. RESULTS: Median concentration of NT-proSST was 592 [IQR 450-783] pmol/L. During follow-up for 6 [3-10] years, 413 (31%) patients died, of which 176 deaths (43%) were attributable to cardiovascular causes. The age and sex adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality were 1.48 (95%CI 1.14 - 1.93) and 2.21 (95%CI 1.49 - 3.28). However, after further adjustment for cardiovascular risk factors there was no independent association of log NT-proSST with mortality, which was almost entirely attributable to adjustment for serum creatinine. There were no significant differences in Harrell's C statistics to predict mortality for the models with and without NT-proSST: both 0.79 (95%CI 0.77 - 0.82) and 0.81 (95%CI 0.77 - 0.84). CONCLUSIONS: NT-proSST is unsuitable as a biomarker for cardiovascular and all-cause mortality in stable outpatients with T2DM.

Shuidouchi (Fermented Soybean) Fermented in Different Vessels Attenuates HCl/Ethanol-Induced Gastric Mucosal Injury.

Shuidouchi (Natto) is a fermented soy product showing in vivo gastric injury preventive effects. The treatment effects of Shuidouchi fermented in different vessels on HCl/ethanol-induced gastric mucosal injury mice through their antioxidant effect was determined. Shuidouchi contained isoflavones (daidzein and genistein), and GVFS (glass vessel fermented Shuidouchi) had the highest isoflavone levels among Shuidouchi samples fermented in different vessels. After treatment with GVFS, the gastric mucosal injury was reduced as compared to the control mice. The gastric secretion volume (0.47 mL) and pH of gastric juice (3.1) of GVFS treated gastric mucosal injury mice were close to those of ranitidine-treated mice and normal mice. Shuidouchi could decrease serum motilin (MTL), gastrin (Gas) level and increase somatostatin (SS), vasoactive intestinal peptide (VIP) level, and GVFS showed the strongest effects. GVFS showed lower IL-6, IL-12, TNF-α and IFN-γ cytokine levels than other vessel fermented Shuidouchi samples, and these levels were higher than those of ranitidine-treated mice and normal mice. GVFS also had higher superoxide dismutase (SOD), nitric oxide (NO) and malonaldehyde (MDA) contents in gastric tissues than other Shuidouchi samples. Shuidouchi could raise IκB-α, EGF, EGFR, nNOS, eNOS, Mn-SOD, Gu/Zn-SOD, CAT mRNA expressions and reduce NF-κB, COX-2, iNOS expressions as compared to the control mice. GVFS showed the best treatment effects for gastric mucosal injuries, suggesting that glass vessels could be used for Shuidouchi fermentation in functional food manufacturing.

[Effects of octreotide on liver gluconeogenesis in obesity rats fed a high fat diet].

OBJECTIVE: To verify the effects of octreotide on liver gluconeogenesis in high fat diet-induced obesity rat. METHODS: Male SD rats were randomly assigned to control (n = 16) and high-fat diet group (n = 40). After 24 weeks, obese rats selected from high-fat diet group were placed into obese group (n = 16) and octretide-treated group (n = 16). Rats in the octreotide-treated group were subcutaneously injected with octreotide per 12 h (40 mg/kg body weight) for 8 days. Body lengths, body weight, fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), fasting serum insulin and plasma somatostatin (SST) levels were measured. The Lee' s index and HOMA index were calculated. Expression of glucose-6-phosphatase (G6pase), phosphoenolpyruvate carboxykinase (Pepck) and forkhead box-containing protein 0 subfamily-1 (Foxol) mRNA were measured by RT-PCR. Foxol protein in nuclear and cytoplasm were quantified by western blotting. RESULTS: Compared with control group, body weight, FPG, TG, TC, insulin and HOMA index in obese group were significantly increased. Octreotide treatment showed obviously reduced levels of the parameters. The plasma SST levels in the obese group tended to decrease compared with that in the control group (P >0. 05), while plasma SST levels was increased in the octreotide-treated group compared with that in the obese group (P <0. 05). Obese rats display more G6pase, Pepck and Foxol mRNA and higher ratio of nuclear Foxol protein to cytoplasm Foxol protein than control rats (P < 0. 01), whereas octreotide intervention reversed those changes (P <0. 01). CONCLUSION: The administration of octreotide can ameliorate abnormal enhancement of hepatic gluconeogenesis, which might be attributed to the reduced activity and expression of Foxol and then decreased expression levels of G6pase and Pepck mRNA.

[Irritable bowel syndrome with extraintestinal manifestations from a position of neuroendocrine pathology].

The aim of this study was to investigate the mechanism (s) of action of gastrointestinal hormones in the pathogenesis of irritable bowel syndrome (IBS), and the correlation between gastrointestinal hormones and psychological factors. Patients with IBS were divided into IBS with normal emotional state ratings and IBS in anxiety-depressive states groups. The two groups were then subdivided into IBS-constipation predominant (IBS-C) and IBS-diarrhea predominant (IBS-D) groups. Non-IBS patients with normal depression and anxiety ratings were recruited as controls. The expression of somatostatin (SS) and vasointestinalpeptid (VIP), motilin in the colonic mucosa was detected by immunohistochemistry and radioimmunoassay. The anxiety-depression scores of patients with IBS were significantly different from those of the control group. The expression levels of SS and VIP, motilin colonic mucosa of the patients with IBS were higher compared with those of the control.group. Furthermore, the expression level of SS in the IBS-C group demonstrated a significantly larger increase than that in the IBS-D group; however, there was no significant difference in the expression of VIP between the IBS-C and IBS-D groups. In addition, the expression levels of SS and VIP, motilin in the IBS groups with normal emotional state ratings were notably different from those in the IBS groups in anxiety-depressive states. Anxiety-depressive states may lead to changes in the secretion of SS and VIP, motilin, and subsequently to changes in gastrointestinal motility and function.

Oral L-arginine before resistance exercise blunts growth hormone in strength trained males.

Acute resistance exercise and L-arginine have both been shown to independently elevate plasma growth hormone (GH) concentrations; however, their combined effect is controversial. The purpose was to investigate the combined effects of resistance exercise and L-arginine supplementation on plasma L-arginine, GH, GH secretagogues, and IGF-1 in strength trained participants. Fourteen strength trained males (age: 25 ± 4 y; body mass: 81.4 ± 9.0 kg; height: 179.4 ± 6.9 cm; and training experience: 6.3 ± 3.4 y) participated in a randomized double-blind crossover design (separated by ~7 days). Subjects reported to the laboratory at 08:00 in a fasted state, consumed L-arginine (ARG; 0.075 g·kg-1 body mass) or a placebo (PLA) before performing an acute bout of resistance exercise (3 sets of 8 exercises, 10 repetitions at ~75% 1RM). Blood samples were collected at rest, before exercise, and at 0, 15, 30, and 60 min of rest-recovery. The ARG condition significantly increased plasma L-arginine concentrations (~120%) while no change was detected in the PLA condition. There were no differences between conditions for GH, GH-releasing hormone, ghrelin, or IGF-1 at any time point. GH-inhibiting hormone was significantly lower in the ARG condition. However, integrated area under the curve for GH was blunted in the ARG condition (L-arginine = 288.4 ± 368.7 vs. placebo = 487.9± 482.0 min·ng·mL1, p < .05). L-arginine ingested before resistance exercise significantly elevated plasma L-arginine concentration but attenuated plasma GH in strength trained individuals despite a lower GHIH. Furthermore our data shows that the GH suppression was not due to a GH or IGF-1 induced autonegative feedback loop.