Pancreatic Polypeptide Levels Research Articles

Exploring the Role of Metabolic Hormones in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. Emerging evidence suggests a potential link between metabolic dysregulation and ALS pathogenesis. This study aimed to investigate the relationship between metabolic hormones and disease progression in ALS patients. A cross-sectional study was conducted involving 44 ALS patients recruited from a tertiary care center. Serum levels of insulin, total amylin, C-peptide, active ghrelin, GIP (gastric inhibitory peptide), GLP-1 active (glucagon-like peptide-1), glucagon, PYY (peptide YY), PP (pancreatic polypeptide), leptin, interleukin-6, MCP-1 (monocyte chemoattractant protein-1), and TNFα (tumor necrosis factor alpha) were measured, and correlations with ALSFRS-R, evolution scores, and biomarkers were analyzed using Spearman correlation coefficients. Subgroup analyses based on ALS subtypes, progression pattern of disease, and disease progression rate patterns were performed. Significant correlations were observed between metabolic hormones and ALS evolution scores. Insulin and amylin exhibited strong correlations with disease progression and clinical functional outcomes, with insulin showing particularly robust associations. Other hormones such as C-peptide, leptin, and GLP-1 also showed correlations with ALS progression and functional status. Subgroup analyses revealed differences in hormone levels based on sex and disease evolution patterns, with male patients showing higher amylin and glucagon levels. ALS patients with slower disease progression exhibited elevated levels of amylin and insulin. Our findings suggest a potential role for metabolic hormones in modulating ALS progression and functional outcomes. Further research is needed to elucidate the underlying mechanisms and explore the therapeutic implications of targeting metabolic pathways in ALS management.

Illuminating the neuropeptide Y4 receptor and its ligand pancreatic polypeptide from a structural, functional, and therapeutic perspective

The neuropeptide Y4 receptor (Y4R), a rhodopsin-like G protein-coupled receptor (GPCR) and the hormone pancreatic polypeptide (PP) are members of the neuropeptide Y family consisting of four receptors (Y1R, Y2R, Y4R, Y5R) and three highly homologous peptide ligands (neuropeptide Y, peptide YY, PP). In this family, the Y4R is of particular interest as it is the only subtype with high affinity to PP over NPY. The Y4R, as a mediator of PP signaling, has a pivotal role in appetite regulation and energy homeostasis, offering potential avenues for the treatment of metabolic disorders such as obesity. PP as anorexigenic peptide is released postprandial from the pancreas in response to food intake, induces satiety signals and contributes to hamper excessive food intake. Moreover, this system was also described to be associated with different types of cancer: overexpression of Y4R have been found in human adenocarcinoma cells, while elevated levels of PP are related to the development of pancreatic endocrine tumors. The pharmacological relevance of the Y4R advanced the search for potent and selective ligands for this receptor subtype, which will be significantly progressed through the elucidation of the active state PP-Y4R cryo-EM structure. This review summarizes the development of novel PP-derived ligands, like Obinepitide as dual Y2R/Y4R agonist in clinical trials or UR-AK86c as small hexapeptide agonist with picomolar affinity, as well as the first allosteric modulators that selectively target the Y4R, e.g. VU0506013 as potent Y4R positive allosteric modulator or (S)-VU0637120 as allosteric antagonist. Here, we provide valuable insights into the complex physiological functions of the Y4R and PP and the pharmacological relevance of the system in appetite regulation to open up new avenues for the development of tool compounds for targeted therapies with potential applications in metabolic disorders.

Associations of Adipocytokines with The Development of Cardiovascular Events in Young People.

The study is an epidemiological cohort study. The analysis included 1240 people aged 25-44 years. The endpoint was combined and included: death from cardiovascular disease, myocardial infarction, probable myocardial infarction, acute cerebrovascular accident, hospitalization for cardiovascular disease, and revascularization. Adipocytokines were determined with a MILLIPLEX panel. In the examined population, 1.7% of cases of cardiovascular events were detected during cohort observation, of which 28.6% were fatal events. In men, cardiovascular endpoints were recorded 4.3 times more often than in women (17 (81%) vs. 4 (19%), p = 0.003). In individuals with cardiovascular events, arterial hypertension (2.6 times), diabetes mellitus (8.6 times), and overweight/obesity (1.5 times) were more often recorded compared to individuals without cardiovascular events. For tumor necrosis factor-alpha (TNFa), the threshold value was 2.5 pg/mL, with sensitivity assessment (Se) at 85.7% and specificity (Sp) at 83.3%. For amylin, the threshold value was 10.5 pg/mL, with Se at 73.7% and Sp at 67.0%. For pancreatic polypeptide (PP), the threshold value was 43.7 pg/mL, with Se at 85.7% and Sp at 56.7%. A method for assessing the risk of cardiovascular events in young people includes determining the levels of amylin, PP, and TNFa in blood serum. The cut-off points for predicting cardiovascular events were levels of amylin above 10.5 pg/mL, PP above 43.7 pg/mL, or a decrease in TNFa below 3.8 pg/mL.

Obesity is associated with impaired postprandial pancreatic polypeptide secretion.

This study aims to compare the levels of serum pancreatic polypeptide (PP), insulin (INS), C-peptide (C-P), and glucagon (GCG) before and after glucose stimulation in type 2 diabetes mellitus (T2DM) patients with different body mass indexes (BMI), analyze the relevant factors associated with PP secretion, and further investigate the role of PP in the development of obesity and diabetes. Data were collected from 83 patients from the hospital. The subjects were divided into normal-weight group, overweight group, and obese group according to their BMI. All subjects were tested with the standard bread meal test (SBMT). PP and relevant parameters were measured, and the area under the curve (AUC) was calculated after 120min of SBMT. AUCpp (AUC of PP) was used as the dependent variable, and the potential influencing factors were used as independent variables for multiple linear regression analysis. The obese and overweight groups had significantly lower PP secretion than the normal-weight group (485.95 pg·h/ml, 95% CI 76.16-895.74, p = 0.021; 664.61 pg·h/ml, 95% CI 285.46-1043.77, p = 0.001) at 60min postprandial. PP secretion in the obese and overweight groups was also significantly lower than that in the normal-weight group (520.07 pg·h/ml, 95% CI 186.58-853.56, p = 0.003; 467.62 pg·h/ml, 95% CI 159.06-776.18, p = 0.003) at 120min postprandial. AUCpp was negatively associated with BMI (r = -0.260, p = 0.017) and positively associated with AUCGCG (r = 0.501, p< 0.001). Multiple linear regression analysis showed that there was a linear correlation between AUCGCG, BMI, and AUCpp (p< 0.001, p = 0.008). The regression equation was calculated as follows: AUCpp = 1772.255-39.65 × BMI + 0.957 × AUCGCG (R2=54.1%, p< 0.001). Compared with normal-weight subjects, overweight and obese subjects had impaired PP secretion after glucose stimulation. In T2DM patients, PP secretion was mainly affected by BMI and GCG. The Ethics Committee of the Affiliated Hospital of Qingdao University. http://www.chictr.org.cn, identifier ChiCTR2100047486.

Portion control tableware differentially impacts eating behaviour in women with and without overweight

Portion control tableware has been described as a potentially effective approach for weight management, however the mechanisms by which these tools work remain unknown. We explored the processes by which a portion control (calibrated) plate with visual stimuli for starch, protein and vegetable amounts modulates food intake, satiety and meal eating behaviour. Sixty-five women (34 with overweight/obesity) participated in a counterbalanced cross-over trial in the laboratory, where they self-served and ate a hot meal including rice, meatballs and vegetables, once with a calibrated plate and once with a conventional (control) plate. A sub-sample of 31 women provided blood samples to measure the cephalic phase response to the meal. Effects of plate type were tested through linear mixed-effect models. Meal portion sizes (mean ± SD) were smaller for the calibrated compared with the control plate (served: 296 ± 69 vs 317 ± 78 g; consumed: 287 ± 71 vs 309 ± 79 g respectively), especially consumed rice (69 ± 24 vs 88 ± 30 g) (p < 0.05 for all comparisons). The calibrated plate significantly reduced bite size (3.4 ± 1.0 vs 3.7 ± 1.0 g; p < 0.01) in all women and eating rate (32.9 ± 9.5 vs 33.7 ± 9.2 g/min; p < 0.05), in lean women. Despite this, some women compensated for the reduced intake over the 8 h following the meal. Pancreatic polypeptide and ghrelin levels increased post-prandially with the calibrated plate but changes were not robust. Plate type had no influence on insulin, glucose levels, or memory for portion size. Meal size was reduced by a portion control plate with visual stimuli for appropriate amounts of starch, protein and vegetables, potentially because of the reduced self-served portion size and the resulting reduced bite size. Sustained effects may require the continued use of the plate for long-term impact.

Counter-regulatory responses to postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia vs surgical and non-surgical control individuals

Aims/hypothesisPost-bariatric hypoglycaemia is an increasingly recognised complication of bariatric surgery, manifesting particularly after Roux-en-Y gastric bypass. While hyperinsulinaemia is an established pathophysiological feature, the role of counter-regulation remains unclear. We aimed to assess counter-regulatory hormones and glucose fluxes during insulin-induced postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia after Roux-en-Y gastric bypass vs surgical and non-surgical control individuals.MethodsIn this case–control study, 32 adults belonging to four groups with comparable age, sex and BMI (patients with post-bariatric hypoglycaemia, Roux-en-Y gastric bypass, sleeve gastrectomy and non-surgical control individuals) underwent a postprandial hypoglycaemic clamp in our clinical research unit to reach the glycaemic target of 2.5 mmol/l 150–170 min after ingesting 15 g of glucose. Glucose fluxes were assessed during the postprandial and hypoglycaemic period using a dual-tracer approach. The primary outcome was the incremental AUC of glucagon during hypoglycaemia. Catecholamines, cortisol, growth hormone, pancreatic polypeptide and endogenous glucose production were also analysed during hypoglycaemia.ResultsThe rate of glucose appearance after oral administration, as well as the rates of total glucose appearance and glucose disappearance, were higher in both Roux-en-Y gastric bypass groups vs the non-surgical control group in the early postprandial period (all p<0.05). During hypoglycaemia, glucagon exposure was significantly lower in all surgical groups vs the non-surgical control group (all p<0.01). Pancreatic polypeptide levels were significantly lower in patients with post-bariatric hypoglycaemia vs the non-surgical control group (median [IQR]: 24.7 [10.9, 38.7] pmol/l vs 238.7 [186.3, 288.9] pmol/l) (p=0.005). Other hormonal responses to hypoglycaemia and endogenous glucose production did not significantly differ between the groups.Conclusions/interpretationThe glucagon response to insulin-induced postprandial hypoglycaemia is lower in post-bariatric surgery individuals compared with non-surgical control individuals, irrespective of the surgical modality. No significant differences were found between patients with post-bariatric hypoglycaemia and surgical control individuals, suggesting that impaired counter-regulation is not a root cause of post-bariatric hypoglycaemia.Trial registrationClinicalTrials.gov NCT04334161Graphical abstract

Worsening Postural Tachycardia Syndrome Is Associated With Increased Glucose-Dependent Insulinotropic Polypeptide Secretion.

Postural tachycardia syndrome (POTS) is characterized by excessive upright tachycardia and disabling presyncopal symptoms, which are exacerbated after consuming a high-carbohydrate meal; it is unknown, however, what is the precise underlying mechanism. We seek to investigate the effect of glucose intake on orthostatic hemodynamic changes and gastrointestinal hormone secretion in POTS. Prospective, case-control study, 12 women with POTS who reported a postprandial worsening of their POTS symptoms and 13 age-matched female controls received 75-g oral glucose and 20 mg/kg acetaminophen to assess nutrient absorption. Hemodynamic, gastrointestinal hormone and acetaminophen levels were measured for up to 120 minutes postingestion while supine and standing. Patients with POTS had significant orthostatic tachycardia, 48.7±11.2 versus 23.3±8.1 bpm, P=0.012 and elevated upright norepinephrine levels, 835.2±368.4 versus 356.9±156.7 pg/mL, P=0.004. After oral glucose, upright heart rate significantly increased in POTS, 21.2±11.9% versus 6.0±19.9%, P=0.033 with a concomitant decline in upright stroke volume, -10.3±11.90% versus 3.3±13.7%, P=0.027; total peripheral resistance, blood pressure and cardiac output remained unaltered. Acetaminophen rate of appearance was similar between groups (P=0.707), indicating comparable nutrient absorption rates. POTS had increased plasma levels of C-peptide (P=0.001), GIP (glucose-dependent insulinotropic polypeptide; P=0.001), peptide YY (P=0.016), and pancreatic polypeptide (P=0.04) following glucose consumption, but only GIP had a time-dependent association with the worsening upright tachycardia and stroke volume fall. The glucose-induced worsening orthostatic tachycardia in POTS was associated with a decline in SV; these changes occurred while GIP, a splanchnic vasodilator, was maximally elevated.

Pancreatic and gut hormone responses to mixed meal test in post-chronic pancreatitis diabetes mellitus

ObjectiveMore than one-third of chronic pancreatitis patients will eventually develop diabetes, recently classified as post-chronic pancreatitis diabetes mellitus (PPDM-C). This study was aimed to investigate the pancreatic and gut hormone responses to a mixed meal test in PPDM-C patients, compared with non-diabetic chronic pancreatitis (CP), and type 2 diabetes patients or healthy controls. Design and methodsSixteen patients with PPDM-C, 12 with non-diabetic CP as well as 10 with type 2 diabetes and healthy controls were recruited. All participants underwent mixed meal tests, and blood samples were collected for measurements of blood glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, peptide YY, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Indices of insulin sensitivity and secretion were calculated. Repeated measures analysis of variance was performed. ResultsParticipants with PPDM-C exhibited decreases in both fasting and postprandial responses of C-peptide (P < 0.001), insulin (P < 0.001), ghrelin (P < 0.001) and PYY (P = 0.006) compared to participants with type 2 diabetes and healthy controls. Patients with CP showed blunted glucagon, PP and incretin reactions, while the responses were increased in patients with PPDM-C compared to controls. The level of insulin sensitivity was higher for PPDM-C than type 2 diabetes (P < 0.01), however the indices for early/late-phase and overall insulin secretion (P < 0.01) were lower. ConclusionsPatients with PPDM-C are characterized by decreased C-peptide, insulin, ghrelin and PYY responses, and similar levels of glucagon, PP, GIP and GLP-1 compared to those with type 2 diabetes. The above findings, when confirmed in a larger population, may prove helpful to establish the diagnosis of PPDM-C, and should promote study on underlying pathophysiological mechanisms.

S500 Presence of Methane in the Fasting Breath Is Associated With a Lower Rise in Pancreatic Polypeptide After Modified Sham-Feeding: An Insight into the Connection Between Vagal Dysfunction and Methane

Introduction: The vagus nerve as a key part of the parasympathetic system regulates gut motility and is implicated in numerous diseases. Pancreatic Polypeptide modified sham-feeding test (PP MSF) is an indirect method to measure vagal tone by measuring serum pancreatic polypeptide levels after chewing but not swallowing food (Balaji et al. JAMA surgery 2002). Excess intestinal methane (CH4) is associated with constipation and is thought to act as a gasotransmitter via the cholinergic pathway. We aimed to evaluate the association between fasting exhaled CH4 and vagal dysfunction as measured by the PP MSF. Methods: Utilizing a natural-language processor, patients with a lactulose breath test (LBT) and PP MSF were identified from Jan 2010 to Oct 2020. Patient demographics, medical history known to affect vagal dysfunction, and a history of esophagectomy or fundoplication were collected. For LBT, patients were asked to eat a low-fermentable diet and fasted for 12 hours prior to the test. Baseline (fasting) CH4 measurements corrected to breath CO2 levels were collected for this study. For the PP MSF, patients fasted for 12 hours then were asked to chew and spit out a hamburger without swallowing. Serum PP levels were measured before and after MSF in 5-minute intervals for 30 minutes. Percent rise in PP from baseline were calculated and compared between patients that had detectable (CH4 > 0 ppm) vs undetectable (CH4 = 0 ppm) CH4 on their baseline LBT. Results: Forty-three patients (27.9% males, median age = 51 ± 17.8 years) were included in the cohort. Eighteen patients (41.8%) had detectable fasting CH4 (median CH4 = 3.0 ± 12.4 ppm). There was no difference in baseline characteristics or prespecified risk factors affecting vagal dysfunction between those who had detectable and undetectable CH4 (Table 1). Patients with CH4 had a significantly lower rise in PP after MSF (4.9% ± 49.0 vs 42.2% ± 96.1, p = 0.01) (Figure 1). Subgroup analysis for patients without esophagectomy or fundoplication showed that detectable CH4 is associated with numerically lower rise in PP (13.4% ± 38.0 vs 39.6% ± 49.9, p = 0.07). Conclusion: This is the first study to show that a detectable CH4 in the breath is associated with a lower rise in PP MSF. We hypothesize that CH4 may be altering vagal tone by affecting the cholinergic pathway. Mechanistic animal models and prospective human studies without esophagectomy or fundoplication are needed to confirm these findings.Table 1.: Demographics and Characteristics of Patients with Constipation*. *The baseline period was defined as the 6 months before the index date; †Includes lubiprostone, linaclotide and plecanatide. CIC, chronic idiopathic constipation; SD, standard deviation.Figure 1.: a) Patients with CH4 had significantly lower rise in PP than those without CH4. b) Mean PP levels plotted over time. Percent rise was significantly lower in patients with detectable CH4 (42.2% vs 4.9%, p = 0.01). PP = pancreatic polypeptide, CH4 = methane.

224-LB: A Study to Evaluate the Glucagon and Incretin Responses and Identify the Role of Extrapancreatic Glucagon in Patients with Fibrocalcific Pancreatic Diabetes

Aim: The aim of this study is to evaluate glucagon and incretin responses in patients with FCPD. Methods: Nine FCPD patients and six age- and body mass index-matched healthy controls were subjected to 75 g oral glucose tolerance test (OGTT) followed by isoglycemic intravenous glucose infusion (IIGI). Blood samples were analyzed for incretins and glucagon at nine pre-specified time-points over 3 h and the area under curve was calculated. Results: Glucagon was significantly higher during OGTT compared to IIGI in FCPD patients (98.8 ± 13 pg/ml vs. 63.4 ± 7 pg/ml, P = 0.03) and was also higher when compared to controls (98.8 ± 13 pg/ ml vs. 65.8 ± 18 pg/ml, P = ns). FCPD patients showed very low basal and stimulated c-peptide (0.43 ± 0.14 ng/ml and 1.09 ± 0.3 ng/ ml, respectively) and pancreatic polypeptide (12.3 ± 0.0pg/ml and 12.0 ± 0.6 pg/ml, respectively) levels. Glucagon-like peptide-1 (GLP-1) was significantly higher in cases on OGTT when compared to controls (44.5 ± 9.2 pM vs. 12.8 ± 7.5 pM, P = 0.02). Oxyntomodulin was also insignificantly higher in cases on OGTT when compared to controls (1252 ± 350 pg/ml vs. 859.8 ± 165 pg/ml, P = 0.43). GIP was lower in cases on IIGI when compared to controls (52.9 ± 23.9 pg/ml vs. 144.5 ± 36.1 pg/ml, P = 0.045) and there was blunted response on OGTT as well (106.8 ± 40.3 pg/ml vs. 557.8 ± 96.4 pg/ml, P = 0.003). Discussion: We found hyperglucagonemia in FCPD on OGTT, which was suppressed on IIGI. Increase in L-cell products: GLP-1 and oxyntomodulin and a good correlation between glucagon and GLP-1 during OGTT were suggestive of extrapancreatic glucagon production probably from L-cell. The blunted GIP could probably be due to: inadequate pancreatic enzyme supplements, a selective PC-2 enzyme up-regulation or a negative feedback regulation from extrapancreatic glucagon. Conclusion: Extrapancreatic glucagon does exist in FCPD and may contribute to postprandial hyperglycemia and lower GIP levels. Disclosure A. Shankar: None.

Auricular vagal nerve stimulation enhances gastrointestinal motility and improves interstitial cells of Cajal in rats treated with loperamide.

Gastrointestinal (GI) motility disorders affect a large proportion of the population with limited treatment options. The aims of this study were to investigate the potential of a non-invasive method of auricular vagal nerve stimulation (aVNS) for treating GI dysmotility and to explore possible mechanisms involving slow waves and interstitial cells of Cajal (ICC). Normal rats were treated daily with loperamide for 1 week and then treated, while still on daily loperamide, with aVNS/Sham-aVNS for another 1week. Gastric emptying (GE), small intestine transit (SIT), and GI slow waves were measured. The plasma level of pancreatic polypeptide (PP) and noradrenaline (NE) was assessed by ELISA. ICC in the gastric antrum were detected by immunohistochemistry. (a) aVNS significantly increased the percentage of normal GI slow waves (p<0.05 for both fasting and postprandial states, vs. Sham-aVNS) and accelerated GE (p<0.05, vs. Sham-aVNS) and SIT (p<0.05, vs. Sham-aVNS) impaired by loperamide. (b) aVNS increased plasma PP (p<0.01) and decreased plasma NE (p<0.01), compared with Sham-aVNS. (c) Gastric ICC was decreased by loperamide (p<0.01) but increased after aVNS (p<0.01, vs. Sham aVNS). Loperamide induces upper GI dysmotility. aVNS accelerates upper GI transit and improving pace-making activity mediated via the ICC. Non-invasive aVNS may have a therapeutic potential for upper GI dysmotility.

Effect of Acute Sprint Exercise on Myokines and Food Intake Hormones in Young Healthy Men.

Physical exercise is known to influence hormonal mediators of appetite, but the effect of short-term maximal intensity exercise on plasma levels of appetite hormones and cytokines has been little studied. We investigated the effect of a 30 s Wingate Test, followed by a postprandial period, on appetite sensations, food intake, and appetite hormones. Twenty-six physically active young males rated their subjective feelings of hunger, prospective food consumption, and fatigue on visual analogue scales at baseline, after exercise was completed, and during the postprandial period. Blood samples were obtained for the measurement of nesfatin-1, ghrelin, leptin, insulin, pancreatic polypeptide (PP), human growth factor (hGH) and cytokine interleukin-6 (IL-6), irisin and plasma lactate concentrations, at 30 min before exercise, immediately (210 s) after exercise, and 30 min following a meal and at corresponding times in control sedentary males without ad libitum meal intake, respectively. Appetite perceptions and food intake were decreased in response to exercise. Plasma levels of irisin, IL-6, lactate, nesfatin-1 and ghrelin was increased after exercise and then it was returned to postprandial/control period in both groups. A significant rise in plasma insulin, hGH and PP levels after exercise was observed while meal intake potentiated this response. In conclusion, an acute short-term fatiguing exercise can transiently suppress hunger sensations and food intake in humans. We postulate that this physiological response involves exercise-induced alterations in plasma hormones and the release of myokines such as irisin and IL-6, and supports the notion of existence of the skeletal muscle–brain–gut axis. Nevertheless, the detailed relationship between acute exercise releasing myokines, appetite sensations and impairment of this axis leading to several diseases should be further examined.

GPR120 Regulates Pancreatic Polypeptide Secretion From Male Mouse Islets via PLC-Mediated Calcium Mobilization.

The free fatty acid receptor G protein-coupled receptor 120 (GPR120) is expressed in pancreatic islets, but its specific cell distribution and function have not been fully established. In this study, a GPR120-IRES-EGFP knockin (KI) mouse was generated to identify GPR120-expressing cells with enhanced green fluorescence proteins (EGFP). EGFP-positive cells collected from KI mouse islets by flow cytometry had a significantly higher expression of pancreatic polypeptide (PP) evidenced by reverse transcriptase (RT)-quantitative polymerase chain reaction (qPCR). Single-cell RT-PCR and immunocytochemical double staining also demonstrated the coexpression of GPR120 with PP in mouse islets. The GPR120-specific agonist TUG-891 significantly increased plasma PP levels in mice. TUG-891 significantly increased PP levels in islet medium in vitro, which was markedly attenuated by GPR120 small interfering RNA treatment. TUG-891-stimulated PP secretion in islets was fully blocked by pretreatment with YM-254890 (a Gq protein inhibitor), U73122 (a phospholipase C inhibitor), or thapsigargin (an inducer of endoplasmic reticulum Ca2+ depletion), respectively. TUG-891 triggered the increase in intracellular free Ca2+ concentrations ([Ca2+]i) in PP cells, which was also eliminated by YM-254890, U73122, or thapsigargin. GPR120 gene expression was significantly reduced in islets of high-fat diet (HFD)-induced obese mice. TUG-891-stimulated PP secretion was also significantly diminished in vivo and in vitro in HFD-induced obese mice compared with that in normal-chow diet control mice. In summary, this study demonstrated that GPR120 is expressed in mouse islet PP cells and GPR120 activation stimulated PP secretion via the Gq/PLC-Ca2+ signaling pathway in normal-chow diet mice but with diminished effects in HFD-induced obese mice.

SAT-650 Novel Insights into the Entero-Insular Axis in Fibrocalcific Pancreatic Diabetes: An Isoglycemic Intravenous Glucose Infusion (IIGI) Study from India

In tropical countries including India, one of the common causes for young onset diabetes mellitus (DM) is “Fibro Calcific Pancreatic Diabetes” (FCPD) characterized by progressive pancreatic destruction. Despite this, glucagon has been found to be elevated in FCPD (1,2). The L-Cells in gut produce glucagon like peptide- 1 (GLP-1) and oxyntomodulin which are products of glucagon gene, thus raising probability of extra-pancreatic glucagon in FCPD. To test this hypothesis we performed 75grams oral glucose tolerance test (OGTT) followed by IIGI on separate days on nine FCPD and six healthy subjects. The latter procedure ensured matched glucose levels achieved during OGTT. Glucagon and incretins were measured at nine pre-specified time points. We found an increase in L-Cell products: GLP-1 (44.5±9.2pM vs. 12.4±4.5pM, p=0.02) and Oxyntomodulin (1252±350pg/ml vs. 859.8±165pg/ml, p=0.43) along with significant rise in glucagon during OGTT (98.8±13pg/ml vs. 63.4±7pg/ml, p=0.03) despite flat basal & stimulated C-peptide (0.43±0.14ng/ml and 1.09±0.3ng/ml, respectively) and Pancreatic polypeptide (12.3±0.0pg/ml and 14.7±1.7pg/ml, respectively) levels.Paradoxically, gastric inhibitory polypeptide (GIP) levels were low in FCPD (106.8±40.3pg/ml vs. 557.8±96.4pg/ml, p=0.003). We speculate that the hyperglucagonemia is extra-pancreatic (L-Cell) in origin and may also contribute to the dichotomous incretin response in FCPD.

Pheochromocytoma With Adrenergic Biochemical Phenotype Shows Decreased GLP-1 Secretion and Impaired Glucose Tolerance.

Impaired glucose homeostasis is a common finding in pheochromocytoma (PHEO), especially with adrenergic phenotype. The possible contribution of incretin dysfunction to dysglycemia in PHEO patients has not been studied. To compare changes in pancreatic endocrine function and gut hormones' production during a liquid meal test before and 1 year after adrenalectomy. In a prospective study, we included 18 patients with PHEO (13 females) with adrenergic biochemical phenotype. A liquid meal test with predefined isocaloric enteral nutrition was performed to evaluate dynamic changes in pancreatic hormones and incretins. During the meal test, insulin levels were significantly lower before adrenalectomy only in the early phase of insulin secretion, but changes in area under the curve (AUC) did not reach statistical significance (AUC = 0.07). Plasma glucagon (AUC < 0.01) and pancreatic polypeptide levels (AUC < 0.01) were suppressed in comparison with the postoperative state. Impaired response to the meal was found preoperatively for glucagon-like peptide-1 (GLP-1; AUC P < 0.05), but not glucose-dependent insulinotropic polypepide (GIP; AUC P = 0.21). No significant changes in insulin resistance indices were found, except for the homeostatic model assessment-beta index, an indicator of the function of islet β cells, which negatively correlated with plasma metanephrine (R = -0.66, P < 0.01). Our study shows suppression of pancreatic α and β cell function and impaired GLP-1 secretion during a dynamic meal test in patients with PHEO, which is improved after its surgical treatment. These data demonstrate a novel and potentially significant interconnection between excessive catecholamine production and the secretion of glucoregulatory hormones.

A novel method of sacral nerve stimulation for colonic inflammation.

Vagal nerve stimulation has been reported to treat inflammation with promising results. The aims of our study were to optimize sacral nerve stimulation (SNS) methodologies for colonic inflammation in a rodent model of colitis and to investigate autonomic and cytokine mechanisms. Three major efforts were made in optimizing SNS: (a) to determine the best stimulation duration: SNS-0.5h daily, SNS-1h daily, and SNS-3h daily with the parameters set at 5Hz, 10seconds on, 90seconds off; (b) to determine the best stimulation position: bilateral, bipolar, and unipolar stimulation; (c) to determine the best stimulation parameters: our 5Hz intermittent stimulation vs 14Hz-210μs continuous stimulation. Inflammatory responses were assessed by the disease activity index (DAI), histological analyses, and the myeloperoxidase (MPO) activity. Levels of inflammatory cytokines, norepinephrine (NE), and pancreatic polypeptide (PP) in both plasma and colon tissues were assessed. Both SNS-1h and SNS-3h significantly ameliorated intestinal inflammation; SNS-1h was superior to SNS-3h. Bipolar but not bilateral or unipolar stimulation improved the inflammation in colitis. SNS with 5Hz intermittent stimulation but not the 14Hz continuous SNS was better for treating colitis in rats. SNS with the optimized stimulation parameters increased vagal activity and decreased sympathetic activity. CONCLUSION& INFERENCES: Bipolar stimulation for 1hour daily using intermittent 5Hz parameters is most effective in improving colonic inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines and increasing anti-inflammatory cytokines via the modulation of the autonomic function.

Pancreatic Hormone Responses to Mixed Meal Test in New-onset Prediabetes/Diabetes After Non-necrotizing Acute Pancreatitis.

To investigate the pancreatic hormone responses to mixed meal test, in particular changes in insulin secretion, insulin sensitivity, and their interrelationship, in individuals with new-onset prediabetes or diabetes after non-necrotizing acute pancreatitis (NODAP) compared with healthy controls. Twenty-nine individuals with NODAP and 29 age-and sex-matched healthy controls were recruited. All participants (after fasting for at least 8 h) were given 12 oz. of BOOST drink and blood samples were collected before and after stimulation to measure insulin, C-peptide, glucagon, and pancreatic polypeptide. Indices of insulin sensitivity (HOMA-IS, 1/fasting insulin, Raynaud, and Matsuda) and insulin secretion (HOMA-β, Stumvoll, insulinogenic index 30' and 60') were calculated. Repeated measures analyses were conducted in the unadjusted and adjusted models. Insulin and C-peptide levels were significantly higher in individuals with NODAP compared with controls during mixed meal test in both the unadjusted (P=0.001 for both) and adjusted (P=0.004 and P=0.006, respectively) models. HOMA-IS (P=0.005), 1/fasting insulin (P=0.018), Raynaud index (P=0.018), and Matsuda index (P=0.021) were significantly lower in individuals with NODAP, whereas HOMA-β (P=0.028) and Stumvoll index (P=0.013) were significantly higher. Glucagon and pancreatic polypeptide levels did not differ significantly between NODAP and controls during mixed meal test in both the unadjusted (P=0.345 and P=0.206, respectively) and adjusted (P=0.359 and P=0.158, respectively) models. Decreased insulin sensitivity, β-cell compensation, and no significant change in postprandial levels of glucagon and pancreatic polypeptide characterize NODAP. The above findings may help develop an evidence-based protocol with a view to optimize control of glucose homeostasis in NODAP.

Effects and Mechanisms of Vagal Nerve Stimulation on Body Weight in Diet-Induced Obese Rats.

Vagal nerve stimulation (VNS) has recently been indicated as a novel method for treating obesity. However, the optimal stimulation parameters were unknown and mechanisms were poorly understood. The aim of this study was to investigate the effects of VNS on food intake and body weight in diet-induced obesity (DIO) rats and its possible mechanism involving autonomic functions and gut hormones. Ten control rats and 16 DIO rats were chronically implanted with one pair of electrodes in the subdiaphragmatic vagal nerve. VNS with different stimulation parameters and sham-VNS were performed in control rats. In a chronic study, 8 DIO rats were applied with VNS and another 8 DIO rats were treated with sham-VNS for 4weeks. Food intake, body weight, gastric emptying, heart rate variability (HRV), and gut hormones were evaluated. In DIO rats, the food intake (p < 0.001) and body weight (p < 0.001) were significantly decreased in the VNS group, compared with the sham-VNS group. VNS decreased the sympathovagal ratio (p = 0.003) and increased vagal activity (p = 0.032) assessed from the spectral analysis of HRV. It also increased plasma levels of glucagon-like peptide-1 (p = 0.012), polypeptide YY (p = 0.008), and pancreatic polypeptide (p = 0.008) in DIO rats. Physiologically, VNS delayed solid gastric emptying (p < 0.001) and increased gastric volume (p = 0.004). VNS with appropriate parameters reduced food intake and body weight by delaying gastric emptying mediated via the enhancement of vagal activity and release of anorexigenic hormones.

Glucose-Dependent Insulinotropic Polypeptide Is a Pancreatic Polypeptide Secretagogue in Humans.

Glucose-dependent insulinotropic polypeptide (GIP) has been suggested to stimulate the secretion of pancreatic polypeptide (PP), an islet hormone thought to regulate gut motility, appetite, and glycemia. To determine whether human GIP1-42 (hGIP) stimulates PP secretion. As glycemia modulates the secretion of PP, we measured plasma PP concentrations from 2 studies in healthy men (n = 10) and in patients with type 2 diabetes (T2D) (n = 12), where hGIP1-42 had been administered intravenously during fasting glycemia, hyperglycemia (12 mmol/L), and insulin-induced hypoglycemia (targets: 2.5 mmol/L [healthy]; 3.5 mmol/L [T2D]). Porcine GIP1-42 (pGIP) was also infused intra-arterially in isolated porcine pancreata (n = 4). Mean fasting plasma glucose concentrations were approximately 5 mmol/L (healthy) and approximately 8 mmol/L (T2D). At fasting glycemia, PP concentrations were higher during intravenous hGIP1-42 infusion compared with saline in healthy men (mean [standard error of the mean, SEM], net incremental areas under the curves (iAUCs)[0-30min], 403 [116] vs -6 [57] pmol/L × min; P = 0.004) and in patients with T2D (905 [177] vs -96 [86] pmol/L × min; P = 0.009). During hyperglycemic clamping, mean [SEM] PP concentrations were significantly higher during hGIP1-42 infusion compared with saline in patients with T2D (771 [160] vs -183 [117] pmol/L × min; P = 0.001), but not in healthy individuals (-8 [86] vs -57 [53] pmol/L × min; P = 0.69). When plasma glucose levels were declining in response to exogenous insulin, mean [SEM] PP concentrations were higher during hGIP1-42 infusion compared with saline in healthy individuals (294 [88] vs -82 [53] pmol/L × min; P = 0.0025), but not significantly higher in patients with T2D (586 [314] vs -120 [53]; P = 0.070). At target hypoglycemia, PP levels surged in both groups during both hGIP1-42 and saline infusions. In isolated pancreata, pGIP1-42 increased mean [SEM] PP output in the pancreatic venous effluent (baseline vs infusion, 24[5] vs 79 [16] pmol/min x min; P = 0.044). GIP1-42 increases plasma PP secretion in healthy individuals, patients with T2D, and isolated porcine pancreata. Hyperglycemia blunts the stimulatory effect of hGIP1-42 in healthy individuals, but not in patients with T2D.

Genistein diet improves body weight, serum glucose and triglyceride levels in both male and female ob/ob mice.

PurposeDiabetic obesity in the leptin-deficient ob/ob mouse is associated with weight gain, and hyperglycemia, along with hyperinsulinemia. We have previously examined the effects of genistein (a naturally occurring isoflavone found in soy) on metabolic disturbances in the ob/ob mouse and demonstrated beneficial effects of genistein (600 mg genistein/kg diet, for 4-weeks) on T3 production and corticosterone status. The goal of this study was to examine whether dietary genistein could prevent, or at least lessen, the typical phenotype in this murine model of diabetic-obesity, and to assess potential sex-differences.Patients and methodsThe ob/ob mice (male and female) aged 4–5 weeks were randomly assigned to one of two diets for a period of 4-weeks: standard rodent diet, or genistein-containing diet (600 mg genistein/kg diet). Comparisons were made to a lean control group.ResultsGenistein diet significantly reduced body weight by 12% in females and 9% in males. Genistein significantly lowered serum glucose levels by 18% in females and 43% in males, yet had no effect on serum insulin. Genistein diet significantly lowered serum triglyceride levels in both ob/ob male and female mice returning them to lean levels. In females only, genistein significantly reduced serum pancreatic polypeptide levels by 56% and increased serum GIP levels 2.3-fold. Genistein had sex-dependent effects on hepatic steatosis: in females, genistein further increased the % fat area and the fat droplet diameter 2.6-fold, along with additionally increasing hepatic TBARS.ConclusionThe results from this study indicate interesting beneficial effects of genistein diet for both male and female ob/ob mice.