Pancreatic hormones response-generated machine learning model to help distinguish sporadic pancreatic cancer from new-onset diabetes cohort.

e16235 Background: Diabetes mellitus (DM), a paraneoplastic phenomenon, can develop earlier than other symptoms in pancreatic cancer (PaC) patients. Enhanced surveillance is encouraged on all elderly patients with new-onset DM. However, it is a challenge to differentiate newly developed PaCDM from type 2 DM (T2DM). Thus, we investigated the differences of pancreatic hormones responses and functions between PaCDM and T2DM patients, and developed discriminative model by machine learning algorithms. Methods: PaC patients with normal blood glucose (PaCNG) or with new-onset DM (PaCDM) were recruited. For each case, age and gender matched newly developed T2DM patients and healthy volunteers were selected as controls. After ≥10 hours fasting, all participants underwent a mixed meal stimulation test (MMTT). Blood samples were collected at 0, 15, 30, 60 and 120 min to measure insulin, C-peptide, glucagon, and pancreatic polypeptide (PP). Indices of insulin sensitivity (HOMA-IS, HOMA-IR) and insulin secretion (HOMA-β, insulinogenic index 30’ and 120’) were calculated. Increases in hormone levels were compared among groups with repeated measure analysis. Four machine learning algorithms (Random Forest, Logistic Regression, Support Vector Machines, Naïve bayes) were used to develop quadri-separated discriminative models of PaCDM based on baseline characteristics, pancreatic hormones and insulin indices listed above. Results: Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared to T2DM. The AUC of insulin were comparatively lower in PaCDM; between-group differences were observed at the fasting (197.15 ± 16.59 pg/mL to 537.96 ± 118.69 pg/mL; P = 0.040) and 15 min (523.94 ± 81.15 pg/mL to 1182.51 ± 219.35 pg/mL; P = 0.036) time-points. No statistical differences among groups were found for glucagon. The mean peak PP concentration after MMTT in PaCDM group (466.67 ± 79.05 pg/mL) was higher than control group (258.54 ± 31.36 pg/mL, P = 0.034), but not statistically different to T2DM patients (452.34 ± 62.96 pg/mL, P = 0.892). PaCDM patients had lower insulin secretion capacity but better insulin sensitivity compared to T2DM patients. Eight indices (age, HbA1c, CA19-9, peak concentration of glucose, area above basal of PP, HOMA-IR, HOMA-IS, HOMA-β) were recruited for model development. And the discriminative model generated by random forest algorithm obtained best performance (AUC = 1.000, CA = 0.963, F-1 = 0.941, Precision = 0.889, Recall = 1.000, Specificity = 0.947; model verified). Conclusions: PaCDM patients tend to present with lower β-cell function and better insulin resistance compared to T2DM patients. As our model based on machine learning algorithm generates a good result for discrimination, the above findings may help with early screening for sporadic PaC in new-onset DM. Clinical trial information: ChiCTR1800018247.

Expected values for gastrointestinal and pancreatic hormone concentrations in healthy volunteers in the fasting and postprandial state

Background Gastrointestinal hormones regulate intestinal transit, control digestion, influence appetite and promote satiety. Altered production or action of gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY), may contribute to the biological basis of obesity and altered glucose homeostasis. However, challenges in analytical methodology and lack of clarity on expected values for healthy individuals have limited progress in this field. The aim of this study was to describe expected concentrations of gastrointestinal and pancreatic hormones in healthy volunteers following a standardized meal test (SMT) or 75 g oral glucose tolerance test (OGTT). Methods A total of 28 healthy volunteers (12 men, 16 women; mean age 31.3 years; mean body mass index 24.9 kg/m2) were recruited to attend a hospital clinic on two occasions. Volunteers had blood sampling in the fasting state and were given, in randomized order, an oral glucose tolerance test (OGTT) and standardized mixed liquid meal test with venepuncture at timed intervals for 4 h after ingestion. Analytical methods for gut and pancreatic hormones were assessed and optimized. Concentrations of gut and pancreatic hormones were measured and used to compile ranges of expected values. Results Ranges of expected values were created for glucose, insulin, glucagon, GLP-1, GIP, PYY and free fatty acids in response to a standardized mixed liquid meal or OGTT. Intact proinsulin and C-peptide levels were also measured following the OGTT. Conclusions These ranges of expected values can now be used to compare gut hormone concentrations between healthy individuals and patient groups.

Some results of studying of mechanisms of effect of drinking mineral waters and prospect of further development of this problem

In article the main achievements in a problem of studying of mechanisms of treatment-and-prophylactic use of drinking mineral waters are analysed. The important role of their nonspecific influence due to existence of a stressorny component, activation of digestive organs and increase in products of gastrointestpnalny and pancreatic hormones is proved. Increase in activity of enteroinsulyarny interrelations at intake of mineral waters provides optimization of the broken metabolic reactions. It is revealed that against the background of course intake of mineral waters the resistance to insulin due to optimization of hormonal and receptor interaction decreases. The role of activization of pro-oxidatic reactions in improvement of sensitivity of fabrics to insulin is discussed. Various methods of increase in medical potential of mineral waters due to change of algorithms of their use, enrichment are analyzed by vitamins and phytodrugs, nanoparticles of metals. The scheme of realization of biological potential of mineral water at its internal reception is offered.

Glucose availability but not changes in pancreatic hormones sensitizes hepatic AMPK activity during nutritional transition in rodents

The cellular energy sensor AMP-activated protein kinase (AMPK) is a metabolic regulator that mediates adaptation to nutritional variations to maintain a proper energy balance in cells. We show here that suckling-weaning and fasting-refeeding transitions in rodents are associated with changes in AMPK activation and the cellular energy state in the liver. These nutritional transitions were characterized by a metabolic switch from lipid to glucose utilization, orchestrated by modifications in glucose levels and the glucagon/insulin ratio in the bloodstream. We therefore investigated the respective roles of glucose and pancreatic hormones on AMPK activation in mouse primary hepatocytes. We found that glucose starvation transiently activates AMPK, whereas changes in glucagon and insulin levels had no impact on AMPK. Challenge of hepatocytes with metformin-induced metabolic stress strengthened both AMPK activation and cellular energy depletion under limited-glucose conditions, whereas neither glucagon nor insulin altered AMPK activation. Although both insulin and glucagon induced AMPKα phosphorylation at its Ser485/491 residue, they did not affect its activity. Finally, the decrease in cellular ATP levels in response to an energy stress was additionally exacerbated under fasting conditions and by AMPK deficiency in hepatocytes, revealing metabolic inflexibility and emphasizing the importance of AMPK for maintaining hepatic energy charge. Our results suggest that nutritional changes (i.e. glucose availability), rather than the related hormonal changes (i.e. the glucagon/insulin ratio), sensitize AMPK activation to the energetic stress induced by the dietary transition during fasting. This effect is critical for preserving the cellular energy state in the liver.

Significance of chromogranin A and synaptophysin in pancreatic neuroendocrine tumors

The two most commonly used immunohistochemical markers for neuroendocrine cells and their tumors are chromogranin A (CgA) and synaptophysin (SPY). CgA is a marker for neuroendocrine secretory granules of four pancreatic hormones and gastrin while SPY is a marker for synaptic vesicles in neuroendocrine cells, which release classic neurotransmitters such as acetylcholine and others. CgA is involved in synthesis and secretion of peptide hormones through exocytosis while function of SPY is elusive. Thirty-five pancreatic neuroendocrine tumors (Pan-NETs) were studied, consisting of 14 insulinomas, 8 gastrinomas, 2 glucagonomas, 6 pancreatic polypeptidomas and 5 non-functioning tumors, and were immunostained for four pancreatic hormones, gastrin, CgA and SPY. Majority of Pan-NETs were less immunostained for the endocrine hormones and CgA than the normal pancreatic endocrine cells. CgA immunostaining mostly correlates with each hormone staining in non-β-cell tumors while SPY immunostaining recognizes endocrine cells diffusely in the cytoplasm. CgA immunostaining is less in insulinomas than in non-β-cell tumors, and CgA immunostaining may distinguish CgA-weaker insulinomas from CgA-stronger non-β-cell tumors. CgA immunostaining may be used as an independent marker for biological aggressiveness in non-β-cell Pan-NETs. The serum CgA levels are higher in subjects harboring non-β-cell tumors than those harboring insulinomas, and the serum CgA elevate in parallel to the increasing metastatic tumor mass. Thus, CgA positive immunostaining in Pan-NETs correlate with the elevated serum levels of CgA for diagnosing CgA-positive non-β-cell Pan-NETs and the increasing serum CgA levels indicate increasing metastatic tumor mass.