Pancreatic Dysfunction Research Articles

Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion.

Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of microRNAs (miRNAs). However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improves insulin secretion and glucose intolerance in db/db mice. Supporting the function of EVs' miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs shows their distribution in mouse pancreatic islets. Tracing the injected AAV-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat results in upregulating miR-27a-5p in EVs and serum, and elicits mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolishes the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EVs' miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus.

An innovative surgical approach for solid pseudopapillary neoplasm with duodenal invasion in a pediatric patient: a case report

BackgroundPediatric pancreatic tumors, especially with duodenal invasion, are exceptionally rare and a strategy for their treatment has not been established. A pancreaticoduodenectomy is often the desired treatment, but may be over-invasive for solid pseudopapillary neoplasm (SPN). This study reports an innovative surgical approach for SPN with duodenal invasion using pancreatic enucleation and endoscopically guided partial duodenectomy.Case presentationAn 11-year-old girl complained of malaise and presented with severe anemia; imaging revealed a tumor of undetermined origin, involving the pancreatic head and descending duodenum. Intraoperative findings showed tumor adherence to the pancreatic head and endoscopy revealed invasion of the duodenum. The tumor was enucleated from the pancreatic head, and partial duodenectomy was performed under endoscopically guided direct visualization. Pathology confirmed SPN with duodenal invasion, and no residual tumor. Although a Grade B pancreatic fistula occurred postoperatively, it was managed conservatively. At the 15-month follow-up, no signs of tumor recurrence, duodenal stenosis, or pancreatic dysfunction were evident.ConclusionsGiven the good prognosis of SPN, we believe that enucleation from the pancreatic head combined with an endoscopically guided partial duodenectomy could be a useful and less invasive alternative to pancreaticoduodenectomy for cases with duodenal invasion.

Engineered tools to study endocrine dysfunction of pancreas.

Pancreas, a vital organ with intricate endocrine and exocrine functions, is central to the regulation of the body's glucose levels and digestive processes. Disruptions in its endocrine functions, primarily regulated by islets of Langerhans, can lead to debilitating diseases such as diabetes mellitus. Murine models of pancreatic dysfunction have contributed significantly to the understanding of insulitis, islet-relevant immunological responses, and the optimization of cell therapies. However, genetic differences between mice and humans have severely limited their clinical translational relevance. Recent advancements in tissue engineering and microfabrication have ushered in a new era of in vitro models that offer a promising solution. This paper reviews the state-of-the-art engineered tools designed to study endocrine dysfunction of the pancreas. Islet on a chip devices that allow precise control of various culture conditions and noninvasive readouts of functional outcomes have led to the generation of physiomimetic niches for primary and stem cell derived islets. Live pancreatic slices are a new experimental tool that could more comprehensively recapitulate the complex cellular interplay between the endocrine and exocrine parts of the pancreas. Although a powerful tool, live pancreatic slices require more complex control over their culture parameters such as local oxygenation and continuous removal of digestive enzymes and cellular waste products for maintaining experimental functionality over long term. The combination of islet-immune and slice on chip strategies can guide the path toward the next generation of pancreatic tissue modeling for better understanding and treatment of endocrine pancreatic dysfunctions.

Examination of duodenal and colonic microbiome changes in mouse models of acute and chronic pancreatitis

The exocrine pancreas is the main source of digestive enzymes which are released from secretory vesicles of acinar cells into the small intestine. Enzymes, including amylases, proteases and lipases, degrade the ingested food and thus determine the nutritional substrate for the gut microbiota. Acute (AP) and chronic pancreatitis (CP) are associated with a transitional or progressive exocrine pancreatic dysfunction, we analysed in the present study how an experimental induction of pancreatitis in mouse models affects the colonic and duodenal microbiome composition. Evaluation by 16 S rRNA gene sequencing revealed specific microbiome changes in colonic as well as in duodenal samples in different models of AP and CP. Mild acute pancreatitis, which is associated with a transient impairment of pancreatic secretion showed only minor changes in microbial composition, comparable to the ones seen in progressive dysfunctional mouse models of CP. The strongest changes were observed in a mouse model of severe AP, which suggest a direct effect of the immune response on gut microbiome in addition to a pancreatic dysfunction. Our data indicate that highly dysbiotic microbiome changes during pancreatitis are more associated with the inflammatory reaction than with a disturbed pancreatic secretion.

A metabolic dysfunction-associated steatotic liver acinus biomimetic induces pancreatic islet dysfunction in a coupled microphysiology system

Preclinical and clinical studies suggest that lipid-induced hepatic insulin resistance is a primary defect that predisposes to dysfunction in islets, implicating a perturbed liver-pancreas axis underlying the comorbidity of T2DM and MASLD. To investigate this hypothesis, we developed a human biomimetic microphysiological system (MPS) coupling our vascularized liver acinus MPS (vLAMPS) with pancreatic islet MPS (PANIS) enabling MASLD progression and islet dysfunction to be assessed. The modular design of this system (vLAMPS-PANIS) allows intra-organ and inter-organ dysregulation to be deconvoluted. When compared to normal fasting (NF) conditions, under early metabolic syndrome (EMS) conditions, the standalone vLAMPS exhibited characteristics of early stage MASLD, while no significant differences were observed in the standalone PANIS. In contrast, with EMS, the coupled vLAMPS-PANIS exhibited a perturbed islet-specific secretome and a significantly dysregulated glucose stimulated insulin secretion response implicating direct signaling from the dysregulated liver acinus to the islets. Correlations between several pairs of a vLAMPS-derived and a PANIS-derived factors were significantly altered under EMS, as compared to NF conditions, mechanistically connecting MASLD and T2DM associated hepatic-factors with islet-derived GLP-1 synthesis and regulation. Since vLAMPS-PANIS is compatible with patient-specific iPSCs, this platform represents an important step towards addressing patient heterogeneity, identifying disease mechanisms, and advancing precision medicine.

8433 Elucidation of the Molecular Basis of Human and Mouse Pancreatic β-Cell Senescence Induced by Hyperglycemia

Abstract Disclosure: K. Iwasaki: None. P. Carapeto: None. C. Aguayo-Mazzucato: None. Background and AIM: Senescent cells accumulate with age and contribute to the development of chronic diseases, including Type 2 Diabetes (T2D). Whereas senescence is an important pathogenic mechanism in diabetes, the role of hyperglycemia as a metabolic driver of pancreatic β-cells has not been clarified. The aim of this study is to elucidate the molecular basis of hyperglycemia-induced pancreatic β-cell senescence using human and rodent islets. Methods: 1) Human islets were cultured for 2 weeks in 20.2 mM high (HG) or 2.8mM low glucose (LG), and analyzed by qPCR and glucose-responsive insulin secretion (GSIS) to explore the molecular basis of senescence in ex vivo. To test the effects of senescent cell removal, senolytics Dasatinib (1μM) and Quercetin (20μM) (DQ) were used. 2) To evaluate the effects of hyperglycemia in vivo, we transplanted mouse and human islets under the kidney capsule of normoglycemic (NG) or streptozocin-induced hyperglycemic (Stz-Db) immunodeficient mice for two weeks. Graft function was evaluated by intraperitoneal glucose tolerance test and cellular identity using qPCR or immunohistochemistry. DQ (5mg/kg/day + 50mg/kg/day) was used to evaluate the effects of removing senescent cells in transplantation (Tx). To investigate the effect of specific removal of p16-positive senescent β-cells in transplanted islets, INK-ATTAC mice islets (p16Ink4a-mediated apoptosis by targeted activation of caspases) were transplanted into Stz-Db and treated with BB homodimer (BB) to remove p16+ cells or vehicle. Results: (1) Human islets from 5 healthy donors cultured in HG had an increased senescence index (mean of senescence markers p16, p21 and HMGB1 mRNA) when compared to LG islets (p<0.05) and lost glucose responsiveness as evaluated by ex vivo GSIS compared to LG (p<0.05). 2) Human islets (1000IEQ) were transplanted to Stz-Db or NG mice. In Stz-Db graft, P21 mRNA significantly increased with decreased expression of β-cell genes when compared to NG. Stz-Db mice treated with DQ (Db-DQ) for 5 days after Tx, significantly decreased expression of senescence index (p<0.05) and increased in β-cell index (mean of β-cell hallmark genes) (p<0.05) at mRNA levels. Stz-Db mice transplanted with INK-ATTAC mice islets had lower fed glucose levels, decreased p16 mRNA, increased expression β-cell hallmark genes and improved insulin secretion ex vivo after removal of p16+ cells. Conclusion: Sustained exposure of human islets to hyperglycemia induced cellular senescence, leading to pancreatic β-cell dysfunction and loss of cellular identity. Furthermore, elimination of senescent cells may protect pancreatic β-cells from hyperglycemia-induced functional decline, which may have potential clinical application in both Type 1 Diabetes and T2D. Presentation: 6/2/2024

8343 The Role Of Pancreatic Nerve Activity On The Development Of Beta Cell Dysfunction With The Macrophage-Beta Cell Interaction

Abstract Disclosure: J. Yu: None. Y. Wang: None. L. Sha: None. Islet inflammation is a vital factor to the beta cell dysfunction which is driven by inflammatory cytokines TNF-α and IL-1β released by resident macrophages. Pancreatic nerve innervates islet function and our previous study suggested that pancreatic nerve activity might involved in the development of pancreatic beta cell dysfunction. However, it is not known whether pancreatic nerve activity modulates macrophage activity and contributes to the macrophage - beta cell interaction. The aim of our study was to investigate the role of nerve activity on it and the possible mechanism. Methods: Sprague Dawley Rats and high fat diet-induced obese rates were used. An intrapancreatic nerve truck with its intact innervated pancreatic islets were used for the study. The nerve activity was evoked with electric nerve stimulation and insulin and ATP released by beta cells, TNF-α released by macrophages, and IL-1β released mainly by macrophages were measured with nerve activation. Results: Insulin secretion was induced significantly with the nerve activation (8 Hz). With nerve activation, ATP level was significantly increased by 25.5 ± 11.7%. The increased releases of insulin and ATP were abolished with cholinergic M receptor blocker atropine. With nerve activation, TNF-α and IL-1β levels were increased by 25.3±7.6% and 51.8±11.7%, respectively (p<0.05). Interestingly, the increases of TNF-α and IL-1β with nerve activation were also blocked by atropine. Since it is known that acetylcholine does not induce pro-inflammatory cytokine release in macrophages, we suspected that the nerve activity induced TNF-α and IL-1β releases were indirect. ATP is likely a candidate for the indirect effect as receptors. With applying Suramin, a ATP receptor blocker, nerve activation increased TNF-α release was inhibited significantly and IL-1β release was trended to inhibited. atropine, an M receptor blocker, compared with the Control group, decreased by 88.0±3.7% and 63.1±19.6%, respectively (p< 0.01). In obese rats, nerve activation increased TNF-α and IL-1β content by 68.1 ± 22.6% and 39.7 ± 7.4%, respectively, and suramin significantly inhibited the nerve activation induced increase of TNF-α release and trended to inhibit IL-1β release. Conclusion: Our results suggested that the pancreatic nerve activity contribute to the macrophage-beta cell interaction in the development of beta cells dysfunction by enhancing ATP release from islet beta cells. Presentation: 6/3/2024

Preoperative risk-stratified analysis: External versus internal pancreatic stents in pancreatoduodenectomy

BackgroundSeveral risk-stratified studies have compared the outcomes of external and internal pancreatic stents in pancreatoduodenectomy (PD), but no resolute standard for a fistula-mitigation strategy exists. The study investigated the efficacy of these stents in a preoperative risk-stratified setting. MethodsData from 285 patients who underwent PD with pancreaticojejunostomy using an external or internal stent from 2015 to 2023 were analyzed. The preoperative pancreatic fistula score (preFRS) was used to classify patients into low-risk (preFRS: 0–5) and high-risk (preFRS: 6–8) groups. ResultsPreFRS accurately predicted the risk of clinically relevant postoperative pancreatic fistula (CR-POPF) as 0% and >40% in patients with preFRS ≤1 and ≥7, respectively. Although no significant difference was observed in postoperative outcomes in low-risk patients, the external stent significantly reduced CR-POPF (21% vs 44%, P = .024) and postpancreatectomy hemorrhage (PPH, 0% vs 19%, P = .02) in high-risk patients, leading to the superiority of the external stent in the entire cohort in terms of CR-POPF (12% vs 24%, P = .033) and PPH (1% vs 11%, P = .013). There were no significant differences in stent-related complications or pancreatic dysfunction. External stent malfunction occurred in 14% and significantly affected CR-POPF development in both low- (20% vs 0%, P < .01) and high-risk groups (60% vs 14%, P = .021). ConclusionThe external pancreatic stent showed a more beneficial effect on CR-POPF and PPH, especially in high-risk patients, without increasing other complications. Risk-stratified strategy and improving stent management might enhance postoperative outcomes.

Review on the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway in diabetes: mechanistic insights and therapeutic implications.

This review explores the pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the pathogenesis of diabetes and its complications, highlighting the therapeutic potential of various oral hypoglycemic drugs targeting this pathway. NLRP3 inflammasome activation, triggered by metabolic stressors like hyperglycemia, hyperlipidemia, and free fatty acids (FFAs), leads to the release of pro-inflammatory cytokines interleukin-1β and interleukin-18, driving insulin resistance, pancreatic β-cell dysfunction, and systemic inflammation. These processes contribute to diabetic complications such as nephropathy, neuropathy, retinopathy, and cardiovascular diseases (CVD). Here we discuss the various transcriptional, epigenetic, and gut microbiome mediated regulation of NLRP3 activation in diabetes. Different classes of oral hypoglycemic drugs modulate NLRP3 inflammasome activity through various mechanisms: sulfonylureas inhibit NLRP3 activation and reduce inflammatory cytokine levels; sodium-glucose co-transporter 2 inhibitors (SGLT2i) suppress inflammasome activity by reducing oxidative stress and modulating intracellular signaling pathways; dipeptidyl peptidase-4 inhibitors mitigate inflammasome activation, protecting against renal and vascular complications; glucagon-like peptide-1 receptor agonists attenuate NLRP3 activity, reducing inflammation and improving metabolic outcomes; alpha-glucosidase inhibitors and thiazolidinediones exhibit anti-inflammatory properties by directly inhibiting NLRP3 activation. Agents that specifically target NLRP3 and inhibit their activation have been identified recently such as MCC950, Anakinra, CY-09, and many more. Targeting the NLRP3 inflammasome, thus, presents a promising strategy for managing diabetes and its complications, with oral hypoglycemic drugs offering dual benefits of glycemic control and inflammation reduction. Further research into the specific mechanisms and long-term effects of these drugs on NLRP3 inflammasome activity is warranted.

Prospective Study on the Effects of Marijuana Smoking on Lipase and Amylase Activities among Adult Nigerians

Marijuana consumption is prevalent among young adults in Nigeria, and its effects on various physiological systems are of growing concern. This study investigates the impact of marijuana use on digestive enzymes, specifically serum amylase and lipase, to understand its potential implications on digestive health. This cross-sectional study was conducted in 120 participants comprising of 60 marijuana smokers and 60 non-smokers. Sociodemographic and lifestyle data were collected through structured questionnaires. Serum amylase and lipase activity levels were measured by spectrophotometric method and compared between the two groups. Statistical analysis was performed to assess differences and correlations. The study revealed that marijuana smokers had significantly higher serum amylase and lipase activities compared to non-smokers. Lipase activity correlated positively (r=0.425, p=0.019) with duration of marijuana use. Amylase activity was higher among males than females (r=-0.40, p=0.028). No significant correlation was found between the quantity of marijuana consumed and enzyme activities. Chronic marijuana consumption was associated with increased serum amylase and lipase activities, indicating potential alterations in pancreatic function. These findings suggest that marijuana use may have adverse effects on digestive health, warranting further investigation into the long-term implications. It is recommended that healthcare providers monitor digestive enzyme activities in marijuana users to detect early signs of pancreatic dysfunction.

Nicotinamide Mononucleotide (NMN) Ameliorates Free Fatty Acid-Induced Pancreatic β-Cell Dysfunction via the NAD+/AMPK/SIRT1/HIF-1α Pathway.

As the sole producers of insulin under physiological conditions, the normal functioning of pancreatic β cells is crucial for maintaining glucose homeostasis in the body. Due to the high oxygen and energy demands required for insulin secretion, hypoxia has been shown to play a critical role in pancreatic β-cell dysfunction. Lipid metabolism abnormalities, a common metabolic feature in type 2 diabetic patients, are often accompanied by tissue hypoxia caused by metabolic overload and lead to increased free fatty acid (FFA) levels. However, the specific mechanisms underlying FFA-induced β-cell dysfunction remain unclear. Nicotinamide mononucleotide (NMN), a naturally occurring bioactive nucleotide, has garnered significant attention in recent years for its effectiveness in replenishing NAD+ and alleviating various diseases. Nevertheless, studies exploring the mechanisms through which NMN influences β-cell dysfunction remain scarce. In this study, we established an in vitro β-cell dysfunction model by treating INS-1 cells with palmitate (PA), including control, PA-treated, and PA combined with NMN or activator/inhibitor groups. Compared to the control group, cells treated with PA alone showed significantly reduced insulin secretion capacity and decreased expression of proteins related to the NAD+/AMPK/SIRT1/HIF-1α pathway. In contrast, NMN supplementation significantly restored the expression of pathway-related proteins by activating NAD+ and effectively improved insulin secretion. Results obtained using HIF-1α and AMPK inhibitors/activators further supported these findings. In conclusion, our study demonstrates that NMN reversed the PA-induced downregulation of the NAD+/AMPK/SIRT1/HIF-1α pathway, thereby alleviating β-cell dysfunction. Our study investigated the mechanisms underlying PA-induced β-cell dysfunction, examined how NMN mitigates this dysfunction and offered new insights into the therapeutic potential of NMN for treating β-cell dysfunction and T2DM.

Metformin and vitamin D combination therapy ameliorates type 2 diabetes mellitus-induced renal injury in male Wistar rats.

Diabetic kidney disease is a major microvascular diabetes mellitus (DM) complication clinically associated with a gradual renal function decline. Although metformin is a common drug for managing DM, however, monotherapy treatment with any antidiabetic drug will necessitate dosage increment since type 2 DM (T2DM) deteriorates over time due to the increasing pancreatic β-cell dysfunction and will eventually require a combination therapy approach with another antidiabetic medication. Vitamin D is a food supplement that has been proven to have antidiabetic and reno-protective activities. Hence, we explore the combination of vitamin D and metformin on T2DM-induced renal dysfunction. Thirty male Wistar rats were randomized into five (5) groups: control, diabetes untreated, diabetics treated with metformin, vitamin D, and vitamin D + metformin. Vitamin D and metformin significantly reversed DM-induced hyperglycemia, electrolyte imbalance, and dyslipidemia. Also, vitamin D and metformin reversed T2DM-induced increase in serum creatinine and urea and renal lactate, LDH, and oxido-inflammatory response. These observed alterations were accompanied by an increase in proton pump activities and modulation of Nrf2/Nf-κB and XO/UA signaling. This study revealed that vitamin D and/or metformin ameliorated T2DM-induced renal injury.

Neonatal diabetes mellitus – manifestation of GATA-6 syndrome

GATA6 syndrome is an unusual genetic disorder that presents complications during pregnancy, congenital heart defects, neonatal diabetes, and severe pancreatic dysfunction. The cause of the syndrome is a de novo mutation in the GATA6 gene, located on chromosome 18. We present the case of a patient who exhibited congenital heart defects and severe hyperglycemia from the neonatal period, caused by pancreatic agenesis. The diagnosis was established based on molecular genetic analyses. Insulin and pancreatic enzyme replacement therapy provide a favorable prognosis in pancreatic agenesis, significantly reducing neonatal mortality associated with this drastic diagnosis.

Forecasting glucose values for patients with type 1 diabetes using heart rate data

Background:Type 1 Diabetes Mellitus (T1DM) is a chronic metabolic disease affecting millions of people worldwide. T1DM requires patients to continuously monitor their blood glucose levels. Due to pancreatic dysfunctions, patients use insulin injections to correct glucose values by synthetic insulin. Continuous Glucose Monitoring (CGM) is a system which includes an algorithm allowing to measure (and in some cases to predict) glucose levels at a frequent sampling time. This enable implementing advanced devices, including automated insulin pump delivery. Nevertheless, CGM still presents some limitations, including (i) the delay (time lag) in detecting change in glucose levels compared to the traditional blood glucose measurement, and (ii) the lack of a sufficient and acceptable time to accurately predict glucose values. Methods:We propose a framework based on a Gated Recurrent Unit (GRU) model to forecast both short- and long-term glucose values using heart rate (HR) and interstitial glucose (IG) values. The framework acquires HR and IG data and predicts glucose values with higher precision compared to state-of-the-art models. For training and testing the proposed framework, we used the OhioT1DM Dataset, which includes physiological data such as HR and IG values collected over an 8-week observation period. Additionally, we validated our framework using two other glucose datasets to ensure its generalizability across different HR and IG sampling frequencies. The proposed framework can be used to optimize the CGM system by incorporating patient HR measurements, thereby improving the prediction of short- and long-term glucose levels and reducing risks associated with conditions like hypoglycemia. Results:Experimental tests were conducted using HR and IG data from the OhioT1DM Dataset, as well as from two additional T1DM patient datasets. We analyzed 6 patients from Ohio dataset while we validated the algorithm on 23 patients coming from two different university hospitals (6 from the University of Catanzaro medical hospital and 17 gathered from a validated study at IRCCS San Matteo Hospital in Pavia) for a total number of 29 patients. Our framework demonstrates an improvement in forecasting IG values in terms of RMSE and MAE for different choice of prediction horizons (PH). In the case of a PH of 5, 10, 20, 30, and 60 min, we reach an RMSE of 5.0, 9.38, 15.27, 20.48, and 34.16 respectively. The framework is freely available as an open-source, with an example dataset on a GitHub repository (see https://github.com/rafgia/attention_to_glycemia). Conclusion:Our framework offers a promising solution for improving glucose level prediction and management in T1DM patients. By leveraging a GRU model and incorporating HR and IG values, we achieve more precise glucose level forecasting compared to state-of-the-art models. This approach not only enhances the accuracy of glucose predictions but also mitigates the risks associated with hypoglycemia.

Image J as the quantification tool in endosonography strain elastography may be reflected in the disturbance of endocrine pancreatic dysfunction.

Pancreatic fibrosis is one of the main pathological features of chronic pancreatitis (CP), suggesting a strong relationship between CP and pancreatic ductal cancer. There was no available data about pancreatic fibrosis and pancreatic dysfunction in the early CP (ECP) using endosonography (EUS). Asymptomatic patients with pancreatic enzyme abnormalities (AP-P; n = 56) and patients with ECP (n = 21) were determined by the absence of abnormal findings on upper gastrointestinal endoscopy, abdominal ultrasonography, and abdominal computed tomography. An Olympus EUS (GF-UCT 260; Olympus) was used to perform EUS. Open software "Image J", developed by NIH, was used to measure the surface area fraction of the designated elastic blue region. The maximum value among the pancreatic head, pancreatic body, and pancreatic tail was defined as the ELST-blue score. The exocrine and endocrine pancreatic functions were evaluated using the N-benzoyl-l-tyrosyl-p-aminobenzoic acid (BT-PABA) test and homeostasis model assessment of β-cell function (HOMA-β) value, respectively. EUS score, lobularity, and hyperechoic foci/strands in patients with ECP were significantly (p < 0.001) higher than those in patients with AP-P. In addition, there were no significant differences in the BT-PABA test (73.1 ± 25.5, 68.5 ± 15.6) and HOMA-β (93.1 ± 67.4, 73.5 ± 139.7) between patients with ECP and AP-P. The ELST-blue score measured by image J as the quantification tool in EUS strain elastography in patients with ECP was significantly higher (p = 0.002) than that in patients with AP-P. Interestingly, the ELST-blue score was significantly associated with HOMA-β in patients with ECP. The ELST-blue score may be a useful tool for the evaluation of endocrine pancreatic dysfunction in the ECP.

Dynamics of inflammatory markers in patients with normal and impaired glucose metabolism during lung exacerbation treatment

Cystic fibrosis (CF) is one of the most common autosomal-recessive inherited diseases. The primary genetic defect in CF is aligned CFTR gene mutation which encodes a membrane protein functioning as cAMP-depended chloride channel. Classic phenotypical manifestations of CF include chronic obstructive pulmonary disease with bronchiectasis, persisting infection (St. aureus, Ps. aeruginosa, B. cepacia) and aberrant inflammatory response, as well as exocrine pancreatic insufficiency with malabsorption, hypotrophy and growth retardation. CFTR deficiency is also accompanied by β-cell pancreatic dysfunction, causing glucose metabolism disturbances and CF-related diabetes. The aim of the study was the comparison of inflammatory markers dynamics in patients with normal and disturbed glucose metabolism during pulmonary exacerbation treatment. The study included 10 patients with impaired glucose tolerance (Group 1) and 24 patients with normal carbohydrate metabolism (Group 2). Patients of the two groups did not significantly differ in demographic characteristics, pulmonary function test and body mass index parameters, as well as in the number of F508del mutation carriers and in the number of those who were infected with Ps. aeruginosa and B. cepacia complex. Blood sampling was performed twice: before and after a routine course of antibiotic therapy. Plasma levels of biomarkers including the antibodies to single- and double-stranded DNA (ss-DNA-IgG, ds-DNA-IgG, respectively), the hormones (dehydroepiandrosterone (DHEA) and DHEA sulfate), C-reactive protein (CRP), Mn-dependent superoxide dismutase (Mn-SOD), and the cytokines (tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), IFNα, tissue growth factor-β1 (TGF-β1), interleukin-4 (IL-4), IL-6, IL-10, IL-17A) were assessed using commercial immunoassay kits. Our study shows that antibiotic treatment did not have a sufficient influence on levels of inflammatory markers in patients with disturbances of glucose metabolism while patients with normal glucose tolerance demonstrated a significant reduction in inflammatory marker values after the therapy. The data may suggest both impaired effectivity of antibiotic treatment and aberrant inflammatory response in patients with glucose intolerance.

Development of irreversible pancreatic ductal change triggered by pancreatic duct stenting in chronic pancreatitis.

Stent-induced ductal change is a complication of endoscopic pancreatic stent placement for chronic pancreatitis, potentially leading to irreversible changes that may contribute to pancreatic dysfunction. This study aimed to examine the long-term outcomes of stent-induced ductal change and evaluate factors that correlate with the development of irreversible ductal changes. Between January 2008 and December 2022, 52/223 patients with chronic pancreatitis in whom an S-type plastic stent was successfully placed from the main papilla for duct stricture were detected with stent-induced ductal change on pancreatography at stent removal. We retrospectively investigated the clinical features of patients whose main pancreatic duct was reassessed by endoscopic pancreatography after >1month without stent and whose residual stent-induced ductal change was irreversible. The patients with chronic pancreatitis with stent-induced ductal change (n=28) (elevated change, 15; stricture change, 13) were evaluated using follow-up pancreatography. Eleven patients (39.3%) showed residual change associated with stent-induced ductal change, the degree of which was partial improvement, no change, and obstructive change in one, seven, and three patients, respectively. Stricture changes during stent removal and duration of stent placement that triggered ductal changes were significantly associated with the development of residual ductal changes. Irreversible stent-induced ductal change in patients with chronic pancreatitis was associated with stricture changes in the main pancreatic duct and continued plastic-stent placement. Careful evaluation of the pancreatic duct is required during plastic-stent placement. Early plastic-stent removal may result in an effective response to the development of stent-induced ductal change.

Biomimetic nanoplatform with microbiome modulation and antioxidant functions ameliorating insulin resistance and pancreatic β-cell dysfunction for T2DM management

Insulin resistance and pancreatic β-cell dysfunction are the main pathogenesis of type 2 diabetes mellitus (T2DM). However, insulin therapy and diabetes medications do not effectively solve the two problems simultaneously. In this study, a biomimetic oral hydrogen nanogenerator that leverages the benefits of edible plant-derived exosomes and hydrogen therapy was constructed to overcome this dilemma by modulating gut microbiota and ameliorating oxidative stress and inflammatory responses. Hollow mesoporous silica (HMS) nanoparticles encapsulating ammonia borane (A) were used to overcome the inefficiency of H2 delivery in traditional hydrogen therapy, and exosomes originating from ginger (GE) were employed to enhance biocompatibility and regulate intestinal flora. Our study showed that HMS/A@GE not only considerably ameliorated insulin resistance and liver steatosis, but inhibited the dedifferentiation of islet β-cell and enhanced pancreatic β-cell proportion in T2DM model mice. In addition to its antioxidant and anti-inflammatory effects, HMS/A@GE augmented the abundance of Lactobacilli spp. and tryptophan metabolites, such as indole and indole acetic acid, which further activated the AhR/IL-22 pathway to improve intestinal-barrier function and metabolic impairments. This study offers a potentially viable strategy for addressing the current limitations of diabetes treatment by integrating gut-microbiota remodelling with antioxidant therapies.

PERIAPICAL INFLAMMATORY LESIONS AND DIABETES MELLITUS TYPE II– A REVIEW

Periapical periodontitis is a chronic inflammatory disease, caused by endodontic infection, and its development is regulated by the host immune/inflammatory response. Metabolic disorders, which are largely dependent on life style such as eating habits, have been interpreted as a “metabolically-triggered” low-grade systemic inflammation and may interact with periapical periodontitis by triggering immune modulation. Diabetes mellitus (DM) is a group of complex multisystem metabolic disorders due to a deficiency in insulin secretion caused by pancreatic β-cell dysfunction and/or insulin resistance in liver and muscle. Objective: In this paper, the current status of knowledge regarding the relationship between periapical inflammation and diabetes mellitus type II is reviewed. Material and method: Research was conducted on scientific papers published on Medline - Pub med in the past 10 years (from 2012-2022). The search was performed using the Mesh (Medical Subject Headings) key words: periapical inflammatory lesions, periapical periodontitis and diabetes mellitus type II. Results: Several studies have analyzed the possible association between periapical inflammatory lesions and diabetes mellitus type II. The results of studies carried mainly in animal models, less in humans suggested association between endodontic variables such as apical periodontitis, root canal treatment and diabetes mellitus type 2.The demonstration of association does not prove by itself the existence of a cause-effect relationship. Conclusion: A review of the literature showed connection between periapical inflammatory lesions and diabetes mellitus type II, but prospective case control clinical studies are needed for further clarifying this relation.

Immune checkpoints and pancreatic beta cell dysfunction in HIV.

We explored the impact of immune dysregulation on pancreatic beta cell injury in HIV patients. Analyzing 105 participant samples, we observed lower IL-21 levels and elevated immune checkpoint levels (e.g. PD-1, CD27+, CD40+) in untreated HIV patients. Notably, soluble TIM-3 correlated positively with improved beta cell function and inversely with beta cell stress, suggesting its potential role in beta cell protection in untreated HIV.