Advancing Diabetes Research: A Novel Islet Isolation Method from Living Donors.

Pancreatic islet isolation is critical for type 2 diabetes research. Although -omics approaches have shed light on islet molecular profiles, inconsistencies persist; on the other hand, functional studies are essential, but they require reliable and standardized isolation methods. Here, we propose a simplified protocol applied to very small-sized samples collected from partially pancreatectomized living donors. Islet isolation was performed by digesting tissue specimens collected during surgery within a collagenase P solution, followed by a Lympholyte density gradient separation; finally, functional assays and staining with dithizone were carried out. Isolated pancreatic islets exhibited functional responses to glucose and arginine stimulation mirroring donors' metabolic profiles, with insulin secretion significantly decreasing in diabetic islets compared to non-diabetic islets; conversely, proinsulin secretion showed an increasing trend from non-diabetic to diabetic islets. This novel islet isolation method from living patients undergoing partial pancreatectomy offers a valuable opportunity for targeted study of islet physiology, with the primary advantage of being time-effective and successfully preserving islet viability and functionality. It enables the generation of islet preparations that closely reflect donors' clinical profiles, simplifying the isolation process and eliminating the need for a Ricordi chamber. Thus, this method holds promises for advancing our understanding of diabetes and for new personalized pharmacological approaches.

Beta-cell function and glucose metabolism in patients with chronic pancreatitis.

AIMS: Chronic pancreatitis (CP) is - along with acute pancreatitis - the most frequent cause of diabetes of the exocrine pancreas (DEP). Although insulin deficiency is widely accepted as the major feature of DEP, it is still unclear whether diabetes associated with CP is characterized by additional or different functional defects of the insulin secretory machinery. To identify possible functional defects specifically induced by CP, we performed a cross-sectional study in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes mellitus (DM) comparing patients with and without CP (CP vs. NCP). METHODS: We administered an oral glucose tolerance test (OGTT) to all participants and, according to their glucose tolerance, classified them as NGT, IGT and DM. Insulin sensitivity and beta-cell functional parameters were derived from OGTT, hyperglycemic clamp and hyperinsulinemic euglycemic clamp. RESULTS: Studying 146 subjects, we found that beta-cell function and insulin secretion were significantly lower in CP compared to NCP patients. However, when we classified the subjects according to OGTT-derived glucose tolerance, we found no differences in beta-cell function or in insulin sensitivity between CP and NCP with the same glucose tolerance status. Of note, we found that arginine-stimulated insulin secretion is reduced only in subjects with CP and DM compared to NCP subjects with DM. CONCLUSIONS: Patients with CP had no specific alterations in insulin secretion and beta-cell function. However, in patients diagnosed with diabetes, we found a lower arginine-stimulated insulin secretion, a marker of reduced functional mass.

Neuropancreatology: The Nervous System and Pain Management in Pancreatic Diseases.

The intricate network of the pancreatic nervous system plays a fundamental role in physiologic functions of the endocrine and exocrine pancreas. Several pancreatic diseases affect the normal functionality of the pancreatic nervous system. This chronic derangement leads to anatomical alterations, such as neural hypertrophy and increased nerve density. Perineural invasion is a prominent feature of pancreatic cancer, contributing to cancer progression and metastasis. Despite the fact that these pathogenic mechanisms are still incompletely studied and understood, the constant occurrence of these alterations highlights their importance in the pathophysiology of the pancreatic diseases. The occurrence of anatomical changes is strictly linked to the appearance of pain. Pancreatic pain has peculiar features, and its management is complex in clinical practice. In the present review, the evidence on lifestyle, pharmacological and interventional approaches for the management of pancreatic pain is presented. Analgesic therapy is the cornerstone of pain treatment. However, it is important to identify the individual characteristic of the patients and personalize the approach to pain management. Nevertheless, the incomplete efficacy of these strategies makes this field an area of unmet needs. The study of neuroplasticity is crucial to understand the mechanisms that regulate the pathophysiology of pancreatic diseases. Several trials testing new drugs with specific neuromodulatory effects are ongoing. However, further studies are needed to investigate crucial targets to develop novel therapies for the modulation of the nervous system and the prevention of complications of pancreatic diseases. This comprehensive review summarizes the importance of the nervous system in pancreatic diseases with a special focus on its anatomy and physiology, its pathophysiological features and clinical relevance in pancreatic disease, the treatment of pancreatic pain, and the identification of future trends of research.

Drug-Induced Acute Pancreatitis in Adults: Focus on Antimicrobial and Antiviral Drugs, a Narrative Review.

Acute pancreatitis (AP) is an acute inflammation of the pancreas caused by the activation of digestive enzymes in the pancreatic tissue. The main causes of AP are cholelithiasis and alcohol abuse; less commonly, it can be caused by drugs, with a prevalence of up to 5%. Causal associations between drugs and pancreatitis are largely based on case reports or case series with limited evidence. We reviewed the available data on drug-induced AP, focusing on antimicrobial drugs and antivirals, and discussed the current evidence in relation to the classification systems available in the literature. We found 51 suspected associations between antimicrobial and antiviral drugs and AP. The drugs with the most evidence of correlation are didanosine, protease inhibitors, and metronidazole. In addition, other drugs have been described in case reports demonstrating positive rechallenge. However, there are major differences between the various classifications available, where the same drug being assigned to different probability classes. It is likely that the presence in multiple case reports of an association between acute pancreatitis and a drug should serve as a basis for conducting prospective randomized controlled trials to improve the quality of the evidence.

Physical Activity and Type 2 Diabetes: In Search of a Personalized Approach to Improving ß-Cell Function.

Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases worldwide. Lifestyle interventions, including diet and physical activity (PA), are fundamental non-pharmacological components of T2DM therapy. Exercise interventions are strongly recommended for people with or at risk of developing or already with overt diabetes, but adherence to PA guidelines in this population is still challenging. Furthermore, the heterogeneity of T2DM patients, driven by differing residual ß-cell functionality, as well as the possibility of practicing different types and intensities of PA, has led to the need to develop tailored exercise and training plans. Investigations on blood glucose variation in response to exercise could help to clarify why individuals do not respond in the same way to PA, and to guide the prescription of personalized treatments. The aim of this review is to offer an updated overview of the current evidence on the effects of different regimens and modalities of PA regarding glucose sensing and ß-cell secretory dynamics in individuals with prediabetes or T2DM, with a special focus on ß-cell function.

Antibiotic Utilization in Acute Pancreatitis: A Narrative Review.

Acute pancreatitis is a complex inflammatory disease with significant morbidity and mortality. Despite advances in its management, the role of antibiotics in the prophylaxis and treatment of acute pancreatitis remains controversial. The aim of this comprehensive review is to analyze current evidence on the use of antibiotics in acute pancreatitis, focusing on prophylactic and therapeutic strategies. Prophylactic use aims to prevent local and systemic infections. However, recent studies have questioned the routine use of antibiotics for prophylaxis and highlighted the potential risks of antibiotic resistance and adverse effects. In selected high-risk cases, such as infected necrotizing pancreatitis, prophylactic antibiotic therapy may still be beneficial. As for therapeutic use, antibiotics are usually used to treat infected pancreatic necrosis and extrapancreatic infections. When selecting an antibiotic, the microbiologic profile and local resistance patterns should be considered. Combination therapy with broad-spectrum antibiotics is often recommended to cover both Gram-positive and Gram-negative pathogens. Recent research has highlighted the importance of individualized approaches to antibiotic use in acute pancreatitis and underscored the need for a tailored approach based on patient-specific factors. This review also highlights the potential role of new antimicrobial agents and alternative strategies, such as probiotics, in the management of acute pancreatitis.

State-of-the-Art and Upcoming Innovations in Pancreatic Cancer Care: A Step Forward to Precision Medicine.

Pancreatic cancer remains a social and medical burden despite the tremendous advances that medicine has made in the last two decades. The incidence of pancreatic cancer is increasing, and it continues to be associated with high mortality and morbidity rates. The difficulty of early diagnosis (the lack of specific symptoms and biomarkers at early stages), the aggressiveness of the disease, and its resistance to systemic therapies are the main factors for the poor prognosis of pancreatic cancer. The only curative treatment for pancreatic cancer is surgery, but the vast majority of patients with pancreatic cancer have advanced disease at the time of diagnosis. Pancreatic surgery is among the most challenging surgical procedures, but recent improvements in surgical techniques, careful patient selection, and the availability of minimally invasive techniques (e.g., robotic surgery) have dramatically reduced the morbidity and mortality associated with pancreatic surgery. Patients who are not candidates for surgery may benefit from locoregional and systemic therapy. In some cases (e.g., patients for whom marginal resection is feasible), systemic therapy may be considered a bridge to surgery to allow downstaging of the cancer; in other cases (e.g., metastatic disease), systemic therapy is considered the standard approach with the goal of prolonging patient survival. The complexity of patients with pancreatic cancer requires a personalized and multidisciplinary approach to choose the best treatment for each clinical situation. The aim of this article is to provide a literature review of the available treatments for the different stages of pancreatic cancer.

An update on pancreatic regeneration mechanisms: Searching for paths to a cure for type 2 diabetes.

BACKGROUND: Over the last decades, various approaches have been explored to restore sufficient ß-cell mass in diabetic patients. Stem cells are certainly an attractive source of new ß-cells, but an alternative option is to induce the endogenous regeneration of these cells. SCOPE OF REVIEW: Since the exocrine and endocrine pancreatic glands have a common origin and a continuous crosstalk unites the two, we believe that analyzing the mechanisms that induce pancreatic regeneration in different conditions could further advance our knowledge in the field. In this review, we summarize the latest evidence on physiological and pathological conditions associated with the regulation of pancreas regeneration and proliferation, as well as the complex and coordinated signaling cascade mediating cell growth. MAJOR CONCLUSIONS: Unraveling the mechanisms involved in intracellular signaling and regulation of pancreatic cell proliferation and regeneration may inspire future investigations to discover potential strategies to cure diabetes.

Nutrition in Acute Pancreatitis: From the Old Paradigm to the New Evidence.

The nutritional management of acute pancreatitis (AP) patients has widely changed over time. The "pancreatic rest" was the cornerstone of the old paradigm, and nutritional support was not even included in AP management. Traditional management of AP was based on intestinal rest, with or without complete parenteral feeding. Recently, evidence-based data underlined the superiority of early oral or enteral feeding with significantly decreased multiple-organ failure, systemic infections, surgery need, and mortality rate. Despite the current recommendations, experts still debate the best route for enteral nutritional support and the best enteral formula. The aim of this work is to collect and analyze evidence over the nutritional aspects of AP management to investigate its impact. Moreover, the role of immunonutrition and probiotics in modulating inflammatory response and gut dysbiosis during AP was extensively studied. However, we have no significant data for their use in clinical practice. This is the first work to move beyond the mere opposition between the old and the new paradigm, including an analysis of several topics still under debate in order to provide a comprehensive overview of nutritional management of AP.

First-phase insulin secretion: can its evaluation direct therapeutic approaches?

Our work is aimed at unraveling the role of the first-phase insulin secretion in the natural history of type 2 diabetes mellitus (T2DM) and its interrelationship with insulin resistance and with ß cell function and mass. Starting from pathophysiology, we investigate the impact of impaired secretion on glucose homeostasis and explore postmeal hyperglycemia as the main clinical feature, underlining its relevance in the management of the disease. We also review dietary and pharmacological approaches aimed at improving early secretory defects and restoring residual ß cell function. Furthermore, we discuss possible approaches to detect early secretory defects in clinical practice. By providing a journey through human and animal data, we attempt a unification of the recent evidence in an effort to offer a new outlook on ß cell secretion.

Diagnostic and Prognostic Role of Extracellular Vesicles in Pancreatic Cancer: Current Evidence and Future Perspectives.

Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately diagnose, classify, and predict the biological behavior of this tumor. Therefore, it is imperative to develop new and improved strategies to detect pancreatic lesions in the early stages of cancerization with greater sensitivity and specificity. Extracellular vesicles, including exosome and microvesicles, are membrane-coated cellular products that are released in the outer environment. All cells produce extracellular vesicles; however, this process is enhanced by inflammation and tumorigenesis. Based on accumulating evidence, extracellular vesicles play a crucial role in pancreatic cancer progression and chemoresistance. Moreover, they may represent potential biomarkers and promising therapy targets. The aim of the present review is to review the current evidence on the role of extracellular vesicles in pancreatic cancer.

Pancreatic Cancer Resistance to Treatment: The Role of Microbiota.

Pancreatic cancer (PC) is an aggressive malignancy and the fourth leading cause of cancer death in the United States and Europe. It is estimated that PC will be the second leading cause of cancer death by 2030. In addition to late diagnosis, treatment resistance is a major cause of shortened survival in pancreatic cancer. In this context, there is growing evidence that microbes play a regulatory role, particularly in therapy resistance and in creating a microenvironment in the tumor, that favors cancer progression. The presence of certain bacteria belonging to the gamma-proteobacteria or mycoplasmas appears to be associated with both pharmacokinetic and pharmacodynamic changes. Recent evidence suggests that the microbiota may also play a role in resistance mechanisms to immunotherapy and radiotherapy. However, the interactions between microbiota and therapy are bilateral and modulate therapy tolerance. Future perspectives are increasingly focused on elucidating the role of the microbiota in tumorigenesis and processes of therapy resistance, and a better understanding of these mechanisms may provide important opportunities to improve survival in these patients.

Clinical Implications of Helicobacter pylori Antibiotic Resistance in Italy: A Review of the Literature.

Helicobacter pylori (H. pylori) resistance to antibiotics has increased worldwide in recent decades, especially to clarithromycin. As a result, the World Health Organization (WHO) identified clarithromycin-resistant H. pylori as a "high priority" pathogen in 2017. As international guidelines recommend empirical therapy as first-line treatment, it is crucial to know local resistance rates and history of antibiotic use to determine the most appropriate first-line antibiotic treatment. Italy is one of the European countries with the highest prevalence of H. pylori infection and the highest percentage of antibiotic-resistant H. pylori. The aim of this review is to summarize all data on H. pylori antibiotic resistance in Italy in order to quantify the current rate and determine the most effective therapeutic approach. The study confirms an elevated level of resistance to clarithromycin, metronidazole, and levofloxacin in Italy. In addition, our results show a satisfactory eradication rate for a bismuth-based regimen when used as first- or second-line treatment. Naive patients are also successfully treated with clarithromycin-based quadruple therapies. Considering the good results of bismuth-based therapy as recovery therapy, this argues for the potential use of clarithromycin quadruple therapy as a first-line treatment.

Autoimmune Pancreatitis: From Pathogenesis to Treatment.

Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. In this review, we focused on the pathogenesis of the disease to develop a tool that could facilitate diagnosis and lead to the discovery of new therapeutic strategies to combat autoimmune pancreatitis and its relapses. The standard therapy for AIP is oral administration of corticosteroids. Rituximab (RTX) has also been proposed for induction of remission and maintenance therapy in relapsing AIP-1. In selected patients, immunomodulators such as azathioprine are used to maintain remission. The strength of this review, compared with previous studies, is that it focuses on the clear difference between the two types of autoimmune pancreatitis with a clearly delineated and separate pathogenesis. In addition, the review also considers various therapeutic options, including biologic drugs, such as anti-tumor necrosis factor (TNF) therapy, a well-tolerated and effective second-line therapy for AIP type 2 relapses or steroid dependence. Other biologic therapies are also being explored that could provide a useful therapeutic alternative to corticosteroids and immunosuppressants, which are poorly tolerated due to significant side effects.

Risk factors for the occurrence of ampullary tumors: A case-control study.

BACKGROUND: The incidence of ampullary tumors is increasing but data on association with an increased exposure to certain risk factors are scanty. OBJECTIVE: To investigate risk and protective factors associated with the occurrence of ampullary tumors and whether these factors differ between ampullary tumors of the intestinal and pancreatobiliary subtypes or between adenomas and carcinomas. METHODS: The association between a large set of exposome features and ampullary tumors occurrence was investigated in a bi-centric case-control study after ethic committee approval and power calculation. RESULTS: In 223 histologically confirmed patients and 446 controls, previous cholecystectomy (odd ratio [OR] = 2.07; 95% confidence interval [CI] = 1.34-3.20) and proton pump inhibitors use (OR = 1.66; 95% CI = 1.16-2.37) were associated with increased risk of ampullary tumors, aspirin use (OR = 0.57; 95% CI = 0.36-0.90) and light alcohol intake (OR = 0.54; 95% CI = 0.38-0.76) with reduced risk. A previous cholecystectomy was also associated with tumors of intestinal subtype and with both adenomas and carcinomas, and proton pump inhibitors use with adenomas only. Smoking, body mass index, family history of cancers, previous ulcer, diabetes and use of statins, insulin and metformin were not significant factors. CONCLUSION: This is the first case-control study specifically highlighting factors associated with the occurrence of ampullary tumors. We report factors that are novel and plausible, in keeping with mechanisms described for other gastrointestinal tumors and with potential clinical relevance.

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features.

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

Humoral Predictors of Malignancy in IPMN: A Review of the Literature.

Pancreatic cystic lesions are increasingly detected in cross-sectional imaging. Intraductal papillary mucinous neoplasm (IPMN) is a mucin-producing subtype of the pancreatic cyst lesions arising from the pancreatic duct system. IPMN is a potential precursor of pancreatic cancer. The transformation of IPMN in pancreatic cancer is progressive and requires the occurrence of low-grade dysplasia, high-grade dysplasia, and ultimately invasive cancer. Jaundice, enhancing mural nodule >5 mm, main pancreatic duct diameter >10 mm, and positive cytology for high-grade dysplasia are considered high-risk stigmata of malignancy. While increased levels of carbohydrate antigen 19-9 (CA 19-9) (>37 U/mL), main pancreatic duct diameter 5-9.9 mm, cyst diameter >40 mm, enhancing mural nodules <5 mm, IPMN-induced acute pancreatitis, new onset of diabetes, cyst grow-rate >5 mm/year are considered worrisome features of malignancy. However, cross-sectional imaging is often inadequate in the prediction of high-grade dysplasia and invasive cancer. Several studies evaluated the role of humoral and intra-cystic biomarkers in the prediction of malignancy in IPMN. Carcinoembryonic antigen (CEA), CA 19-9, intra-cystic CEA, intra-cystic glucose, and cystic fluid cytology are widely used in clinical practice to distinguish between mucinous and non-mucinous cysts and to predict the presence of invasive cancer. Other biomarkers such as cystic fluid DNA sequencing, microRNA (mi-RNA), circulating microvesicles, and liquid biopsy are the new options for the mini-invasive diagnosis of degenerated IPMN. The aim of this study is to review the literature to assess the role of humoral and intracystic biomarkers in the prediction of advanced IPMN with high-grade dysplasia or invasive carcinoma.

Microbiota in Pancreatic Diseases: A Review of the Literature.

The gut microbiota is a critical element in the balance between human health and disease. Its impairment, defined as dysbiosis, is associated with gastroenterological and systemic diseases. Pancreatic secretions are involved in the composition and changes of the gut microbiota, and the gut microbiota may colonize the pancreatic parenchyma and be associated with the occurrence of diseases. The gut microbiota and the pancreas influence each other, resulting in a "gut microbiota-pancreas axis". Moreover, the gut microbiota may be involved in pancreatic diseases, both through direct bacterial colonization and an indirect effect of small molecules and toxins derived from dysbiosis. Pancreatic diseases such as acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis, and pancreatic cancer are common gastroenterological diseases associated with high morbidity and mortality. The involvement of the microbiota in pancreatic diseases is increasingly recognized. Therefore, modifying the intestinal bacterial flora could have important therapeutic implications on these pathologies. The aim of this study is to review the literature to evaluate the alterations of the gut microbiota in pancreatic diseases, and the role of the microbiota in the treatment of these diseases.