Pancreatic Diabetes Research Articles

The role of noncoding RNAs in pancreatic birth defects.

Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy pancreatic cells to replace malfunctioning cells has been considered a promising cure for pancreatic diseases including birth defects. However, such therapies are currently unavailable in the clinic. The developmental gene regulatory network underlying pancreatic development must be reactivated for in vivo regeneration and recapitulated in vitro for cell replacement therapy. Thus, understanding the mechanisms driving pancreatic development will pave the way for regenerative therapies. Pancreatic progenitor cells are the precursors of all pancreatic cells which use epigenetic changes to control gene expression during differentiation to generate all of the distinct pancreatic cell types. Epigenetic changes involving DNA methylation and histone modifications can be controlled by noncoding RNAs (ncRNAs). Indeed, increasing evidence suggests that ncRNAs are indispensable for proper organogenesis. Here, we summarize recent insight into the role of ncRNAs in the epigenetic regulation of pancreatic development. We further discuss how disruptions in ncRNA biogenesis and expression lead to developmental defects and diseases. This review summarizes in vivo data from animal models and in vitro studies using stem cell differentiation as a model for pancreatic development.

Multi-regulator of EZH2-PPARs Therapeutic Targets: A Hallmark for Prospective Restoration of Pancreatic Insulin Production and Cancer Dysregulation.

The unexpected rise in cancer and diabetes statistics has been a significant global threat, inciting ongoing research into various biomarkers that can act as innovative therapeutic targets for their management. The recent discovery of how EZH2-PPARs' regulatory function affects the metabolic and signalling pathways contributing to this disease has posed a significant breakthrough, with the synergistic combination of inhibitors like GSK-126 and bezafibrate for treating these diseases. Nonetheless, no findings on other protein biomarkers involved in the associated side effects have been reported. As a result of this virtual study, we identified the gene-disease association, protein interaction networks between EZH2-PPARs and other protein biomarkers regulating pancreatic cancer and diabetes pathology, ADME/Toxicity profiling, docking simulation and density functional theory of some natural products. The results indicated a correlation between obesity and hypertensive disease for the investigated biomarkers. At the same time, the predicted protein network validates the link to cancer and diabetes, and nine natural products were screened to have versatile binding capacity against the targets. Among all natural products, phytocassane A outperforms the standard drugs' (GSK-126 and bezafibrate) in silico validation for drug-likeness profiles. Hence, these natural products were conclusively proposed for additional experimental screening to complement the results on their utility in drug development for diabetes and cancer therapy against the EZH2-PPARs' new target.

Pancreatogenic diabetes: what is it and what to do about it?

Pancreatogenic diabetes: what is it and what to do about it?

Machine learning for post-acute pancreatitis diabetes mellitus prediction and personalized treatment recommendations

Post-acute pancreatitis diabetes mellitus (PPDM-A) is the main component of pancreatic exocrine diabetes mellitus. Timely diagnosis of PPDM-A improves patient outcomes and the mitigation of burdens and costs. We aimed to determine risk factors prospectively and predictors of PPDM-A in China, focusing on giving personalized treatment recommendations. Here, we identify and evaluate the best set of predictors of PPDM-A prospectively using retrospective data from 820 patients with acute pancreatitis at four centers by machine learning approaches. We used the L1 regularized logistic regression model to diagnose early PPDM-A via nine clinical variables identified as the best predictors. The model performed well, obtaining the best AUC = 0.819 and F1 = 0.357 in the test set. We interpreted and personalized the model through nomograms and Shapley values. Our model can accurately predict the occurrence of PPDM-A based on just nine clinical pieces of information and allows for early intervention in potential PPDM-A patients through personalized analysis. Future retrospective and prospective studies with multicentre, large sample populations are needed to assess the actual clinical value of the model.

Association of Diabetes Mellitus and Pancreatic Cancer: Literature Review

Despite the metabolic activity, especially related to endocrinological disease, diabetes mellitus seems to be intrinsically associated with pancreatic cancer, studies in this line of research are still limited and without a detailed description of the disorders that confirm the association between them. Thus, the present study aims, in essence, through the literature review method, to present the association of pancreatic neoplasia and diabetes mellitus, seeking to evaluate the mechanism of association between the endocrinological presentation studied as a causality factor or possible consequence in the face of the neoplasm condition, as well as evaluating the possibility of screening, according to associative confirmation, of patients with diabetes mellitus in relation to the development of pancreatic cancer, considering that this neoplasm has one of the highest mortality rates ever described in the literature.

Fibrocalculous Pancreatic Diabetes - a Unique Differential among Diabetic.

Fibrocalculous pancreatic diabetes is a unique variant of diabetesmellitus and also known as type 3c diabetes mellitus. It is related to the patient who is young, non-alcoholic and belonging predominantly from the tropical region. It is a severe form of diabetes which can also be linked to the fact that it predisposes to malignancy.1 Among the variants of diabetes that we commonly encounter, fibrocalculous pancreatic diabetes has been rarely diagnosed in the developing countries. With the advancement of diagnostic capacity, it can be identified clinically and managed efficiently. It should be considered in patients with typical features of diabetes, abdominal pain, and pancreatic calculi. There is limited reporting of this case in Nepal because of misdiagnosis, so we are reporting a 40 years male who presented with recurrent episodes of abdominal pain with mucus mixed stool for the last 28 years and was diagnosed as fibrocalculous pancreatic diabetes. Keywords: Blood glucose; eastern Nepal; fibrocalculous pancreatic diabetes; pancreas.

Identification of Differential Metabolites Between Type 2 Diabetes and Postchronic Pancreatitis Diabetes (Type 3c) Based on an Untargeted Metabolomics Approach.

A nontargeted metabolomics approach was established to characterize serum metabolic profile in type 3c diabetes mellitus (T3cDM) secondary to chronic pancreatitis and compare with T2DM. Forty patients were recruited for metabolite analysis based on liquid chromatography-mass spectrometry. Cluster heatmap and KEGG metabolic pathway enrichment analysis were used to analyze the specific and differential metabolites. The receiver operating characteristics (ROCs) were generated and correlation analysis with clinical data was conducted. Metabolites including sphingosine, lipids, carnitine, bile acid, and hippuric acid were found to be different between T2DM and T3cDM, mainly enriched in bile acid biosynthesis, fatty acid biosynthesis, and sphingolipid metabolic pathways. The ROCs were generated with an area under the curve of 0.907 (95% confidence interval, 0.726-1) for the model with 15 metabolites. T3cDM is characterized by increased sphingosine, carnitine, bile acid, and most lipids, providing novel biomarkers for clinical diagnosis and a future direction in research on pathophysiological mechanisms.

The Cause and Effect Relationship of Diabetes after Acute Pancreatitis.

Acute pancreatitis (AP) is an acute inflammation of the pancreas associated with high morbidity and mortality. Endocrine pancreatic insufficiency secondary to AP has drawn increasing attention in recent years. The aim of this paper is to analyze the available clinical and experimental literature to determine the cause and effect relationship of diabetes type 3c (T3cDM; pancreatogenic diabetes) after acute pancreatitis. The clinico-pathological features and management challenges of pancreatogenic diabetes overlap with other secondary causes of diabetes. A complex pathogenesis involving pancreatic exocrine insufficiency, dysfunction of insulin secretion, and insulin resistance is likely the cause of T3cDM after AP. To obtain an improved understanding of the pathophysiology of diabetes after AP, more research is now needed to understand the risk of complications related to the pancreas and diabetes in these patients.

Signaling pathway of targeting the pancreas in the treatment of diabetes under the precision medicine big data evaluation system.

Diabetes is a chronic noncommunicable disease, which is related to lifestyle, environmental and other factors. The main disease of diabetes is the pancreas. Inflammation, oxidative stress and other factors can interfere with the conduction of various cell signaling pathways, thus inducing pancreatic tissue lesions and diabetes. Precision medicine covers epidemiology, preventive medicine, rehabilitation medicine and clinical medicine. On the basis of precision medicine big data analysis, this paper takes pancreas as the target to analyze the signal pathway of diabetes treatment. This paper analyzes from the five aspects of the age structure of diabetes, the blood sugar control standard of type 2 elderly diabetes mellitus, the changes in the number of diabetic patients, the ratio of patients using pancreatic species and the changes in blood sugar using the pancreas. The results of the study showed that targeted pancreatic therapy for diabetes reduced the diabetic blood glucose rate by approximately 6.94%.

Pancreatic Organoids: A Frontier Method for Investigating Pancreatic-Related Diseases.

The pancreas represents an important organ that has not been comprehensively studied in many fields. To fill this gap, many models have been generated, and traditional models have shown good performance in addressing pancreatic-related diseases, but are increasingly struggling to keep up with the need for further research due to ethical issues, genetic heterogeneity and difficult clinical translation. The new era calls for new and more reliable research models. Therefore, organoids have been proposed as a novel model for the evaluation of pancreatic-related diseases such as pancreatic malignancy, diabetes, and pancreatic cystic fibrosis. Compared with common traditional models, including 2D cell culture and gene editing mice, organoids derived from living humans or mice cause minimal harm to the donor, raise fewer ethical concerns, and reasonably address the claims of heterogeneity, which allows for the further development of pathogenesis studies and clinical trial analysis. In this review, we analyse studies on the use of pancreatic organoids in research on pancreatic-related diseases, discuss the advantages and disadvantages, and hypothesize future trends.

Abstract 128: In Vivo Downregulation Of Pancreatic Amylin In Diabetic Mice Improves Recognition Memory

Hypersecretion of amylin, a β-cell hormone that regulates satiation, is common in individuals with prediabetes and is associated with pancreatic amyloid deposition and type-2 diabetes. Evidence has emerged that increased circulating levels of amyloid-forming human amylin may potentially impair brain function. Because mouse amylin is non-amyloidogenic, we generated transgenic mice with conditional pancreatic expression of amyloid-forming human amylin to study how in vivo knockdown of human amylin expression influences brain function during the development of type-2 diabetes. Males and females were fed a high-fat diet starting at 3 months of age to induce amylin hypersecretion and glucose dysregulation. Males developed hyperglycemia at 5 months of age, whereas females showed glucose dysregulation 3-4 months later. At 5 months of age, human amylin-expressing male mice were randomly assigned to either amylin downregulation group (by peritoneal tamoxifen injection) or control group (maintained amylin expression) (n = 10/group). Two months later, we assessed brain function with the novel object recognition test and performed comparative non-targeted metabolomics and global RNA-seq analyses of hippocampal tissue. Mice with downregulated human amylin show enhanced recognition memory index (p < 0.001) and lower blood glucose levels (p < 0.001) compared to those that continued to express human amylin. This was associated with increased hippocampal levels of glycolysis metabolites, including lactic acid (p < 0.01), glucose-6-phosphate (p = 0.06), and fructose (p = 0.07). Hippocampal gene-expression patterns between the two mouse groups revealed extensive compensatory changes in gene expression related to glucose metabolism. In conclusion, amylin downregulation in diabetic mice improves systemic glucose homeostasis and memory. Molecular processes associated with improved memory involve increased hippocampal glycolytic fluxes and compensatory gene expression.

The unique pathophysiological features of diabetes mellitus secondary to total pancreatectomy: proposal for a new classification distinct from diabetes of the exocrine pancreas

ABSTRACT Introduction Diabetes of the exocrine pancreas (DEP; a.k.a. pancreatic diabetes or pancreatogenic diabetes or type 3c diabetes mellitus or T3cDM) refers to different diabetes types resulting from disorders of the exocrine pancreas. DEP is characterized by the structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction. Among these forms, new-onset diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features, for which we propose a new nomenclature such as post-total pancreatectomy diabetes mellitus (PTPDM). Areas covered TP results in the complete loss of pancreatic parenchyma, with subsequent absolute insulinopenia and lifelong need for exogenous insulin therapy. Patients with PTPDM also exhibit deficiency of glucagon, amylin and pancreatic polypeptide. These endocrine abnormalities, coupled with increased peripheral insulin sensitivity, deficiency of pancreatic enzymes and TP-related modifications of gastrointestinal anatomy, can lead to marked glucose variability and increased risk of iatrogenic (insulin-induced) severe hypoglycemic episodes (‘brittle diabetes’). Expert opinion We believe that diabetes mellitus secondary to TP should not be included in the DEP spectrum in light of its peculiar pathophysiological and clinical features. Therefore, we propose a new classification for this entity, that would likely provide more accurate prognosis and treatment strategies.

Immune cell infiltration in the pancreas of type 1, type 2 and type 3c diabetes.

The different types of diabetes differ in disease pathogenesis but share the impairment or loss of β-cell function leading to chronic hyperglycaemia. While immune cells are present throughout the whole pancreas in normality, their number and activation is increased in diabetes. Different patterns and composition of inflammation could be observed in type 1, type 2 and type 3c diabetes. Immune cells, pancreatic stellate cells and fibrosis were present in the islet microenvironment and could add to β-cell dysfunction and therefore development and progression of diabetes. First studies investigating the use of anti-inflammatory drugs demonstrate their ability to rescue remaining β-cell function and their potential benefit in diabetes treatment. This article provides an overview of immune cell infiltrates in different types of diabetes, highlights the knowledge of their impact on β-cell function and introduces the potential of immunomodulatory strategies.

Management of Type 3c Diabetes in an Elite Tactical Athlete.

The presentation of Type 3c diabetes is atypical, accounting for 0.5-1% of all types of diabetes. Combining this with the healthy Special Operations community is even more profound. A 38-year-old active-duty male in Special Operations developed acute abdominal pain and vomiting while deployed. He was diagnosed with severe acute necrotizing pancreatitis secondary to Type 3c diabetes, and the management of his condition became increasingly difficult. This case highlights Type 3c diabetes and the complexity of formulating a comprehensive treatment plan for a tactical athlete.

Other specific types of diabetes and exocrine pancreatic insufficiency (update2023)

The heterogenous category "specific types of diabetes due to other causes" encompasses disturbances in glucose metabolism due to other endocrine disorders such as acromegaly or hypercortisolism, drug-induced diabetes (e.g. antipsychotic medications, glucocorticoids, immunosuppressive agents, highly active antiretroviral therapy (HAART), checkpoint inhibitors), genetic forms of diabetes (e.g. Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, Down‑, Klinefelter- and Turner Syndrome), pancreatogenic diabetes (e.g. postoperatively, pancreatitis, pancreatic cancer, haemochromatosis, cystic fibrosis), and some rare autoimmune or infectious forms of diabetes. Diagnosis of specific diabetes types might influence therapeutic considerations. Exocrine pancreatic insufficiency is not only found in patients with pancreatogenic diabetes but is also frequently seen in type1 and long-standing type2 diabetes.

PECULIARITIES OF FORMATION OF CARBOHYDRATE METABOLISM DISORDERS WITH COMORBID CHRONIC PANCREATITIS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

The aim: To determine glycemic condition, regulation of carbohydrate metabolism, degree of insulin resistance in patients with chronic pancreatitis with its isolated course and with comorbid COPD and diabetes mellitus. Materials and methods: 110 patients with chronic pancreatitis were examined. The first group of patients included 38 individuals with an isolated course of chronic pancreatitis (1 group), 2nd group included 35 patients with chronic pancreatitis and COPD, 3rd group included 37 patients with chronic pancreatitis and COPD and type 3c diabetes mellitus. The control group (CCOPD) included 32 individuals with isolated COPD, the control group (CDM) includes 34 individuals with isolated type 2 diabetes mellitus. All the patients were examined for functional state of the pancreas and carbohydrate metabolism was assessed. Results: Patients suffering from chronic pancreatitis with COPD and diabetes mellitus developed 3.2 times increased glucose concentration on an empty stomach. Blood glucagon content in all patients was lower in comparison with that of practically healthy individuals which is indicative of an insufficient glucagon secretion by α-cells of the pancreas. Pancreatic polypeptide content in the blood was lower in patients with chronic pancreatitis and COPD and T3c diabetes mellitus in comparison with the reference value. Conclusions: A comorbid course of chronic pancreatitis with exacerbated COPD is associated with more intensive disturbances in carbohydrate metabolism regulation and glycaemia parameters in comparison with an isolated course of chronic pancreatitis. In case comorbidity includes a chronic pancreatitis, chronic obstructive pulmonary disease and diabetes mellitus, the most unfavorable glycemic profile is found which is indicative of carbohydrate metabolism decompensation.

Сахарный диабет в исходе хронического панкреатита: особенности течения и терапии

Aim: To demonstrate a clinical case of a patient with diabetes mellitus secondary to chronic pancreatitis, who needs not only compensation for carbohydrate metabolism, but also correction of exocrine pancreatic insufficiency. Key points. The patient noted a significant improvement in well-being against the background of adequate hypoglycemic therapy (nighttime metformin, sodium-glucose co-transporter type 2 inhibitors and glucagon-like peptide-1 receptor agonist, basal insulin glargine) and enzyme-replacement therapy with pancreatin minimicrospheres at a dose of 50,000 IU on main meals and up to 25,000 ED at snacks. When evaluating the glycemic profile of continuous glucose monitoring showed stabilization of blood glucose at the target range. According to the results of laboratory tests, the patient showed not only normalization of carbohydrate metabolism, but also an initially reduced level of total protein, vitamins and minerals. Conclusion. Administration of drugs used to treat patients with type 2 diabetes mellitus for the management of patients with diabetes secondary to chronic pancreatitis is justified. At the same time, the addition of insulin is often necessary. For this group of patients, the enzyme replacement therapy of exocrine pancreatic insufficiency is as important for the correction of metabolic disorders as the usual hypoglycemic therapy. Keywords: pancreatogenic diabetes mellitus, chronic pancreatitis, exocrine pancreatic insufficiency.

High Clinical and Genetic Similarity Between Chronic Pancreatitis Associated With Light-to-Moderate Alcohol Consumption and Classical Alcoholic Chronic Pancreatitis.

Heavy alcohol consumption and genetic factors represent the 2 major etiologies of chronic pancreatitis (CP). However, little is so far known about the clinical features and genetic basis of light-to-moderate alcohol consumption-related CP (LMA-CP). A cross-sectional analysis was performed on 1061 Chinese CP patients between 2010 and 2015. CP was classified as classical alcoholic CP (ACP; n= 206), LMA-CP (n= 154), and idiopathic CP (ICP; n= 701). Clinical features and genetic characteristics (PRSS1, SPINK1, CTRC, CFTR variant status) were compared between the different groups. Odds ratios (ORs) with 95% confidence intervals were calculated to ascertain the combinatorial effect of alcohol consumption and gene mutation. Compared with ICP, the clinical features of LMA-CP were characterized by higher rates of developing pancreatic stones, pseudocyst, diabetes, and steatorrhea, which were similar to those associated with ACP. The prevalence of CP-related gene variants in LMA-CP was 38.3%, similar to ACP (39.8%), although significantly lower than ICP (56.2%). Alcohol consumption enhanced the risk of a poor clinical outcome, whereas genetic factors amplified alcohol's effects. Compared with ICP, LMA-CP and ACP were associated with a high risk of pancreatic stones (patients without variants, OR= 2.01 and 2.54; patients with variants, OR= 2.17 and 1.07), pseudocyst (patients without variants, OR= 1.03 and 1.43; patients with variants, OR= 1.67 and 2.14), diabetes mellitus (patients without variants, OR= 0.86 and 1.31; patients with variants, OR= 2.05 and 1.55), and steatorrhea (patients without variants, OR= 1.56 and 2.10; patients with variants, OR= 2.11 and 1.60). Evidence was presented to show that LMA-CP was clinically and genetically similar to ACP but significantly different from ICP. Our findings provide support to the growing view that there is no safe level of alcohol consumption.

Early Detection of Pancreatic Cancer: Opportunities Provided by Cancer-induced Paraneoplastic Phenomena and Artificial Intelligence

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer, with a 5-year survival rate of only 11%. Surgery is the only potential cure for PDAC, but approximately 85% of patients present with unresectable tumors at diagnosis. The difficulty in early detection is attributed to the fact that early PDACs cause few or nonspecific symptoms and are frequently obscure or even invisible in imaging studies such as computed tomography (CT). This review aims to briefly summarize the status of screening/surveillance for PDAC and elaborate on the potential windows of opportunity for early detection through PDAC-induced paraneoplastic phenomena and artificial intelligence (AI)-augmented image analysis. Data Sources: Relevant studies and review articles were searched in PubMed. Study Selection: Studies and articles on human subjects were selected. Results: Surveillance for high-risk individuals with imaging-based tools (endoscopic ultrasound and magnetic resonance image) is now advocated, whereas screening for asymptomatic general populations is not warranted at present. Paraneoplastic syndromes, including pancreatic cancer-associated diabetes and cachexia, are prevalent in PDAC patients and may provide windows of opportunity for early detection. S100A9 and galectin-3 are novel PDAC-derived factors mediating pancreatic cancer-associated diabetes and have shown promise in facilitating the early detection of PDAC. Novel computer-aided detection tools based on AI technologies, including deep learning and radiomic analysis with machine learning, have achieved accurate detection and might supplement human interpretation to improve the sensitivity for early PDAC on CT images. Conclusion: Novel blood-based biomarkers and AI-augmented image analysis may be complementary and hold promise for the early detection of PDAC.

Investigation of polymorphism role in protein structure and function for selected cancer and diabetes disease; a rationale to selection of targets for insilico drug screening

ObjectivesCancer and diabetes are two diseases known to bypass socio-demographic segregation, hence the increased focus on their molecular mechanism for therapeutic intervention. Their connection was unclear using traditional biomedical methods until omics technology shows how specific aetiological factors seem to contribute to their initiation and progression. The Genome-wide association study (GWAS) was considered a ground-breaking tool which highlights the roles specific genetic variations like single nucleotide polymorphisms (SNPs) play in the surveillance, diagnosis and treatment of diseases like cancer and diabetes. MethodsWhile some common missense SNP variants have been investigated and reported, we used bioinformatics tools to predict all known conditions previously reported to link pancreatic cancer and diabetes mellitus subtypes based on metabolism and cell proliferation for their structural and functional significance. The variants were limited to five known genes: epigenetic regulators (EZH2, SIRT1) and pan-peroxisome proliferator-activated receptors (PPARA, PPARD, PPARG). ResultsThe class filter shows that obesity is a common risk factor. In the result projected, six missense variant rs1232898090, rs1800206, rs1801282, rs1805192 rs121909244 and rs777334819 were discovered to be associated with fifteen different deleterious amino acid point change in the PPARA and PPARG genes. Likewise, the phyre 2 and SwissModel homology modelling analysis revealed proteins with an identifier; 2FVJ, 2P54, 3DZU, 3E00, 4BCR and 6FZG to be common with high alignment coverage and percentage identity for the missense SNP variants. ConclusionOverall, this analysis provides important insights into how genetic variants can be selected, screened and proposed to inform target selection for other downstream insilico and experimental validation, significant in developing new therapeutics for cancer and diabetes.