Differential Diagnosis of Post Pancreatitis Diabetes Mellitus Based on Pancreatic and Gut Hormone Characteristics.

CONTEXT: Distinguishing different types of diabetes is important in directing optimized treatment strategies and correlated epidemiological studies. OBJECTIVE: Through detailed analysis of hormone responses to mixed meal tolerance test (MMTT), we aimed to find representing characteristics of post-acute pancreatitis diabetes mellitus (PPDM-A) and post-chronic pancreatitis diabetes mellitus (PPDM-C). METHODS: Participants with PPDM-A, PPDM-C, type 1 diabetes, type 2 diabetes, and normal controls (NCs) underwent MMTT. Fasting and postprandial responses of serum glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, gastric inhibitory peptide (GIP), glucagon like peptide-1 (GLP-1), and peptide YY (PYY) were detected and compared among different groups. Focused analysis on calculated insulin sensitivity and secretion indices were performed to determine major causes of hyperglycemia in different conditions. RESULTS: Participants with PPDM-A were characterized by increased C-peptide, insulin, glucagon, and PP, but decreased ghrelin, GIP, and PYY compared with NCs. Patients with PPDM-C showed secretion insufficiency of C-peptide, insulin, ghrelin, and PYY, and higher postprandial responses of glucagon and PP than NCs. In particular, both fasting and postprandial levels of ghrelin in PPDM-C were significantly lower than other diabetes groups. PYY responses in patients with PPDM-A and PPDM-C were markedly reduced. Additionally, the insulin sensitivity of PPDM-A was decreased, and the insulin secretion for PPDM-C was decreased. CONCLUSION: Along with the continuum from acute to chronic pancreatitis, the pathological mechanism of PPDM changes from insulin resistance to insulin deficiency. Insufficient PYY secretion is a promising diagnostic marker for distinguishing PPDM from type 1 and type 2 diabetes. Absent ghrelin secretion to MMTT may help identify PPDM-C.

Impact of stress hyperglycemia on long-term prognosis in acute pancreatitis without diabetes.

Stress hyperglycemia has been confirmed as a strong predictor of poor short-term prognosis in acute pancreatitis. However, whether stress hyperglycemia affects the long-term prognosis of patients with acute pancreatitis is unclear. We aimed to investigate the effect of stress hyperglycemia on the long-term prognosis of non-diabetic patients with acute pancreatitis. This retrospective observational study was conducted on 4055 patients with acute pancreatitis from 1 January 2016 to 31 October 2020. The association between stress hyperglycemia and the prognosis was evaluated using regression modeling. There were 935(71.5%) normoglycemic and 373(28.5%) stress hyperglycemia patients. 46(12.3%) patients with stress hyperglycemia had evidence of diabetes compared with 33(3.5%) patients without stress hyperglycemia (P < 0.001). After multivariate adjustment, patients with stress hyperglycemia were more likely to have evidence of diabetes (OR 2.905, 95% CI 1.688-4.999) compared with normoglycemic. However, stress hyperglycemia is not associated with the recurrence of pancreatitis and progression to chronic pancreatitis. Stress hyperglycemia was independently associated with diabetes secondary to acute pancreatitis. Accordingly, a follow-up diabetes-screening program for AP with stress hyperglycemia is an important part of identifying the disease as soon as possible, delaying islet damage, and improving the prognosis of post-acute pancreatitis diabetes mellitus.

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.

The Prevalence and Characteristics of Exocrine Pancreatic Insufficiency in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background: Exocrine pancreatic insufficiency (EPI) is common in patients with type 2 diabetes. However, the prevalence of EPI varies significantly in different studies. Untreated EPI in these patients can adversely affect their nutrition and metabolism. The aim of this study is to estimate the pooled prevalence of EPI in patients with type 2 diabetes and to explore the potential risk factors. Methods: A systematic search was performed in PubMed, Web of Science, and Embase, which included studies meeting inclusion criteria from 1960 to 1 April 2022. Relevant articles were searched using the combination of Medical Subject Heading (MeSH) terms of "Type 2 diabetes" and "pancreatic exocrine insufficiency." The Stata 16.0 software was used for data analyses. The random-effects model was used to estimate the pooled prevalence rates and 95% CI using "metaprop program." Results: The pooled prevalence of EPI was 22% (95% CI: 15%-31%) in patients with type 2 diabetes and 8% (95% CI: 4%-14%) of them developed severe pancreatic insufficiency. In the subgroup analyses, the prevalence of EPI in type 2 diabetes was correlated with geographic location. The prevalence in Asian countries (35%, 95% CI: 22%-49%) is higher than in Europe (18%, 95% CI: 10%-29%) and Australia (9%, 95% CI: 4%-16%). Furthermore, patients with higher insulin requirements, who are more likely to be insulin-deficient, have a higher prevalence of EPI. The pooled prevalence was 27% (95% CI: 17%-37%) in type 2 diabetes with higher insulin requirement (1 group) and 15% (95% CI: 1%-40%) in patients with lower insulin requirement (2 group). In addition, the morbidity of severe EPI in the higher insulin requirement group (12%, 95% CI: 7%-19%) was sextuple as much as the lower insulin requirement group (2%, 95% CI: 0%-13%). EPI was more common in subjects younger than 60 compared with elderlies (25% vs. 19%). Conclusion: The prevalence of EPI in type 2 diabetes may be overestimated. Furthermore, the higher prevalence may be closely related to ß-cell function. Endocrine disease therapy would potentially represent a novel therapeutic approach for patients with type 2 diabetes and EPI.

Clinical Characteristics of Inpatients With New-Onset Diabetes Mellitus in Eastern China: Based on Novel Clustering Analysis.

Introduction: This study aimed to explore the novel classification of inpatients with new-onset diabetes in Eastern China by the cluster-based classification method and compare the clinical characteristics among the different subgroups. Methods: A total of 1017 Inpatients with new-onset diabetes of five hospitals in Eastern China were included in the study. Clustering analysis was used to cluster the data into five subgroups according to six basic variables. The differences in clinical characteristics, treatments, and the prevalence of diabetes-related diseases among the five subgroups were analyzed by multiple groups comparisons and pairwise comparisons. The risk of diabetes-related diseases in the five subgroups was compared by calculating odd ratio (OR). P value < 0.05 was considered significant. Results: Five subgroups were obtained by clustering analysis with the highest proportion of patients with severe insulin-deficient diabetes (SIDD) 451 (44.35%), followed by patients with mild age-related diabetes (MARD) 236 (23.21%), patients with mild obesity-related diabetes (MOD) 207 (20.35%), patients with severe insulin-resistant diabetes (SIRD) 81 (7.96%), and patients with severe autoimmune diabetes (SAID) 42 (4.13%). Five subtypes had their own unique characteristics and treatments. The prevalence and risk of diabetes-related complications and comorbidities were also significantly different among the five subtypes. Diabetic kidney disease (DKD) was the most common in SIRD group. Patients in SIDD, SIRD, and MARD groups were more likely to develop cardiovascular disease (CVD) and/or stroke, diabetic peripheral vascular disease (DPVD), and diabetic distal symmetric polyneuropathy (DSPN). The prevalence and risk of metabolic syndrome (MS) were the highest in MOD and SIRD groups. Patients in SAID group had the highest prevalence and risk of diabetic ketoacidosis (DKA). Patients with MOD were more likely to develop non-alcoholic fatty liver disease (NAFLD). Conclusions: The inpatients with new-onset diabetes in Eastern China had the unique clustering distribution. The clinical characteristics, treatments, and diabetes-related complications and comorbidities of the five subgroups were different, which may provide the basis for precise treatments of diabetes.

Non-Alcoholic Fatty Liver Disease (NAFLD) Is an Independent Risk Factor for Developing New-Onset Diabetes After Acute Pancreatitis: A Multicenter Retrospective Cohort Study in Chinese Population.

Background: Numerous studies validated frequent glucose dysfunction in patients with acute pancreatitis (AP). However, the prevalence of new-onset diabetes in individuals after a first episode of AP varies widely among previous studies. This study aims to determine the incidence of post-acute pancreatitis diabetes mellitus (PPDM-A) in Chinese people and further identify potential risk factors that influence diabetes development in patients with AP. Methods: This was a multi-center retrospective cohort study including 6009 inpatients with a first attack of AP. A total of 1804 patients with AP without known endocrine pancreatic disorders or other pancreatic exocrine diseases were eligible for analysis. Data was collected from medical records by hospital information system and telephone follow-ups after discharge. The multiple logistic regression analysis was established to evaluate the potential influencing factors of PPDM-A. Results: The prevalence of newly diagnosed diabetes after a first episode of AP in China was 6.2%. Data showed that patients who developed PPDM-A were more likely to be younger (X2 = 6.329, P = 0.012), experienced longer hospital stays (X2 = 6.949, P = 0.008) and had a higher frequency of overweight or obesity (X2 = 11.559, P = 0.003) compared to those with normal glycemia. The frequency of stress hyperglycemia on admission (X2 = 53.815, P < 0.001), hyperlipidemia (X2 = 33.594, P < 0.001) and non-alcoholic fatty liver disease (NAFLD) (X2 = 36.335, P < 0.001) were significantly higher among individuals with PPDM-A compared with control group. Also, patients with PPDM-A were more likely to be hyperlipidemic AP (X2 = 16.304, P = 0.001) and show a higher degree of severity (X2 = 7.834, P = 0.020) and recurrence rate (X2 = 26.908, P < 0.001) of AP compared to those without diabetes. In addition, multiple logistic regression analysis indicated that stress hyperglycemia, hyperlipidemia, NAFLD and repeated attacks of AP were the independent influence factors for developing PPDM-A. Conclusion: Our study first demonstrated the prevalence of secondary diabetes in Chinese patients after AP. The disorder of glucose metabolism in individuals with AP should be regularly evaluated in clinical practice. Further studies are needed to verify the relationship between liver and pancreas in keeping glucose homeostasis under AP condition.

Identification of Inflammation-Related Biomarkers in Diabetes of the Exocrine Pancreas With the Use of Weighted Gene Co-Expression Network Analysis.

Diabetes of the exocrine pancreas (DEP), also commonly described as pancreatogenic diabetes mellitus, is a type of diabetes secondary to abnormalities in pancreatic or exocrine secretion of the pancreas. However, its pathogenesis is not yet known. The aim of this article was to explore the biomarkers of DEP and their potential molecular mechanisms. Based on GSE76896 dataset, which was acquired from Gene Expression Omnibus (GEO), we identified 373 genes by weighted gene co-expression network analysis (WGCNA) and differential expression analysis. In addition, protein-protein interaction (PPI) network analysis and cytoHubba were used to screen potential hub genes. Five hub genes were determined, comprising Toll-like receptor 4 (TLR4), ITGAM, ITGB2, PTPRC, and CSF1R. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways suggested macrophage activation and Toll-like receptor signaling pathway as important pathophysiological features of DEP. CIBERSORT suggested that TLR4 may regulate the immune pathway via macrophages. Next, we validated the expression and receiver operating characteristic curve (ROC) of the hub genes using the GSE164416 dataset. In addition, we used miRNet to predict the target miRNAs of hub genes and intersected them with common miRNAs in diabetes from the Human MicroRNA Disease Database (HMDD), which was used to propose a possible mechanistic model for DEP. The miRNA-mRNA network showed that has-miR-155-5p/has-miR-27a-3p/has-miR-21-5p-TLR4 might lead to TLR4 signaling pathway activation in DEP. In conclusion, we identified five hub genes, namely, TLR4, ITGAM, ITGB2, PTPRC, and CSF1R, as biomarkers to aid in the diagnosis of DEP and conducted an in-depth study of the pathogenesis of DEP at the genetic level.

Pancreatic cancer-associated diabetes mellitus is characterized by reduced ß-cell secretory capacity, rather than insulin resistance.

AIMS: The early distinction of pancreatic cancer associated diabetes (PaCDM) in patients with elderly diabetes is critical. However, PaCDM and type 2 diabetes mellitus (T2DM) remain indistinguishable. We aim to address the differences between the pancreatic and gut endocrine hormones of patients with PaCDM and T2DM. METHODS: A total of 44 participants underwent mixed meal tolerance test (MMTT). Fasting and postprandial concentrations of insulin, C-peptide, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) were measured. Insulin sensitivity and secretion indices were calculated. One-way ANOVA with post-hoc analysis was used for statistical analysis. RESULTS: Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared with T2DM. Baseline concentrations and AUCs differed. PaCDM patients showed lower insulin secretion capacity but better insulin sensitivity than T2DM patients. The peak concentration and AUC of PP in T2DM group were higher than healthy controls, but in accordance with PaCDM. PaCDM patients presented lower baseline GLP-1 concentration than T2DM patients. No between-group differences were found for glucagon and GIP. CONCLUSIONS: PaCDM patients had a lower baseline and postprandial insulin and C-peptide secretion than T2DM patients. Reduced insulin secretion and improved peripheral sensitivity were found in PaCDM patients compared with T2DM.

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

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

Identification of Hub Genes and Potential ceRNA Networks of Diabetic Nephropathy by Weighted Gene Co-Expression Network Analysis.

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients, and is the main cause of end-stage renal disease. The exact molecular mechanism of DN is not fully understood. The aim of this study was to identify novel biomarkers and mechanisms for DN disease progression by weighted gene co-expression network analysis (WGCNA). From the GSE142153 dataset based on the peripheral blood monouclear cells (PBMC) of DN, we identified 234 genes through WGCNA and differential expression analysis. Gene Ontology (GO) annotations mainly included inflammatory response, leukocyte cell-cell adhesion, and positive regulation of proteolysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways mostly included IL-17 signaling pathway, MAPK signaling pathway, and PPAR signaling pathway in DN. A total of four hub genes (IL6, CXCL8, MMP9 and ATF3) were identified by cytoscape, and the relative expression levels of hub genes were also confirmed by RT-qPCR. ROC curve analysis determined that the expression of the four genes could distinguish DN from controls (the area under the curve is all greater than 0.8), and Pearson correlation coefficient analysis suggested that the expression of the four genes was related to estimated glomerular filtration rate (eGFR) of DN. Finally, through database prediction and literature screening, we constructed lncRNA-miRNA-mRNA network. We propose that NEAT1/XIST/KCNQ1T1-let-7b-5p-IL6, NEAT1/XIST-miR-93-5p-CXCL8 and NEAT1/XIST/KCNQ1T1-miR-27a-3p/miR-16-5p-ATF3 might be potential RNA regulatory pathways to regulate the disease progression of early DN. In conclusion, we identified four hub genes, namely, IL6, CXCL8, MMP9, and ATF3, as markers for early diagnosis of DN, and provided insight into the mechanisms of disease development in DN at the transcriptome level.

Two sides of the pancreas: Exocrine insufficiency is correlated with endocrine dysfunction in type 2 diabetes.

BACKGROUND: Recently, numerous studies validated frequent pancreatic exocrine dysfunction in patients with diabetes. However, the prevalence of pancreatic exocrine insufficiency (PEI) in diabetes mellitus (DM) varies widely among studies. This study aims to determine the prevalence of PEI in Chinese people with type 2 DM (T2DM) by measuring the fecal elastase-1 (FE-1) levels and further identify potential factors that influence pancreatic exocrine function in patients with T2DM. METHODS: A total of 85 patients with T2DM without known exocrine pancreatic disorders or digestive system diseases were recruited. Fecal samples were submitted to measure FE-1 levels, and blood samples were collected to investigate pancreatic endocrine function and metabolic biomarkers in all participants. The multiple logistic regression analysis was established to evaluate the influencing factors of PEI in patients with T2DM. The potential predictors of PEI were examined using receiver operating characteristic (ROC) curves. RESULTS: The prevalence of PEI measured by low FE-1 in T2DM was 18.8%. The Spearman correlation demonstrated that the FE-1 level was inversely correlated with DM duration (r =  - 0.360, P = 0.001) and glycated hemoglobin (HbA1c) level (r =  - 0.228, P = 0.036). A highly significant positive association was observed between FE-1 and fasting C-peptide (FCP) levels (r = 0.451, P < 0.001). Furthermore, the multiple logistic regression analysis showed that FCP was an independent influencing factor of PEI (OR = 0.204, P = 0.024, 95% CI: 0.051-0.813). The ROC analysis indicated that the FCP level had a predictive value for low FE-1 (AUC = 0.793, P < 0.001) with an optimal cutoff value of 1.20 ng/ml. CONCLUSION: Chinese patients with T2DM show high PEI prevalence. FCP may be a potential predictor of pathological exocrine function in T2DM. The exocrine and endocrine functions of patients with T2DM in clinical practice should be evaluated. Further studies are needed to clarify the internal association between exocrine and endocrine pancreases.

Orderliness/Disorderliness Is Mentally Associated With Construal Level and Psychological Distance.

People are innately capable of exploring and detecting orderliness and of attempting to make the world in which they live more orderly rather than more disorderly. Construal level theory asserts that the same stimuli can be represented abstractly or concretely and that psychological distance can affect the construal level. No research, however, has examined whether perceived orderliness/disorderliness is mentally associated with construal level and psychological distance. In this study, by using the Implicit Association Test (IAT), we conducted 10 studies to examine this possibility. The results of studies 1A-1B showed that people tended to associate high-level construal concepts with orderliness concepts and low-level construal concepts with disorderliness concepts. By contrast, the results of studies 2A-5B revealed that people associated psychologically proximal concepts with orderliness concepts and psychologically distal concepts with disorderliness concepts. These studies demonstrated that orderliness/disorderliness is associated with both construal level and psychological distance, but in opposite directions, suggesting that construal level and psychological distance may have distinct natures.