Study Of Clinical Features And Current Treatment Status Of Chronic Pancreatitis-related Type 3c Diabetes Mellitus And Preliminary Investigation Of Related Mechanisms

Part Ⅰ.Construction and basic characteristics of the cohort of type 3c diabetes mellitus associated with chronic pancreatitisBackground&Objective:Chronic pancreatitis(CP)is an irreversible pancreatic disease characterized by chronic inflammation and progressive fibrosis,which could eventually lead to the development of pancreatic endocrine insufficiency,named CP-related type 3c diabetes mellitus(hereinafter referred to as CP-T3cDM).Compared with type 1 and type 2 diabetes,CP-T3cDM is characterized by wider blood glucose fluctuations,poorly controlled hyperglycemia,and more severe hyperglycemia-related complications.However,the clinical characteristics of CP-T3cDM patients are unknown,the glycemic control is unsatisfactory and the influencing factors are unclear.The construction of the cohort can help to clarify the clinical characteristics of CP-T3cDM,analyze the influencing factors of glycemic control,and further explore the optimal regimen of glycemic control.In this study,we constructed a clinical cohort of patients with CP-T3cDM,and analyzed their baseline data and current glucose-lowering regimens in order to better understand the clinical characteristics of CP-T3cDM and provide reference for optimizing the glycemic management of CP-T3cDM.Methods:This cohort retrospectively included all patients with a diagnosis of CP and diabetes mellitus who were admitted to our gastroenterology department between January 2018 and September 2021.General information(including name,age,gender,body mass index,history of smoking,history of alcohol consumption,etc.),CP-related medical history information,diabetes mellitus-related medical history and detailed treatment information were collected and statistically analyzed.Results:(1)The cohort initially enrolled 1205 patients with a diagnosis of CP,and after rigorous screening,a total of 224 patients with CP-T3cDM who met the criteria were finally enrolled in the study cohort,with a mean age of(48.1 ± 12.5)years,including 183(81.7%)males.The mean age at diagnosis of CP was(45.0±12.8)years,the mean age at diagnosis of diabetes was(45.6 ± 12.3)years,and the median duration of diabetes was 24(6-36)months,of which 137 patients(61.2%)had poor glycemic control(HbAlc>7%).158 patients(70.5%)were idiopathic CP,53 patients(23.7%)were alcoholic chronic pancreatitis(ACP),6 patients(2.7%)were hereditary CP,and 7 patients(3.1%)had other etiologies such as abnormal pancreatic duct anatomy and traumatic CP.1 19 patients(53.1%)were smokers and 97 patients(43.3%)had a history of alcohol consumption.(2)The proportion of ACP(27.9%vs 4.9%,P<0.01)and smokers(63.4%vs 7.3%,P<0.01)among male CP-T3cDM patients was significantly higher than that among female CPT3cDM patients.However,the age at first onset of CP,age at CP diagnosis,age at diabetes diagnosis,acute pancreatitis episode history,steatorrhea,main pancreatic duct morphology,degree of pancreatic atrophy,and overall treatment of CP were not significantly different between the two groups(P>0.05).(3)This cohort included 65 patients with new-onset CPT3cDM who had not received any glucose-lowering therapy,76 patients who took oral hypoglycemic agents alone as the first-line treatment,and 83 patients who used insulin alone or insulin combined with oral medications after failed control with first-line medications.The proportion of patients with good glycemic control was significantly higher in the firstline medication group than in the primary CP-T3cDM group without glucose-lowering therapy(57.9%vs 30.8%,P=0.001)and the second-line medication group(57.9%vs 27.7%,P<0.001).Conclusions:In this study,we found that the glycemic control of CP-T3cDM patients was unsatisfactory,and their glucose lowering regimens were irregular and inconsistent.The establishment of this study cohort lays the foundation for subsequent exploration of factors and potential mechanisms affecting glycemic control in CP-T3cDM patients.Part Ⅱ.The risk factors influencing glycemic status in type 3c diabetes mellitus associated with chronic pancreatitisBackground&Objective:Chronic pancreatitis-associated type 3c diabetes mellitus(CP-T3cDM)has wider glycemic fluctuations and hyperglycemia is difficult to control,yet the factors affecting glycemic control in CP-T3cDM have not been elucidated.The aim of this study was to explore the factors influencing glycemic control status in patients with CP-T3cDM,and identify the risk factors associated with poor glycemic control in patients with CP-T3cDM and early optimization of glycemic control regimens in patients with CP-T3cDM.Methods:This study was based on the above-constructed retrospective cohort including 224 patients with CP-T3cDM,and poor glycemic control was defined as HbA1c>7%according to the level of glycated hemoglobin A1c(HbA1c)at the time of patient admission.Patients with CP-T3cDM were divided into no-treatment,first-line treatment and secondline treatment groups according to the true glucose-lowering regimen they were currently receiving.Univariate and logistic multifactor regression analyses were performed separately for each subgroup to clarify the relevant factors affecting glycemic control.Results:After grouping patients according to the glucose-lowering therapy they received:(1)65 patients with new-onset CP-T3cDM who had never received any glucoselowering therapy,of which 45(69.2%)had poor glycemic control(HbAlc>7%);risk factor analysis revealed that smoking(OR,3.871;95%CI,1.052-14.238;P=0.042)was independent risk factor for hyperglycemia(HbAlc>7%)in patients with primary CPT3cDM.(2)A total of 76 patients in the first-line medication group who took oral medication alone for glucose-lowering therapy,32 of them(42.1%)had poor glycemic control;the results of multifactorial analysis showed that a history of acute pancreatitis(AP)episodes(OR=7.721;95%CI,2.706-22.027;P<0.01)was an independent risk factor for poor glycemic control in the first-line treatment group.(3)A total of 83 patients in the secondline medication group who were switched to insulin injection alone or insulin in combination with other oral medications because of poor control with first-line medication,of whom 60(72.3%)had poor glycemic control;the results of multifactorial analysis showed that smoking(OR=4.276;95%CI,1.108-16.497;P=0.035)was an independent risk factor for poor glycemic control in the second-line medication group.Conclusions:Factors affecting glycemic control in patients with CP-T3cDM are unclear.In a retrospective study of a cohort of 224 patients with CP-T3cDM,we identified a history of AP episodes and smoking as independent risk factors for poor glycemic control in patients with CP-T3cDM.Therefore,patients with CP-T3cDM who have a history of previous AP episodes need to be monitored more carefully for their blood glucose and islet cell function,and smoking cessation in CP patients is strongly recommended to be particularly important in the glycemic management of CP-T3cDM.Part Ⅲ.Unique inflammatory and pro-fibrotic signatures for glycemic status in type 3c diabetes mellitus associated with chronic pancreatitisBackground&Objective:Poor glycemic control is common in type 3c diabetes mellitus secondary to CP;however,little is known about mechanisms specific to CP-T3cDM.It is generally considered that chronic inflammation and pancreatic fibrosis could contribute to hyperglycemia and lead to pancreatogenic diabetes mellitus.Smoking prevalence in patients with CP is high.Previous studies had found that smoking could promote pancreatic fibrosis in models of chronic pancreatitis.Given that the previous part of our study found that the history of acute pancreatitis(AP)episodes and smoking were independent risk factors for poor glycemic control in CP-T3cDM,we hypothesized that inflammation and fibrosis may be potential mechanisms for poor glycemic control.This exploratory study was designed to determine if potential factors(including inflammatory and pro-fibrotic factors)could be detected in patient serum and whether they associate with glycemic status.Methods:A retrospective analysis of human serum samples from our previous established cohort was performed.The levels of inflammatory factors(including MCP-1,MIP-3a,TNF-α,IL-1β)and pro-fibrotic factors(including TGF-β,PDGF-BB)in the serum of CP-T3cDM patients were detected separately by ELISA.The correlation between each index and HbAlc was analyzed by Spearman’s correlation analysis.Results:A total of 39 patients’ samples were included:35 were male and 4 were female patients,and the serum HbAlc level was(7.8 ± 1.6)%.The correlation analysis between the expression levels of each inflammatory and pro-fibrotic factors and HbAlc showed that none of the inflammatory factors was associated with HbAlc,while the levels of the pro-fibrotic factors TGF-β and PDGF-BB were significantly and positively correlated with HbAlc levels(r=0.45,0.53,p-value<0.01 for both).Patients with higher serum profibrotic factors exhibited a significant increase in HbA1c level.Conclusions:The observations from this study indicate that glycemic status in CPT3cDM can be associated with pro-fibrotic signatures.These data indicate that further.hypothesis-driven analyses combining pro-fibrotic factors measurements and detailed glycemic status could be used to develop precision approaches for glycemic management in patients with CP-T3cDM.