Metabolic Sequelae: The Pancreatitis Zeitgeist of the 21st Century

Holistic management of pancreatitis means that gastroenterologists in the 21st Century should think beyond improving in-hospital outcomes of pancreatitis alone. In particular, there is considerable room for optimizing the management of new-onset diabetes, exocrine pancreatic insufficiency, and other metabolic sequelae of pancreatitis. The present article provides state-of-the-art information on classification, terminology, and burden of the common sequelae of pancreatitis. A high-risk group of patients with pancreatitis is identified, which is positioned to benefit the most from the metabolic sequelae surveillance program introduced in this article. The program involves continuous follow-up after pancreatitis diagnosis, with the focus on early identification of new-onset diabetes after pancreatitis and exocrine pancreatic insufficiency. The metabolic sequelae surveillance program is scalable and has the potential to reduce the burden of pancreatitis through tertiary prevention in the decades to come. Holistic management of pancreatitis means that gastroenterologists in the 21st Century should think beyond improving in-hospital outcomes of pancreatitis alone. In particular, there is considerable room for optimizing the management of new-onset diabetes, exocrine pancreatic insufficiency, and other metabolic sequelae of pancreatitis. The present article provides state-of-the-art information on classification, terminology, and burden of the common sequelae of pancreatitis. A high-risk group of patients with pancreatitis is identified, which is positioned to benefit the most from the metabolic sequelae surveillance program introduced in this article. The program involves continuous follow-up after pancreatitis diagnosis, with the focus on early identification of new-onset diabetes after pancreatitis and exocrine pancreatic insufficiency. The metabolic sequelae surveillance program is scalable and has the potential to reduce the burden of pancreatitis through tertiary prevention in the decades to come. Pancreatitis as a disease entity was established in the second half of the 19th Century and there have been several major advances in knowledge. These advances, each corresponding to a pancreatitis zeitgeist (ie, the intellectual climate of an era that facilitates scientific progress), have led to where the disease stands in the first quarter of the 21st Century. With a global incidence of ∼35 cases per 100,000 person-years for acute pancreatitis and ∼10 cases per 100,000 person-years for chronic pancreatitis, acute and chronic pancreatitis are among the most common diseases in routine gastroenterology practice worldwide.1Xiao A.Y. Tan M.L. Wu L.M. et al.Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies.Lancet Gastroenterol Hepatol. 2016; 1: 45-55Abstract Full Text Full Text PDF PubMed Google Scholar,2Sankaran S.J. Xiao A.Y. Wu L.M. et al.Frequency of progression from acute to chronic pancreatitis and risk factors: a meta-analysis.Gastroenterology. 2015; 149: 1490-1500Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar The improved management of pancreatitis over the past few decades, including the growing availability of high-resolution imaging, incremental innovations in endoscopy, and gradual abandonment of open surgery, has contributed to the current lowest in-hospital mortality from pancreatitis on record.1Xiao A.Y. Tan M.L. Wu L.M. et al.Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies.Lancet Gastroenterol Hepatol. 2016; 1: 45-55Abstract Full Text Full Text PDF PubMed Google Scholar,3Petrov M.S. Shanbhag S. Chakraborty M. et al.Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis.Gastroenterology. 2010; 139: 813-820Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar However, the mortality trough has likely been reached because there is no specific treatment on the horizon that would realistically be able to target the pathogenesis of pancreatitis in humans in the foreseeable future.4Lankisch P.G. Treatment of acute pancreatitis: an attempted historical review.Pancreatology. 2010; 10: 134-141Crossref PubMed Scopus (0) Google Scholar,5Stigliano S. Sternby H. de Madaria E. et al.Early management of acute pancreatitis: a review of the best evidence.Dig Liver Dis. 2017; 49: 585-594Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Although a further decrease in deaths from pancreatitis is not expected, the overall burden of pancreatitis can still be meaningfully reduced if the focus of pancreatitis management is expanded beyond the classical secondary prevention (ie, application of effective interventions early in the course of disease with a view to reducing mortality during hospitalization). In particular, tertiary prevention of pancreatitis – aimed at minimizing the development (or effects) of its sequelae after hospital discharge – is poised to become a cornerstone of pancreatitis management in the decades to come.6Petrov M.S. Yadav D. Global epidemiology and holistic prevention of pancreatitis.Nat Rev Gastroenterol Hepatol. 2019; 16: 175-184Crossref PubMed Scopus (339) Google Scholar The unmet need for gastroenterologists to be aware of pancreatitis conferring long-term risks of new-onset diabetes, exocrine insufficiency, and other metabolic sequelae formed the basis for the present article. New-onset diabetes after pancreatitis (NODAP) is defined as diabetes developed in a previously nondiabetic patient with a history of acute pancreatitis or chronic pancreatitis. NODAP is a unified umbrella term and, hence, covers not only diabetes after common pancreatitis etiologies but also diabetes secondary to relatively uncommon entities, such as hereditary pancreatitis, autoimmune pancreatitis, and fibrocalculous pancreatopathy (also referred to as tropical calcific pancreatitis).7Petrov M.S. Basina M. Diagnosing and classifying diabetes in diseases of the exocrine pancreas.Eur J Endocrinol. 2021; 184: R151-R163Crossref PubMed Scopus (0) Google Scholar Diabetes secondary to disconnected pancreatic duct syndrome (that sometimes develops during acute necrotizing pancreatitis) is covered by the term NODAP too.8Thiruvengadam N.R. Forde K.A. Miranda J. et al.Disconnected pancreatic duct syndrome: pancreatitis of the disconnected pancreas and its role in the development of diabetes mellitus.Clin Transl Gastroenterol. 2022; 13e00457Crossref PubMed Google Scholar Identification of NODAP involves the following principal steps (Figure 1). First, the nondiabetic status of a patient with a history of pancreatitis should be confirmed based on the absence of diabetes diagnosis (of any recognized type) in medical records or no recorded changes of lifestyle and use of glucose-lowering medications (for the purpose of treating diabetes) before pancreatitis diagnosis.7Petrov M.S. Basina M. Diagnosing and classifying diabetes in diseases of the exocrine pancreas.Eur J Endocrinol. 2021; 184: R151-R163Crossref PubMed Scopus (0) Google Scholar Patient self-report alone is not sufficient. It is acknowledged that occasionally patients who had symptoms suggestive of pancreatitis for years later present with diabetes at the time of first formal chronic pancreatitis diagnosis. On the other hand, it is known that sometimes chronic pancreatitis can be painless (or even asymptomatic).9Bhullar F.A. Faghih M. Akshintala V.S. et al.Prevalence of primary painless chronic pancreatitis: a systematic review and meta-analysis.Pancreatology. 2022; 22: 20-29Crossref PubMed Scopus (5) Google Scholar Therefore, the operational guideline is pragmatic and based on the date of pancreatitis diagnosis in relation to the date of diabetes diagnosis. In particular, symptoms of abnormal exocrine function of the pancreas (without a formal diagnosis of chronic pancreatitis) in a patient who was later diagnosed with new-onset diabetes is not sufficient to meet the NODAP criteria. Second, biochemical diagnostic criteria should be used to rule out undiagnosed pre-existing diabetes.10Goodger R. Singaram K. Petrov M.S. Prevalence of chronic metabolic comorbidities in acute pancreatitis and its impact on early gastrointestinal symptoms during hospitalization: a prospective cohort study.Biomed Hub. 2021; 6: 111-117Crossref PubMed Google Scholar This is important because undiagnosed pre-existing diabetes contributes approximately one third to the prevalence of diabetes in patients hospitalized for acute pancreatitis (determined based on glycated hemoglobin within 72 hours of hospitalization).11Huang J. Shen Q. Tang W. et al.The clinical significance of serum HbA1c to diagnose diabetes mellitus during acute pancreatitis.Expert Rev Gastroenterol Hepatol. 2023; 17: 385-394Crossref PubMed Scopus (0) Google Scholar Fasting (or random) plasma glucose during hospitalization for pancreatitis should not be used for ruling out pre-existing diabetes because of a high frequency of transient stress-induced hyperglycemia and iatrogenic hyperglycemia (after intravenous glucose infusion or administration of parenteral nutrition) in this population.12Jivanji C.J. Asrani V.M. Windsor J.A. et al.New onset diabetes after acute and critical illness: a systematic review.Mayo Clin Proc. 2017; 92: 762-773Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 13Petrov M.S. Whelan K. Comparison of complications attributable to enteral and parenteral nutrition in severe acute pancreatitis: a systematic review and meta-analysis.Br J Nutr. 2010; 103: 1287-1295Crossref PubMed Scopus (0) Google Scholar, 14Petrov M.S. Zagainov V.E. Influence of enteral versus parenteral nutrition on blood glucose control in acute pancreatitis: a systematic review.Clin Nutr. 2007; 26: 514-523Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Nevertheless, hyperglycemia first identified during hospitalization for pancreatitis may persist long after hospital discharge and, therefore, herald NODAP. The diagnosis of NODAP is established no earlier than 3 months after diagnosis of pancreatitis based on the thresholds for glycated hemoglobin and/or fasting plasma glucose advocated by the American Diabetes Association (Table 1).5Stigliano S. Sternby H. de Madaria E. et al.Early management of acute pancreatitis: a review of the best evidence.Dig Liver Dis. 2017; 49: 585-594Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar The corresponding presequela – new-onset prediabetes after pancreatitis (Figure 2) – is also diagnosed based on the American Diabetes Association thresholds (Table 1).5Stigliano S. Sternby H. de Madaria E. et al.Early management of acute pancreatitis: a review of the best evidence.Dig Liver Dis. 2017; 49: 585-594Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar As an operational means of defining the most uniform group of people, diabetes diagnosed within 3 months after pancreatitis rules out the diagnosis of NODAP. This is because levels of glycated hemoglobin reflect average plasma glucose over the preceding 2–3 months and because disregarding the 3-month lag period leads to a markedly inflated risk of diabetes (adjusted hazard ratios 5.9 and 2.5 within and beyond 3 months after pancreatitis, respectively).5Stigliano S. Sternby H. de Madaria E. et al.Early management of acute pancreatitis: a review of the best evidence.Dig Liver Dis. 2017; 49: 585-594Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar,15Shen H.N. Yang C.C. Chang Y.H. et al.Risk of diabetes mellitus after first-attack acute pancreatitis: a national population-based study.Am J Gastroenterol. 2015; 110: 1698-1706Crossref PubMed Scopus (87) Google Scholar This guideline (Figure 1) has been used in numerous independent original studies from various regions of the world and has consistently met the logical expectations based on pathophysiology (eg, diabetes secondary to chronic pancreatitis requires more insulin than type 2 diabetes, diabetes secondary to chronic pancreatitis has more comorbidities as well as requires more pancreatic enzyme replacement therapy in comparison with diabetes secondary to acute pancreatitis, and higher frequency of hypoglycemia in diabetes secondary to pancreatitis than type 2 diabetes).16Cho J. Scragg R. Pandol S.J. et al.Antidiabetic medications and mortality risk in individuals with pancreatic cancer-related diabetes and postpancreatitis diabetes: a nationwide cohort study.Diabetes Care. 2019; 42: 1675-1683Crossref PubMed Scopus (47) Google Scholar, 17Lee N. Park S.J. Kang D. et al.Characteristics and clinical course of diabetes of the exocrine pancreas: a nationwide population-based cohort study.Diabetes Care. 2022; 45: 1141-1150Crossref PubMed Scopus (1) Google Scholar, 18Shivaprasad C. Gautham K. Shah K. et al.Continuous glucose monitoring for the detection of hypoglycemia in patients with diabetes of the exocrine pancreas.J Diabetes Sci Technol. 2021; 15: 1313-1319Crossref PubMed Scopus (5) Google Scholar, 19Wicks M.M. Barr E.L. Maple-Brown L. Pancreatitis and post-pancreatitis diabetes in Central Australia.Intern Med J. 2023; 53: 568-576Crossref PubMed Scopus (0) Google Scholar, 20Cho J. Scragg R. Petrov M.S. Use of insulin and the risk of progression of pancreatitis: a population-based cohort study.Clin Pharmacol Ther. 2020; 107: 580-587Crossref PubMed Scopus (20) Google Scholar The use of the criteria outlined in the guideline (Figure 1) has also facilitated a meaningful comparison of findings from different centers,6Petrov M.S. Yadav D. Global epidemiology and holistic prevention of pancreatitis.Nat Rev Gastroenterol Hepatol. 2019; 16: 175-184Crossref PubMed Scopus (339) Google Scholar,21Petrov M.S. Post-pancreatitis diabetes mellitus: prime time for secondary disease.Eur J Endocrinol. 2021; 184: R137-R149Crossref PubMed Scopus (44) Google Scholar which is essential for accelerating progress in this highly multidisciplinary field.Table 1Diagnostic Criteria for the Main Metabolic Sequelae and Presequelae of PancreatitisNODAPaAccording to the guideline (Figure 1), establishing the Dx of NODAP (and by extension NOPAP) during and/or within 3 mo of pancreatitis Dx is not recommended. This does not rule out the possibility of initially identifying an abnormal level of fasting plasma glucose during and/or within 3 mo of pancreatitis Dx that subsequently forms the basis for diagnosing NODAP or NOPAP. Meeting the diagnostic criteria for NODAP or NOPAP requires 2 abnormal test results on simultaneous or consecutive testing (when there is no unequivocal hyperglycemia). Both glycated hemoglobin and fasting plasma glucose should be measured on a fresh, never frozen, sample. Glycated hemoglobin should be measured using a method certified by the National Glycohaemoglobin Standardization Program and standardized to the Diabetes Control and Complications Trial reference assay. Point-of-care devices should not be used for diagnosing NODAP or NOPAP. Fasting plasma glucose should be measured after no calorie intake for at least 8 h.EPIbPatients who meet the criteria for both EPI and EPD should be labeled as EPI only. Fecal elastase should not be measured in liquid stool because of the high risk of a false-negative result.OsteoporosiscFragility fractures are deemed to represent underlying osteoporosis, regardless of bone mineral density T score.SequelaeGlycated hemoglobin ≥6.5% (48 mmol/mol)Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L)Coefficient of fat absorption <93%Bone mineral density T score <−2.5NOPAPEPDOsteopeniaPresequelaeGlycated hemoglobin 5.7–6.4% (39–47 mmol/mol)Fasting plasma glucose 100–125 mg/dL (5.6–6.9 mmol/L)Fecal elastase <200 μg/gBone mineral density T score between −1 and −2.5EPD, exocrine pancreatic dysfunction; EPI, exocrine pancreatic insufficiency; NODAP, new-onset diabetes after pancreatitis; NOPAP, new-onset prediabetes after pancreatitis.a According to the guideline (Figure 1), establishing the Dx of NODAP (and by extension NOPAP) during and/or within 3 mo of pancreatitis Dx is not recommended. This does not rule out the possibility of initially identifying an abnormal level of fasting plasma glucose during and/or within 3 mo of pancreatitis Dx that subsequently forms the basis for diagnosing NODAP or NOPAP. Meeting the diagnostic criteria for NODAP or NOPAP requires 2 abnormal test results on simultaneous or consecutive testing (when there is no unequivocal hyperglycemia). Both glycated hemoglobin and fasting plasma glucose should be measured on a fresh, never frozen, sample. Glycated hemoglobin should be measured using a method certified by the National Glycohaemoglobin Standardization Program and standardized to the Diabetes Control and Complications Trial reference assay. Point-of-care devices should not be used for diagnosing NODAP or NOPAP. Fasting plasma glucose should be measured after no calorie intake for at least 8 h.b Patients who meet the criteria for both EPI and EPD should be labeled as EPI only. Fecal elastase should not be measured in liquid stool because of the high risk of a false-negative result.c Fragility fractures are deemed to represent underlying osteoporosis, regardless of bone mineral density T score. Open table in a new tab Figure 2Main metabolic presequelae and sequelae of pancreatitis. Presequelae are precursors of sequelae. Once the criteria for a metabolic sequela have been met (Table 1), the patient with pancreatitis should not be labeled as having the corresponding presequela. EPD, exocrine pancreatic dysfunction; EPI, exocrine pancreatic insufficiency; NODAP, new-onset diabetes after pancreatitis; NOPAP, new-onset prediabetes after pancreatitis.View Large Image Figure ViewerDownload Hi-res image Download (PPT) EPD, exocrine pancreatic dysfunction; EPI, exocrine pancreatic insufficiency; NODAP, new-onset diabetes after pancreatitis; NOPAP, new-onset prediabetes after pancreatitis. Although not every patient with increased blood glucose in the setting of pancreatitis has NODAP, a given individual with diabetes cannot have simultaneously more than one diagnosis of a specific type of diabetes.7Petrov M.S. Basina M. Diagnosing and classifying diabetes in diseases of the exocrine pancreas.Eur J Endocrinol. 2021; 184: R151-R163Crossref PubMed Scopus (0) Google Scholar This is analogous to increased blood pressure; the same patient cannot simultaneously have both primary (essential) hypertension and secondary hypertension (due to a specific cause such as pheochromocytoma, thyroid disease, or Cushing syndrome). Although type 2 diabetes is the most common type of diabetes and primary hypertension is the most common type of arterial hypertension, both are basically diagnoses of exclusion.7Petrov M.S. Basina M. Diagnosing and classifying diabetes in diseases of the exocrine pancreas.Eur J Endocrinol. 2021; 184: R151-R163Crossref PubMed Scopus (0) Google Scholar It follows that healthcare professionals should be aware of secondary diseases and, in particular, identify a specific cause of diabetes (NODAP in the case of gastroenterologists).21Petrov M.S. Post-pancreatitis diabetes mellitus: prime time for secondary disease.Eur J Endocrinol. 2021; 184: R137-R149Crossref PubMed Scopus (44) Google Scholar Furthermore, taking into account that individuals with secondary hypertension are often initially diagnosed with primary hypertension, it is possible that patients with NODAP are initially labeled as having type 2 diabetes (eg, when a history of pancreatitis in the individual with diabetes is not considered or missed).22Viggers R. Jensen M.H. Laursen H.V. et al.Glucose-lowering therapy in patients with postpancreatitis diabetes mellitus: a nationwide population-based cohort study.Diabetes Care. 2021; 44: 2045-2052Crossref PubMed Google Scholar,23Woodmansey C. McGovern A.P. McCullough K.A. et al.Incidence, demographics, and clinical characteristics of diabetes of the exocrine pancreas (type 3c): a retrospective cohort study.Diabetes Care. 2017; 40: 1486-1493Crossref PubMed Scopus (165) Google Scholar Another caveat gastroenterologists should be aware of is that the term “type 3c diabetes,” sometimes used in the past, is a misnomer and its use has never been ratified by any (inter)national professional body in the field of diabetology.7Petrov M.S. Basina M. Diagnosing and classifying diabetes in diseases of the exocrine pancreas.Eur J Endocrinol. 2021; 184: R151-R163Crossref PubMed Scopus (0) Google Scholar The reasons for the confusion were described in detail elsewhere and the use of this term is discouraged.7Petrov M.S. Basina M. Diagnosing and classifying diabetes in diseases of the exocrine pancreas.Eur J Endocrinol. 2021; 184: R151-R163Crossref PubMed Scopus (0) Google Scholar The term “diabetes of the exocrine pancreas” is a modern recommended blanket term for diabetes in the setting of diseases of the exocrine pancreas.7Petrov M.S. Basina M. Diagnosing and classifying diabetes in diseases of the exocrine pancreas.Eur J Endocrinol. 2021; 184: R151-R163Crossref PubMed Scopus (0) Google Scholar The term “postpancreatitis diabetes mellitus” (PPDM) is adopted to describe a subtype of “diabetes of the exocrine pancreas” that encompasses patients with pancreatitis in whom establishing pre-existing diabetes mellitus is unclear (eg, incomplete laboratory data to evaluate the biochemical diagnostic criteria) and, therefore, the absence of proof of diabetes before pancreatitis is taken to mean that the diabetes is incident (by contrast, NODAP requires the presence of proof of not fulfilling the biochemical diagnostic criteria for diabetes mellitus before pancreatitis).21Petrov M.S. Post-pancreatitis diabetes mellitus: prime time for secondary disease.Eur J Endocrinol. 2021; 184: R137-R149Crossref PubMed Scopus (44) Google Scholar This scenario is common in retrospective studies, in particular, population-based investigations that use large administrative databases.17Lee N. Park S.J. Kang D. et al.Characteristics and clinical course of diabetes of the exocrine pancreas: a nationwide population-based cohort study.Diabetes Care. 2022; 45: 1141-1150Crossref PubMed Scopus (1) Google Scholar,20Cho J. Scragg R. Petrov M.S. Use of insulin and the risk of progression of pancreatitis: a population-based cohort study.Clin Pharmacol Ther. 2020; 107: 580-587Crossref PubMed Scopus (20) Google Scholar,22Viggers R. Jensen M.H. Laursen H.V. et al.Glucose-lowering therapy in patients with postpancreatitis diabetes mellitus: a nationwide population-based cohort study.Diabetes Care. 2021; 44: 2045-2052Crossref PubMed Google Scholar PPDM is subdivided into PPDM-A and PPDM-C when acute pancreatitis and chronic pancreatitis, respectively, underlie the diabetes (Figure 1). Although this dichotomy is useful for operationalizing the guideline in the clinic and research setting, limitations of using categorical variables as proxies for continuous phenomena are appreciated. From the pathogenetic point of view alone, PPDM is best seen as a continuous spectrum: diabetes secondary to first attack of non-necrotizing acute pancreatitis lies at one end of the spectrum whereas diabetes secondary to end-stage chronic pancreatitis lies at the other end.21Petrov M.S. Post-pancreatitis diabetes mellitus: prime time for secondary disease.Eur J Endocrinol. 2021; 184: R137-R149Crossref PubMed Scopus (44) Google Scholar The primary driving forces are grossly different – overwhelming insulin resistance (and the resulting compensatory hyperinsulinemia) in the case of the former and critical loss of β cells in the case of the latter.24Bharmal S.H. Kimita W. Ko J. et al.Pancreatic and gut hormones as predictors of new-onset prediabetes after non-necrotising acute pancreatitis: a prospective longitudinal cohort study.Endocr Connect. 2021; 10: 715-724Crossref PubMed Scopus (3) Google Scholar, 25Ko J. Skudder-Hill L. Cho J. et al.The relationship between abdominal fat phenotypes and insulin resistance in non-obese individuals after acute pancreatitis.Nutrients. 2020; 12: 2883Crossref PubMed Scopus (22) Google Scholar, 26Goodarzi M.O. Petrov M.S. Andersen D.K. et al.Diabetes in chronic pancreatitis: risk factors and natural history.Curr Opin Gastroenterol. 2021; 37: 526-531Crossref PubMed Scopus (15) Google Scholar Hence, the pharmacologic management of the 2 subtypes of PPDM is markedly different.27Petrov M.S. Post-pancreatitis diabetes mellitus: investigational drugs in preclinical and clinical development and therapeutic implications.Expert Opin Investig Drugs. 2021; 30: 737-747Crossref PubMed Scopus (9) Google Scholar,28Goodarzi M.O. Petrov M.S. Diabetes of the exocrine pancreas: implications for pharmacological management.Drugs. 2023; 83: 1077-1090Crossref PubMed Scopus (0) Google Scholar At the same time, the key drivers of new-onset diabetes in less polar cases of pancreatitis (eg, diabetes secondary to recurrent acute pancreatitis or early chronic pancreatitis) are not as clear cut. They typically include various degrees of impairment in both insulin sensitivity and β-cell function.21Petrov M.S. Post-pancreatitis diabetes mellitus: prime time for secondary disease.Eur J Endocrinol. 2021; 184: R137-R149Crossref PubMed Scopus (44) Google Scholar,29Petrov M.S. Panorama of mediators in postpancreatitis diabetes mellitus.Curr Opin Gastroenterol. 2020; 36: 443-451Crossref PubMed Scopus (41) Google Scholar The core pathologic signatures of this change in insulin traits are sustained low-grade inflammation, deranged lipid metabolism, and dysfunction of the pancreas-gut-brain axis.30Bharmal S.H. Kimita W. Ko J. et al.Cytokine signature for predicting new-onset prediabetes after acute pancreatitis: a prospective longitudinal cohort study.Cytokine. 2022; 150155768Crossref PubMed Scopus (11) Google Scholar, 31Kimita W. Bharmal S.H. Ko J. et al.Identifying endotypes of individuals after an attack of pancreatitis based on unsupervised machine learning of multiplex cytokine profiles.Transl Res. 2023; 251: 54-62Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 32Gillies N.A. Pendharkar S.A. Singh R.G. et al.Fasting levels of insulin and amylin after acute pancreatitis are associated with pro-inflammatory cytokines.Arch Physiol Biochem. 2017; 123: 238-248Crossref PubMed Scopus (26) Google Scholar, 33Skudder-Hill L. Sequeira I.R. Cho J. et al.Fat distribution within the pancreas according to diabetes status and insulin traits.Diabetes. 2022; 71: 1182-1192Crossref PubMed Google Scholar, 34Bharmal S.H. Ko J. Kimita W. et al.Factors affecting the circulating levels of oxyntomodulin in health and after acute pancreatitis.Pancreas. 2022; 51: 774-783Crossref PubMed Scopus (2) Google Scholar The high frequency of PPDM-C has long been appreciated.26Goodarzi M.O. Petrov M.S. Andersen D.K. et al.Diabetes in chronic pancreatitis: risk factors and natural history.Curr Opin Gastroenterol. 2021; 37: 526-531Crossref PubMed Scopus (15) Google Scholar A 2019 meta-analysis aggregated data from 15 cross-sectional and retrospective cohort studies published between 1981 and 2018.35Zhu X. Liu D. Wei Q. et al.New-onset diabetes mellitus after chronic pancreatitis diagnosis: a systematic review and meta-analysis.Pancreas. 2019; 48: 868-875Crossref PubMed Scopus (0) Google Scholar The study found that the pooled incidence of PPDM-C was 30%. Furthermore, there was the following relationship between incidence of PPDM and time since chronic pancreatitis diagnosis: 15% within 3 years after chronic pancreatitis, 31% in 3–5 years after chronic pancreatitis, and 33% in more than 5 years after chronic pancreatitis.35Zhu X. Liu D. Wei Q. et al.New-onset diabetes mellitus after chronic pancreatitis diagnosis: a systematic review and meta-analysis.Pancreas. 2019; 48: 868-875Crossref PubMed Scopus (0) Google Scholar A 2019 population-based study from New Zealand (as part of the COSMOS program) found that, in comparison with type 2 diabetes, PPDM-C was associated with significantly higher all-cause mortality (adjusted hazard ratio [HR], 1.3).36Cho J. Scragg R. Petrov M.S. Risk of mortality and hospitalization after postpancreatitis diabetes mellitus vs type 2 diabetes mellitus: a population-based matched cohort study.Am J Gastroenterol. 2019; 114: 804-812Crossref PubMed Scopus (0) Google Scholar This was independently confirmed in a 2022 population-based study from Denmark (adjusted HR, 1.5; Figure 3) and a 2022 population-based study from South Korea (adjusted odds ratio [OR], 1.4).17Lee N. Park S.J. Kang D. et al.Characteristics and clinical course of diabetes of the exocrine pancreas: a nationwide population-based cohort study.Diabetes Care. 2022; 45: 1141-1150Crossref PubMed Scopus (1) Google Scholar,37Olesen S.S. Viggers R. Drewes A.M. et al.Risk of major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality in postpancreatitis diabetes mellitus versus type 2 diabetes: a nationwide population-based cohort study.Diabetes Care. 2022; 45: 1326-1334Crossref PubMed Scopus (8) Google Scholar Furthermore, the study from Denmark found that PPDM-C, as compared with type 2 diabetes, was associated with a significantly higher risk of severe hypoglycemia (adjusted HR, 5.3).37Olesen S.S. Viggers R. Drewes A.M. et al.Risk of major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality in postpancreatitis diabetes mellitus versus type 2 diabetes: a nationwide population-based cohort study.Diabetes Care. 2022; 45: 1326-1334Crossref PubMed Scopus (8) G