The occurrence of diabetes mellitus (DM) in pancreatitis is being increasingly recognized lately. Diabetes can develop not only with chronic pancreatitis but even after the first episode of acute pancreatitis (AP). The incidence of diabetes after AP varies from 18% to 23% in 3 years and reaches up to 40% over 5 years. The exact pathogenesis of diabetes after AP is poorly understood and various mechanisms proposed include loss of islet cell mass, AP-induced autoimmunity, and alterations in the insulin incretin axis. Risk factors associated with increased risk of diabetes includes male sex, recurrent attacks of pancreatitis, presence of pancreatic exocrine insufficiency and level of pancreatitic necrosis. Diagnosis of post-pancreatitis DM (PPDM) is often excluded. Treatment includes a trial of oral antidiabetic drugs in mild diabetes. Often, insulin is required in uncontrolled diabetes. Given the lack of awareness of this metabolic disorder after AP, this review will evaluate current information on epidemiology, risk factors, diagnosis and management of PPDM and identify the knowledge gaps.

Metabolic abnormalities in, during and after an episode of acute pancreatitis (AP) are frequent. Diabetes mellitus (DM) due to pancreatic diseases is a commonly seen disorder. Earlier, terminologies like ‘pancreatic diabetes’ or ‘pan-creatogenic diabetes’ were used to describe diabetes after pancreatic diseases[1,2]. Subsequently, American Diabetes Association (ADA) gave the term ‘type 3c diabetes’ in 2002 which later was abandoned[3,4]. Recently, ADA come up with a unified nomenclature of diabetes of exocrine pancreas which include 3 subtypes: (1) Post-pancreatitis DM (PPDM); (2) Pancreatic cancer-related diabetes; and (3) Cystic fibrosis-related diabetes[5].

Until recently, it was considered that PPDM is associated with chronic pancreatitis only. In 2014, Das et al[6] reported in a systematic review that PPDM can develop in pancreatitis patients even after a single episode of AP, identified as post-AP DM (PPDM-A). Subsequently a number of high-quality population-based studies confirmed these findings[7,8]. Despite a number of available studies, PPDM-A remains an under-recognized entity for most physicians, gastroenterologists, surgeons, and endocrinologists. This review consists of diagnostic criteria, epidemiology, pathophysiology, natural course of DM related to AP. We also discuss the predictors, screening recommendations and management of the same.

Often, an episode of AP is not limited to a single episode in a number of patients. A systematic review in 2015 looked at this aspect and found that recurrent AP developed in 21% of the patients within 1 year of the initial episode of AP[9]. Also, chronic pancreatitis developed in 36% of patients after recurrent AP. Dysglycemia can develop in any of these subtypes of pancreatitis. It has been suggested that pathophysiological mechanisms of diabetes are different in these extreme forms of pancreatitis. Since there are two main types of pancreatitis i.e., AP and chronic pancreatitis, PPDM is also subdivided into two types: (1) PPDM-A; and (2) post-chronic pancreatitis DM[10].

Irrespective of the type of pancreatitis, dysglycemia could be a manifestation of stress hyperglycemia, unrecognized diabetes or new-onset diabetes after pancreatitis[5] (Figure 1). Stress hyperglycemia is defined as an elevated level of blood glucose, without elevated glycated hemoglobin A1c (HbA1c ≥ 6.5%), during the course of pancreatitis and/or within 3 mo after hospital admission in patients without a previous diagnosis of diabetes. This stress hyperglycemia is usually transient, and the elevated levels of blood glucose normalize during the follow up period.

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Figure 1 Spectrum of dysglycemia in pancreatitis. PPDM: Post-pancreatitis diabetes mellitus.

Unrecognized diabetes can be unveiled during an episode of pancreatitis and is defined as elevated glycated HbA1c ≥ 6.5% above the diabetes diagnostic threshold, first detected during the course of pancreatitis and/or within 3 mo after hospital admission[5]. New onset diabetes after pancreatitis (NODAP) acknowledges the metabolic effect of acute or chronic pancreatitis on previously normal glucose homeostasis[5]. The NODAP excludes the diabetic patients diagnosed during the episodes of pancreatitis or up to 3 mo after hospital discharge. PPDM includes patients with diabetes in the setting of pancreatitis irrespective of the timing of diabetes onset (Figure 1). In this review, the DM developing after AP i.e., PPDM-A was focused as a point of discussion.

The diagnosis of PPDM should be suspected in all patients with a history of pancreatitis and fulfilling the diagnostic criteria for diabetes by the ADA. The diagnosis of PPDM is more of a diagnosis of exclusion, after excluding the more common stress hyperglycemia, type 1 and type 2 diabetes. The diagnosis of PPDM-A is made in patients with first or recurrent episodes of pancreatitis without clinical or imaging features of chronic pancreatitis. Petrov and Yadav[10] proposed a stepwise and practical algorithm for diagnosing PPDM[10] (Figure 2).

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Figure 2 Diagnostic algorithm to identify post-pancreatitis diabetes mellitus. PPDM: Post-pancreatitis diabetes mellitus; FPG: Fasting plasma glucose; HbA1c: Hemoglobin A1c.

The global incidence of AP 34 cases/100000 of population based on pooled incidence[10,11]. Of these 6 cases/100000 will develop PPDM-A[10]. The course in AP can be mild, moderately severe, or severe which dictates duration of hospitalization and long-term sequelae. More than 80% of patients have a mild course with a hospitalization required for less than a week, while those with moderate to severe AP experience pancreatic necrosis and a protracted hospital course[12]. Long-term sequelae of AP include exocrine pancreatic insufficiency, complications related to pancreatic necrotic collections, and recurrent attacks of AP in up to 21% patients[13,14].

During hospitalization, hyperglycemia could be seen in up to 51% of patients during AP. Hyperglycemia in the early phase may arise from multiple mechanisms such as uncontrolled pre-existing DM, damage to endocrine pancreas or metabolic stress of critical illness[15]. Hyperglycemia is usually considered as a transient complication of AP. However, two recent meta-analyses have revealed the high incidence of AP related to DM observing that approximately 18%-23% patients of AP will develop DM within three years of discharge[6,16]. However, in longitudinal studies with more than five years of follow-up, the cumulative incidence rate of PPDM-A is up to 40%[16]. Moreover, the precise time of onset of pancreatic endocrine dysfunction cannot be determined. Some studies have demonstrated resolution while others have revealed persistence of endocrine dysfunction[7,17]. To summarize, post pancreatitis endocrine dysfunction is common, however it may be reversible in some cases.

The exact mechanism of PPDM-A is poorly understood. However various mechanisms have been proposed which may lead to diabetes due to loss of islet cell mass, AP induced autoimmunity, alterations in insulin incretin axis and common risk factors. In patients with acute necrotizing pancreatitis, the loss of beta cell of islets of Langerhans leads to insulin deficiency resulting in DM. As a result of pancreatic necrosis, reduction or loss in the production and secretion of insulin as well as other islet hormones is expected. Since, a subset of patients with non-necrotizing AP also develop DM during short-term follow up, the pathophysiology of PPDM seems to be dependent on multiple factors other than immediate loss of islets secondary to necrosis of pancreatitis tissue[16]. It has been observed that the insulin requirements in PPDM-A are akin to type 1 diabetes. Hence, the role of autoimmunity is considered as an important factor in this process. In patients with type 1 diabetes, autoantibodies like glutamic acid decarboxylase (70%-80%), insulin associated antibodies, insulinoma associated autoantigen 2, zinc transporter, and/or tetraspanin 7 cause immune mediated beta cell destruction. There is a possibility that post-pancreatitis there could be immune activation, which though is less clearly defined, which destroys β-cells in pancreas. Some reports have also demonstrated generation of β-cell autoantibody in patients with PPDM-A[18]. However, no available study has evaluated the frequency of autoimmunity following an episode of AP.

The AP and type 2 DM share common risk factors like obesity and hypertriglyceridemia. These factors are independently associated with an increased risk for severe pancreatitis which may partly explain PPDM-A[19,20]. The prevalence of obesity is seen in 42% cases of PPDM-A while in type 2 diabetes obesity is seen in 48% cases supporting the evidence of obesity as a high risk for DM after an episode of AP[21]. Although similar data are not available for hypertriglyceridemia, these factors are likely to contribute towards the development of PPDM-A[22].

Pancreatic exocrine insufficiency may occur in up to 30% of the patients within three years of an episode of AP[23]. In such patients, the incretin-insulin axis is disrupted leading to insufficient incretin hormone production. This leads to reduce secretion of incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1, and subsequently leads to PPDM-A[24].

In the past, several studies ranging from single center studies to systematic reviews and meta-analyses, had looked at the development of PPDM-A. A recent systematic review by Zhi et al[16] revealed that the incidence of new-onset DM post-AP on follow up was 23% overall. The authors also found that patients with severe pancreatitis had higher incidence of DM as compared to mild AP (39% vs 14%). In addition, they found that alcohol related pancreatitis had higher incidence of PPDM-A as compared to biliary pancreatitis (28% vs 12%). In a previous systematic review by Das et al[6] a similar incidence of PPDM-A was noted. It was also seen that the risk of diabetes increased two-fold at 5 years as compared to 12 mo, on follow up. A few studies have shown higher incidence ranging from 37% to 60.2%[7-10] while others have shown lower incidence, from 10.9% to 22.5%[7,17].

The etiology, severity and degree of pancreatic necrosis are considered important risk factors for development of PPDM-A[16]. In theory, it is believed that the extent of pancreatic necrosis determines the development of PPDM-A, even though some studies have found no association between post-pancreatitis diabetes and severity of pancreatitis[12,13,25-27]. These studies conjecture other mechanisms like autoimmunity and development of insulin resistance leading to PPDM-A. However, most studies have shown a strong association between severity of pancreatitis, extent of pancreatic necrosis and development of diabetes[16,25,27]. Vipperla et al[27] considered the risk of new-onset diabetes as determined by severity of AP. They derived the results from the general population and calculated the risk of new-onset diabetes after mild AP as 7%-15% and 30%-50% after severe or necrotizing pancreatitis over a period of 3 to 5 years[27]. The extent of necrosis and number of functionally active beta cells were considered major determinants for development of diabetes. Table 1 summarizes all the studies examined the endocrine insufficiency after AP episodes[8,17,25-60].

Incidence of endocrine insufficiency varies from 4.8% to 60.2% after the initial episode of AP. Similarly, exocrine insufficiency develops in 0% to 35%[26,49]. Literature on the development of both exocrine and endocrine insufficiency after episodes of AP is limited. Ho et al[53] in a nationwide cohort study identified that 3% patients develop both exocrine and endocrine insufficiency after an initial episode of AP. The incidence of both exocrine and endocrine insufficiency was less than the individual endocrine (5%) or exocrine insufficiency (45.7%) after the first episode of AP. The study identified that alcohol-associated AP (OR = 1.804; 95%CI: 1.345-2.263; P < 0.001), and ≥ 2 readmissions for AP (OR = 3.190; 95%CI: 2.317-4.063; P < 0.001) were independent predictors for development of both exocrine and endocrine insufficiencies after AP. These risks were similar to the risk factors for development of individual endocrine or exocrine insufficiency[53].

Uomo et al[49] during long term follow up of AP patients managed non-surgically, found that exocrine insufficiency was temporary in patients with endocrine insufficiency. Huang et al[66] also found in the meta-analysis that exocrine insufficiency decreases from 62% to 35% during follow up after AP. These differences in incidences of exocrine insufficiency could be multifactorial and driven by the symptomatic nature, test used for screening, level of pancreatic necrosis during the episode of AP, pancreatic resection during necrosectomy etc.

Das et al[6] in a meta-analysis evaluated the concomitant development of exocrine and endocrine insufficiency after AP. The pooled prevalence of exocrine and endocrine insufficiency after AP was 29% and 43%, respectively. The prevalence of concomitant pancreatic exocrine insufficiency in newly developed prediabetes/DM was 40%. To summarize, the initial exocrine insufficiency after AP being transient recovers in a majority of patients and concomitant endocrine and exocrine insufficiency develops in 3%-17%.

It is well established that AP can lead to DM, however the reverse is less well studied. Epidemiological studies have reported increased incidence of AP in patients with DM. A United States insurance claims database reported 2.83-fold increased risk of AP in diabetic cohort compared to non-diabetic counterpart[67]. In Taiwan, Lee et al[8] reported 1.95-fold higher incidence of AP in diabetics compared to non-diabetics. Same study also reported even higher HR in those who had a history of hyperglycemic episodes so there might be a severity-response relationship[8]. Another study from the United Kingdom reported 1.49-fold higher incidence of AP in patients with type 2 DM[68]. Proposed patho-physiology of increased incidence of AP in DM includes: (1) Chronic hyperglycemia leads to formation of reactive oxygen species, lipid peroxidation and may result in episodes of pancreatitis; (2) Association of comorbid risk factors like obesity, hypertriglyceridemia and gall stone disease which may independently precipitate pancreatitis; (3) Enhanced ryanodine receptor function leading to alteration in calcium metabolism; (4) Certain medications [dipeptidyl peptidase-4 (DPP-4) inhibitors] may enhance AP risk when used for the treatment[8].

Another study has reported structural changes in pancreas in patients with diabetes. Authors found reduced weight and volume of pancreas in patients with type 1 DM, when fibrosis without significant inflammation and ductal changes were observed in autopsy reports. Fecal elastase levels were low in these patients but there were no symptoms of pancreatitis. There were no significant changes in patients with type 2 DM. This study highlighted the complex interplay between exocrine and endocrine pancreas[69]. These studies suggest a bidirectional relationship between DM and AP. More studies are needed for a better understanding of this complex interplay between exocrine and endocrine pancreas.

The pathophysiology of PPDM-A is incompletely understood. Currently the diagnosis of PPDM-A is mainly based on the chronological sequence of pancreatitis diagnosed before the onset of diabetes. Comparative studies of more common subtypes of diabetes like type 1 and type 2 diabetes are lacking. Large prospective epidemiological studies focusing on incidence, risk factors and natural history as well as studies focusing on tailored approaches for diagnosing, screening, preventive and treatment strategies are lacking. Studies with continuous glucose monitoring while using oral anti diabetic drugs and/or insulin can give insights into glycemic management in such patients. Randomized trials comparing insulin vs oral antidiabetic drugs in AP are warranted but may not be ethically viable.

To address these knowledge gaps, the National Institute of Diabetes and Digestive and Kidney Diseases of the United States recently formed a collaborative network referred as Type 1 Diabetes after Acute Pancreatitis Consortium. The objective of this consortium is to conduct large prospective observational studies to focus on pathophysiology, incidence, natural history and identification of risk factors. One such trial is Diabetes RElated to Acute Pancreatitis and its Mechanisms, NCT05197920. Animal models should also be developed to accurately replicate AP related diabetes, to better characterize the pathophysiology of the disease and provide a platform to investigate potential therapeutic interventions. Also, interdisciplinary and collaborative work is needed to address the screening, preventive and treatment approaches.

PPDM-A is increasingly being recognized as a long-term sequel of diseases of exocrine pancreas after the episodes of AP. This is a distinct clinical entity as mechanisms and natural history are different from type 1 and type 2 DM. As there is necrosis and fibrosis involving both the exocrine and endocrine pancreas; concomitant exocrine dysfunction is common. There is involvement of all the subtypes of islet cells of Langerhans which explains the brittle nature of diabetes. The pathophysiology is poorly understood, large prospective cohort and animal studies are needed for better understanding. Also, interdisciplinary and collaborative work is needed to address screening, preventive and treatment approaches.