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. Author manuscript; available in PMC: 2023 Sep 1.
Published in final edited form as: Curr Opin Gastroenterol. 2022 Jul 18;38(5):509–515. doi: 10.1097/MOG.0000000000000864

The spectrum of diabetes in acute and chronic pancreatitis

Søren S Olesen 1,2, Frederico G S Toledo 3, Phil A Hart 4
PMCID: PMC9379856  NIHMSID: NIHMS1827515  PMID: 35881972

Abstract

Purpose of review:

To discuss the spectrum of diabetes related to acute and chronic pancreatitis (which are types of pancreatogenic diabetes) and its overlapping features with type 1 and type 2 diabetes.

Recent findings:

Patients with diabetes related to acute and chronic pancreatitis present clinically within a spectrum of overlapping features with other forms of diabetes. In this spectrum, glucose metabolism alterations range from increased insulin resistance following acute pancreatitis (resembling type 2 diabetes) towards a permanent loss of beta-cell function and impaired insulin secretion in end-stage chronic pancreatitis. Overlapping features with type 1 diabetes (beta cell autoantibodies) and type 2 diabetes (obesity, dyslipidemia, and hereditary/genetic factors) contribute to the heterogeneity of this spectrum.

Summary:

Pancreatogenic diabetes secondary to acute or chronic pancreatitis is a heterogeneous entity with a variable clinical presentation, including many cases that are misdiagnosed and treated as type 2 diabetes. This is problematic as pancreatogenic diabetes is associated with a poor prognosis and entails special considerations for management. Recent discoveries showing overlapping features with type 1 and type 2 diabetes along with an improved understanding of its pathophysiology are expected to improve the diagnosis and treatment of these and other forms of pancreatogenic diabetes.

Keywords: Type 1 diabetes, Type 2 diabetes, Type 3c diabetes, Mechanisms, Pancreatogenic diabetes

INTRODUCTION

Pancreatogenic diabetes, also referred to as type 3c diabetes, is a complication of acute and chronic pancreatitis, occurring in a sizeable proportion of patients during their disease course. In the setting of acute pancreatitis, diabetes was for many years considered a transient phenomenon (“stress-induced hyperglycemia”), but contemporary observational studies have shown that up to 25% of patients with acute pancreatitis develop new-onset diabetes within 3 years (1). This corresponds to a more than two-fold increased diabetes risk compared to matched population-based controls (2). The risk of prediabetes in this context (a strong risk factor for subsequent development of diabetes) may be as high as 40% (3). Similarly, patients with chronic pancreatitis have a high risk of diabetes with a point-prevalence of 30–40% and a 25-year cumulative incidence of approximately 85% from symptom onset (4–6).

The subtypes of diabetes associated with acute and chronic pancreatitis have historically been considered as different entities characterized by distinct pathophysiological mechanisms (7). However, this separation is an oversimplification that does not accurately reflect the complexity of the underlying pancreatic disease process. According to the sentinel acute pancreatitis event (SAPE) hypothesis, patients with pancreatitis lie on a continuum starting with an acute (sentinel) attack of pancreatitis progressing through recurrent acute pancreatitis towards end-stage chronic pancreatitis (8). Pancreatogenic diabetes may develop at any point within this continuum and the progressive metabolic changes can be influenced by both the time course and severity of pancreatic injury (9). On the other hand, recent epidemiological studies have questioned the universal applicability of the SAPE hypothesis as up to 50% of patients with chronic pancreatitis do not have a preceding (clinically evident) attack of acute pancreatitis (10–12). Considering this discontinuity in pancreatitis progression, the development of diabetes is expected to similarly be discontinuous and not an inevitable result of progressive disease in the exocrine pancreas. Consequently, diagnostic complexity arises from a lack of a predictable progression and variable timing of diabetes onset relative to the pancreatitis diagnosis (e.g., prior to the first symptom of pancreatitis, after the first acute pancreatitis event, prior to chronic pancreatitis diagnosis, or following chronic pancreatitis diagnosis). This diagnostic complexity is accentuated by findings from recent studies reporting that many patients with pancreatogenic diabetes share risk factors for type 2 diabetes (4,5,9,13). Furthermore, emerging data also suggest that a subset of patients express autoantibodies directed at islet cell epitopes thus resembling type 1 diabetes (14,15). In the present review, we discuss the spectrum of diabetes in acute and chronic pancreatitis considering these recent findings (Figure 1).

Figure 1.

Figure 1.

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The spectrum of diabetes in patients with acute and chronic pancreatitis. In addition to pathophysiological mechanisms associated with acute and chronic pancreatitis, many patients also harbour type 1 and type 2 diabetes-related risk factors.

THE SPECTRUM OF DIABETES IN PANCREATITIS

According to the SAPE hypothesis, patients with pancreatitis lie on a continuum and a subset of patients progress towards end-stage disease if the responsible etiological risk factors cannot be removed (8). Accordingly, 10% of patients with a single pancreatitis attack and 35% of patients with recurring acute pancreatitis were shown to develop chronic pancreatitis (16), and this “pancreatitis continuum” may influence the pathogenesis of pancreatogenic diabetes (9,17). As such, it has been suggested in the literature that patients experience glucose metabolism defects that range from peripheral insulin resistance after a first attack of acute pancreatitis to permanent and severe loss of beta-cells, manifest by severe insulin deficiency in end-stage chronic pancreatitis (7,18). The putative pathophysiological mechanisms implicated in acute and chronic pancreatitis-related diabetes are summarized in Table 1 and discussed in further detail below.

Table 1.

Putative pathophysiological changes and risk factors observed in acute and chronic pancreatitis related diabetes (adapted and updated from Cui et al (24)).

Acute pancreatitis related diabetes Chronic pancreatitis related diabetes References
Altered physiology
Insulin secretion ↔/↓ ↓↓ 9
Peripheral insulin resistance ↑ ↔ 9, 20
Glucagon response # ↓ 7
Hepatic insulin resistance # ↑ 7, 24, 25
Pancreatic polypeptide response ↓ ↓↓ 7, 24, 25
Contributing risk factors
Reduced exocrine pancreatic function + ++ 4, 5, 26, 27
Impaired incretin hormone response # + 7, 28, 29
Type 2 diabetes related risk factors* ++ + 4, 5, 13
Autoimmunity to islet cells 0–3% 3–7% 14, 15
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↑ = increased, ↓ = decreased, ↓↓ substantially decreased, ↔ = no difference, # = no data currently available

*

Adiposity and family history

The pathophysiology of acute pancreatitis-related diabetes is incompletely understood and probably heterogeneous in the majority of patients. The observation of substantially increased risk for diabetes after mild acute pancreatitis suggests the possibility that the pathogenesis of diabetes after acute pancreatitis involves mechanisms beyond pancreatic necrosis and loss of pancreatic islet cells (1,2) There have been reports suggesting that some patients have insulin resistance after an episode of acute pancreatitis (9,19,20). This may be mediated by chronic low-grade inflammation, altered secretion of intestinal hormones, lipolysis, and changes in iron metabolism which, together with beta cell loss and impaired insulin secretion, all have been suggested to contribute to the decompensation of glucose metabolism in acute pancreatitis-related diabetes (18,21,22). Importantly, the magnitude and time trajectory of insulin resistance, beta cell loss and insulin secretion impairment, as well as any losses in incretin release and effect have yet to be comprehensively quantified along the pancreatitis continuum.

Chronic pancreatitis is characterized by an extensive fibro-inflammatory process of the pancreas that also damages islets (23). The loss of pancreatic islets results in not only decreased beta-cell mass and insulin secretion, but also diminished secretion of pancreatic polypeptide, which has been proposed to induce hepatic insulin resistance in these patients (24,25). Chronic pancreatitis is also often accompanied by other abnormalities that destabilize glucose regulation. For example, loss of alpha cells in islets leads to impaired secretion of glucagon and compromise glucose counter-regulation to hypoglycemia, which may explain the high prevalence of hypoglycemia observed in patients with diabetes and chronic pancreatitis (7). In these patients, the risk of hypoglycemia may also be exacerbated by severe malnutrition and depleted glycogen stores, owing to intestinal malabsorption of nutrients caused by exocrine pancreatic insufficiency, and altered dietary intake (4,5,26,27). Chronic pancreatitis has also been associated with a blunted incretin secretion during oral feeding, which is only partly reversed by pancreatic enzyme replacement therapy (28,29). When combined, these mechanisms contribute to frequent and extreme swings in blood glucose levels that are hard to control (i.e., “brittle diabetes”) (7). A recent pilot study based on continuous glucose monitoring supports this concern (30).

TYPE 1 DIABETES RELATED RISK FACTORS

A case series from the US including children and adolescent patients with recurrent acute and chronic pancreatitis suggested that attacks of pancreatitis may increase the risk for beta-cell autoimmunity (i.e., type 1 diabetes)(14). The proposed mechanism includes modifications of beta-cell antigens and neoepitope generation mediated by pancreatic inflammation with ensuing loss of beta-cell self-tolerance (14). These findings were recently expanded to an adult cohort of patients with recurrent acute and chronic pancreatitis from the NAPS-2 consortium demonstrating the presence of at least one beta cell autoantibody in 35%, and two or more autoantibodies in 7% of patients (15). In contrast to these results, recent studies from other countries did not find support for autoimmunity as a prominent feature of pancreatogenic diabetes in the setting of acute or chronic pancreatitis. For example, in a prospective study from New Zealand, only one out of 152 patients with acute pancreatitis developed glutamic-acid-decarboxylase-65 (GAD-65) antibody positivity during a two-year follow-up period (3). Likewise, in a Danish cross-sectional study including a large (n=5564) cohort of individuals with type 2 diabetes and patients with acute and chronic pancreatitis related diabetes, the prevalence of GAD-65 positivity was similar among individuals with type 2 diabetes and diabetes related to acute and chronic pancreatitis (~3% in all subgroups) (9). Importantly, the US-based studies did not include a comparison group or samples prior to pancreatitis, which prevents the ability to make a causal inference. Taken together, the current evidence does not uniformly support that loss of beta-cell self-tolerance is a common mechanism in pancreatogenic diabetes secondary to acute or chronic pancreatitis, but additional studies are warranted due to the conflicting results. Current initiatives supported by the National Institutes of Health, including the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC) and the Consortium for the Study of Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC), are prospectively collecting data on beta cell autoimmunity in large cohorts of pancreatitis patients at different clinical stages (31). These and similar projects worldwide are expected to help clarify the significance of autoimmune-mediated diabetes in patients with pancreatitis.

TYPE 2 DIABETES RELATED RISK FACTORS

Risk factors for type 2 diabetes include obesity, dyslipidemia, family history of diabetes, and common genetic variants associated with beta-cell dysfunction. Recent studies have highlighted that these risk factors are also often prevalent in many patients with pancreatogenic diabetes (4,5,9,13). As a result, patients with pancreatogenic diabetes may show clinical features of type 2 diabetes, thus rendering these two forms of diabetes difficult to distinguish on clinical grounds alone. For example, a morbidly obese patient with risk factors for type 2 diabetes who develops diabetes 6 months after a mild episode of acute pancreatitis would be hard to classify as to the type of diabetes. In some cases, however, the clinical diagnosis can be established based on medical history. For instance, an obese patient with type 2 diabetes onset 20 years prior to the first episode of acute pancreatitis can be distinguished easily based on the sequence of events, whereas a lean patient who develops diabetes after multiple episodes of acute pancreatitis is more likely to have pancreatogenic diabetes. In other scenarios, a mixed form of diabetes may occur; for example, patients with type 2 diabetes can subsequently experience worse glycemic control after acute pancreatitis, presumably due to injury to beta cells. Conversely, patients with acute or chronic pancreatitis could be more likely to develop pancreatogenic diabetes if they have type 2 diabetes risk factors, such as metabolic syndrome and genetic variants associated with beta-cell dysfunction (13,32).

CLINICAL IMPLICATIONS

Given the diverse clinical presentation of pancreatogenic diabetes and overlapping features with type 1 and type 2 diabetes, it can be difficult to ascertain the mechanisms responsible for glucose control at an individual patient level. Consequently, many cases are misdiagnosed and treated as other diabetes subtypes, particularly type 2 diabetes (33,34). This is problematic as pancreatogenic diabetes has been associated with poor glycemic control, increased insulin requirements, frequent hypoglycemic episodes, and excess mortality compared to type 2 diabetes (33–35). Thus, individuals with pancreatogenic diabetes seem to have special requirements for management, which underlines the importance of distinguishing it from other diabetes subtypes (19). The field, however, is hampered by a lack of specific biomarkers and there is currently a number of initiatives working to close this knowledge gap (19,22,36).

The clinical management of pancreatogenic diabetes secondary to acute or chronic pancreatitis is complicated by the progressive nature of pancreatitis as treatment strategies need to be continuously adjusted. For example, as patients with acute pancreatitis and diabetes progress towards chronic pancreatitis their requirements for insulin may change as a consequence of changes in insulin secretion, insulin resistance, and as glucose counter-regulation becomes compromised (9,17). Hence, the progression of pancreatitis may place patients at excess risk for hyperglycemia-related complications and frequent hypoglycemic episodes unless glucose-lowering therapies are adjusted accordingly. Unfortunately, this is often underrecognized and many patients with pancreatogenic diabetes are clinically managed without knowledge of these special considerations (24). Even when properly recognized, the optimal pharmacological treatment of these patients remains somewhat elusive, because of a lack of clinical trial evidence to inform efficacy and safety as well as an incomplete understanding of the heterogenous pathophysiology of this disease (17).

FUTURE DIRECTIONS

There have been no published studies that have investigated longitudinal changes in glucose metabolism along with pancreatitis progression in individual patients. Previous biomarker studies to distinguish pancreatogenic diabetes from other diabetes subtypes have been focused on cross-sectional assessments (22,36). Future studies should aim to follow patients through the different stages of pancreatitis and the sequence of alterations in glucose metabolism. This information would improve risk stratification models, the identification of patients at excess risk of “brittle diabetes”, and potentially support therapeutic strategies to prevent pancreatogenic diabetes.

From a clinical standpoint, one of the greatest challenges in the management of pancreatogenic diabetes is the subset of patients with “brittle diabetes” who are characterized by poor glycemic control and frequent episodes of hypoglycemia and are typically treated with multiple daily injections of insulin (7). Obtaining satisfactory glycemic control while avoiding hypoglycemia can be a challenge in these patients. Unfortunately, patients with pancreatogenic diabetes are excluded from most studies of new glucose-lowering medications. Incretin-mimetic drugs, such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists, are particularly deserving of study because a proportion of these patients share features with type 2 diabetes and some have a blunted incretin response due to exocrine pancreatic insufficiency (4,27,37). In patients with insulin-treated type 2 diabetes and patients who have undergone total pancreatectomy, incretin-mimetics reduce postprandial glucose excursions and risk of hypoglycemia (38,39). It is possible that these beneficial effects may also occur in pancreatogenic diabetes, particularly when related to chronic pancreatitis. Furthermore, incretin-mimetics therapies are associated with a decreased risk of major adverse cardiovascular events in type 2 diabetes (40). As the burden of cardiovascular comorbidities is increased in patients with pancreatitis, incretin-mimetics might also potentially improve the cardiovascular risk in these patients (23). Notwithstanding these putative beneficial effects, GLP-1 receptor agonists are associated with significant gastrointestinal side effects and weight loss which may hinder their use in this patient population. More importantly, incretin-mimetics have been associated with an increased risk of acute pancreatitis and pancreatic cancer in the general diabetes population, although a causal link has been questioned (41,42). Additional studies are needed to document both the efficacy and safety of incretin-mimetics in pancreatogenic diabetes before they can be widely recommended (43,44). Pharmacoepidemiologic studies are particularly useful for this purpose because of the long latency of pancreatic cancer, which cannot readily be appraised in short-term clinical studies (45). As recently indicated by a population-based study from Denmark, a large proportion of patients with acute and chronic pancreatitis-related diabetes (approximately 20%) have been exposed to incretin-mimetics (34). This supports the feasibility of conducting pharmacoepidemiologic investigations of incretin effects and safety in patients with pancreatogenic diabetes. Finally, the recent identification of beta-cell autoimmunity in a subset of patients with recurrent acute and chronic pancreatitis raises the prospect that one day they might benefit from novel immunological therapies currently being developed to prevent type 1 diabetes.

In addition to an expanded pharmaceutical armamentarium, the introduction of health technologies such as continuous glucose monitoring may offer an advantage. Accordingly, in type 1 diabetes and insulin-treated type 2 diabetes, the use of continuous glucose monitoring devices, as opposed to conventional glucose monitoring, led to improved glycemic control and decreased hypoglycemia risk (46–48). Conceivably, these benefits may also extend to pancreatogenic diabetes, particularly in cases of “brittle diabetes”. Future studies should aim to evaluate the efficacy of continuous glucose monitoring in this context.

CONCLUSIONS

Pancreatogenic diabetes secondary to acute or chronic pancreatitis is a heterogeneous entity with a variable clinical presentation, including many cases that are misdiagnosed and treated as type 2 diabetes. This is problematic as pancreatogenic diabetes is associated with a poor prognosis and entails special considerations for management. Recent discoveries showing overlapping features with type 1 and type 2 diabetes along with an improved understanding of its pathophysiology are expected to improve the diagnosis and treatment of these and other forms of pancreatogenic diabetes.

KEY POINTS.

  • Pancreatogenic diabetes secondary to acute or chronic pancreatitis is a heterogeneous entity with a variable clinical presentation

  • Glucose metabolism alterations range from increased insulin resistance following acute pancreatitis towards a permanent loss of beta-cell function and impaired insulin secretion in end-stage chronic pancreatitis

  • Overlapping features with type 1 diabetes (beta cell autoantibodies) and type 2 diabetes (obesity, dyslipidemia, and hereditary/genetic factors) contributes to the heterogeneity of this spectrum

Funding Support:

This publication was supported by the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under award numbers U01DK108327 (PH), U01DK127388 (PH), and U01DK127377 (FGST). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Conflicts of interest: none

REFERENCES AND RECOMMENDED READING

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