Review
Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer

https://doi.org/10.1016/S2468-1253(16)30106-6Get rights and content

Summary

Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.

Introduction

Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia.1 The most prevalent form is type 2 diabetes, which is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. However, diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas.

Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. The origin of this term is attributed to a table published annually by the American Diabetes Association until 2014,2 which listed four broad types of diabetes in an outline format with III.C indicating diabetes secondary to diseases of the exocrine pancreas, which authors have variably referenced as type IIIC diabetes mellitus and type 3c diabetes mellitus. We favour the term type 3c diabetes mellitus because the use of an Arabic numeral avoids confusion between the Roman numerals for two and three, and is consistent with nomenclature used for type 1 and type 2 diabetes. The lower case “c” is most commonly used in existing literature, so we have also adopted this. However, in contrast to type 1 and type 2 diabetes, it is important to recognise that the term type 3c diabetes incorporates causes of diabetes with different pathophysiologies, which are combined solely for the purposes of classification (panel).

Additional understanding of the different causes of type 3c diabetes is needed to allow us to more precisely define (and name) the different subtypes. We anticipate this nomenclature will undergo future refinement. The two major causative factors in the pathogenesis of diabetes are inadequate pancreatic β-cell function and insulin resistance. These two factors appear to contribute differentially to the hyperglycaemia observed in patients with type 3c diabetes. A comprehensive explanation of the physiology and methods of analysing insulin action and secretion is beyond the scope of this Review, but a synopsis is provided for context in the appendix.

The most commonly identified cause of type 3c diabetes is chronic pancreatitis. For example, in a large single-centre review, the distribution of causes for type 3c diabetes consisted of chronic pancreatitis (79%), pancreatic ductal adenocarcinoma (8%), haemochromatosis (7%), cystic fibrosis (4%), and previous pancreatic surgery (2%; figure).3 The following discussion will focus on type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma on the basis of their disease prevalence and clinical significance.

Section snippets

Estimated prevalence

The true worldwide prevalence of type 3c diabetes is unknown, but there are two possible approaches to generate an estimate. The first approach applies the reported prevalence of diabetes in pancreatic diseases from cohort studies to a broader population. Globally, the incidence of chronic pancreatitis is estimated at 33·7 cases per 100 000 person-years and pancreatic ductal adenocarcinoma 8·1 cases per 100 000 person-years.4 In the USA, the estimated number of prevalent cases of chronic

Diagnostic criteria for type 3c diabetes

There are no universally accepted diagnostic criteria for type 3c diabetes. Conceptually, the diagnosis can be made in patients who meet the three following criteria: those who fulfil the diagnostic criteria for diabetes, those who have a disease of the exocrine pancreas, and those whose diabetes is reasonably certain to be secondary to their exocrine pancreatic disease.

In the only published criteria for type 3c diabetes, Ewald and Bretzel9 proposed the following major criteria (all must be

Diabetes secondary to chronic pancreatitis

Type 3c diabetes is a frequent comorbidity of chronic pancreatitis, with prevalence estimates ranging from 25% to 80%.10, 11, 12, 13, 14 Increased disease duration is an important risk factor for diabetes secondary to chronic pancreatitis. In hereditary pancreatitis, the median age of onset of diabetes is between 38 and 53 years, but the age of onset of diabetes is less well characterised in the acquired forms of chronic pancreatitis.11, 12

During the past two decades, there have been tremendous

Diabetes secondary to pancreatic cancer

The association between pancreatic ductal adenocarcinoma and diabetes has been recognised for more than 150 years, and has been examined in more than 50 case-control and cohort studies. Meta-analyses of these studies have consistently shown a 1·5–2 times increased risk of pancreatic ductal adenocarcinoma in patients with long-standing (>5 years) diabetes, and a greater risk in individuals with diabetes duration of less than 5 years. Type 2 diabetes is associated with insulin resistance,

Knowledge gaps

Our Review of type 3c diabetes reveals several important knowledge gaps. At a foundational level, a better understanding of the pathogenesis is needed to more accurately define and distinguish type 3c diabetes from other diabetes subtypes. Clinically, the associated pancreatic disorders are heterogeneous and preliminary data support the concept that the mechanisms of hyperglycaemia differ in the various forms of type 3c diabetes. Further characterisation of the underlying mechanisms of disease,

Future studies

The Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) was formed in 2015 to undertake a comprehensive clinical, epidemiological, and biological characterisation of patients to understand the complex relationships between chronic pancreatitis (including recurrent acute pancreatitis), diabetes, and pancreatic ductal adenocarcinoma. The key driving forces behind this effort include the increased risk for developing pancreatic ductal adenocarcinoma in those

Search strategy and selection criteria

We identified references for this Review through a search of PubMed for articles published between Jan 1, 1980, and March 1, 2016, with the following search terms: “type 3c OR pancreatogenic OR pancreatogenous OR pancreatic cancer OR pancreatic neoplasms OR pancreatitis” AND “diabetes OR diabetes mellitus”. We identified additional articles through chaining, by examining the bibliographies of these selected articles, and our own files. We included only papers published in English, and selected

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