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
ReviewType 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer
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
References (131)
- et al.
Low prevalence of exocrine pancreatic insufficiency in patients with diabetes mellitus
Pancreatology
(2013) - et al.
Diabetes mellitus secondary to pancreatic diseases (type 3c)—are we neglecting an important disease?
Eur J Intern Med
(2013) - et al.
Risk factors for diabetes mellitus in chronic pancreatitis
Gastroenterology
(2000) - et al.
Clinical and genetic characteristics of hereditary pancreatitis in Europe
Clin Gastroenterol Hepatol
(2004) - et al.
Metabolic control and β cell function in patients with insulin-dependent diabetes mellitus secondary to chronic pancreatitis
Metabolism
(1987) Genetic risk factors for pancreatic disorders
Gastroenterology
(2013)- et al.
Prevalence of microangiopathic complications in hyperglycemia secondary to pancreatic disease
J Diabet Complications
(1988) - et al.
Reduced pancreatic volume and β-cell area in patients with chronic pancreatitis
Gastroenterology
(2009) - et al.
Cytokine-induced inhibition of insulin release from mouse pancreatic β-cells deficient in inducible nitric oxide synthase
Biochem Biophys Res Commun
(2001) - et al.
In vitro hepatic insulin resistance in chronic pancreatitis in the rat
J Surg Res
(1989)
Insulin resistance is a prominent feature of patients with pancreatogenic diabetes
Metabolism
The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance
Regul Pept
Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis: recommendations from PancreasFest 2012
Pancreatology
Pancreatogenic diabetes: special considerations for management
Pancreatology
Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies
Gastroenterology
Diabetes mellitus and risk of pancreatic cancer: a meta-analysis of cohort studies
Eur J Cancer
Probability of pancreatic cancer following diabetes: a population-based study
Gastroenterology
Should pancreas imaging be recommanded in patients over 50 years when diabetes is discovered because of acute symptoms?
Diabetes Metab
New-onset type 2 diabetes mellitus—a high-risk group suitable for the screening of pancreatic cancer?
Pancreatology
Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus
Gastroenterology
New-onset diabetes in pancreatic cancer: a study in the primary care setting
Pancreatology
Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer
Gastroenterology
Islet amyloid polypeptide is not a satisfactory marker for detecting pancreatic cancer
Gastroenterology
Glucose metabolic alterations in isolated and perfused rat hepatocytes induced by pancreatic cancer conditioned medium: a low molecular weight factor possibly involved
Biochem Biophys Res Commun
β-cell function and insulin resistance evaluated by HOMA in pancreatic cancer subjects with varying degrees of glucose intolerance
Pancreatology
2. Classification and diagnosis of diabetes
Diabetes Care
Report of the expert committee on the diagnosis and classification of diabetes mellitus
Diabetes Care
Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c)
Diabetes Metab Res Rev
Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies
Lancet Gastroenterol Hepatol
Incidence, prevalence, and survival of chronic pancreatitis: a population-based study
Am J Gastroenterol
SEER Cancer Statistics Factsheets: Pancreas Cancer
Diabetes mellitus is associated with an exocrine pancreatopathy: conclusions from a review of literature
Pancreas
The natural history of hereditary pancreatitis: a national series
Gut
Occurrence of and risk factors for diabetes mellitus in Chinese patients with chronic pancreatitis
Pancreas
Diabetes and hypoglycemia in chronic pancreatitis
Scand J Gastroenterol
The presence of retinopathy in patients with secondary diabetes following pancreatectomy or chronic pancreatitis
Diabetes Care
Lower-extremity arterial disease in diabetes mellitus due to chronic pancreatitis
Diabetes Metab
Diabetes and pancreatic cancer
Endocr Relat Cancer
Diabetes mellitus correlates with increased risk of pancreatic cancer: a population-based cohort study in Taiwan
J Gastroenterol Hepatol
Predictors for pancreatic cancer diagnosis following new-onset diabetes mellitus
Clin Transl Gastroenterol
Impact of diabetes duration and chronic pancreatitis on the association between type 2 diabetes and pancreatic cancer risk
Diabetes Obes Metab
β-Cell reserve capacity in chronic pancreatitis
Hepatogastroenterology
Natural history of β-cell function in type 1 diabetes
Diabetes
Early alterations in glycemic control and pancreatic endocrine function in nondiabetic patients with chronic pancreatitis
Pancreas
β cell function in patients with chronic pancreatitis and its relation to exocrine pancreatic function
Diabetologia
β-cell dysfunction in chronic pancreatitis
Dig Dis Sci
Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I
Endocrinology
Targeting inflammation in the treatment of type 2 diabetes: time to start
Nat Rev Drug Discov
Interferon-γ decreases nuclear localization of Pdx-1 and triggers β-cell dysfunction in chronic pancreatitis
J Interferon Cytokine Res
Novel blood biomarkers of pancreatic cancer-associated diabetes mellitus identified by peripheral blood-based gene expression profiles
Am J Gastroenterol
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