The unique pathophysiological features of diabetes mellitus secondary to total pancreatectomy: proposal for a new classification distinct from diabetes of the exocrine pancreas

ABSTRACT

Introduction

Diabetes of the exocrine pancreas (DEP; a.k.a. pancreatic diabetes or pancreatogenic diabetes or type 3c diabetes mellitus or T3cDM) refers to different diabetes types resulting from disorders of the exocrine pancreas. DEP is characterized by the structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction. Among these forms, new-onset diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features, for which we propose a new nomenclature such as post-total pancreatectomy diabetes mellitus (PTPDM).

Areas covered

TP results in the complete loss of pancreatic parenchyma, with subsequent absolute insulinopenia and lifelong need for exogenous insulin therapy. Patients with PTPDM also exhibit deficiency of glucagon, amylin and pancreatic polypeptide. These endocrine abnormalities, coupled with increased peripheral insulin sensitivity, deficiency of pancreatic enzymes and TP-related modifications of gastrointestinal anatomy, can lead to marked glucose variability and increased risk of iatrogenic (insulin-induced) severe hypoglycemic episodes (‘brittle diabetes’).

Expert opinion

We believe that diabetes mellitus secondary to TP should not be included in the DEP spectrum in light of its peculiar pathophysiological and clinical features. Therefore, we propose a new classification for this entity, that would likely provide more accurate prognosis and treatment strategies.

KEYWORDS:

• apancreatic diabetes mellitus
• brittle diabetes
• endocrine pancreas
• exocrine pancreas
• islet autotransplantation
• diabetes of the exocrine pancreas
• DEP
• pancreatogenic diabetes mellitus
• post-total pancreatectomy diabetes mellitus
• PTPDM

Acknowledgments

Acknowledgements Figure 1 was partly created with BioRender.com and with images adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com/). Part of the illustrations have also been purchased from https://www.alamy.com/.

Article highlights

• The term diabetes of the exocrine pancreas (DEP) collectively refers to different forms of secondary diabetes mellitus resulting from disorders of the exocrine pancreas and characterized by structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction.

• Diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features due to the complete loss of pancreatic parenchyma. Therefore, we propose that this entity requires a distinct nomenclature, such as post-total pancreatectomy diabetes mellitus (PTPDM) or apancreatic diabetes mellitus.

• PTPDM should be defined as new-onset diabetes mellitus occurring after total pancreatectomy (in the absence of preoperative diabetes or prediabetes) and should not be included in the DEP spectrum.

• PTPDM is characterized by multiple endocrine and metabolic abnormalities, particularly complete insulin deficiency (with subsequent need for lifelong exogenous insulin therapy), increased peripheral insulin sensitivity, and deficiency of other pancreatic hormones (especially glucagon, pancreatic polypeptide, and amylin). Overall, these endocrine abnormalities make PTPDM a diabetes type particularly difficult to manage, conferring an increased risk of iatrogenic (insulin-induced) severe hypoglycemia and marked glucose variability.

• Coupled with the endocrine abnormalities, TP-induced deficiency of pancreatic enzymes (especially if it is not adequately managed) and TP-related modifications of gastrointestinal anatomy can also contribute to the altered glucose homeostasis observed in PTPDM through impaired intestinal transit of biliary fluid, lack of pancreatic juice secretion, accelerated gastric emptying, and impaired and unpredictable digestion and absorption of macronutrients and micronutrients, with resulting malnutrition.

• Due to the aforementioned multiple pancreatic endocrine and exocrine abnormalities, PTPDM has long been regarded as ‘brittle diabetes’, a term aimed to outline its peculiar features of marked glucose variability and abrupt changes in blood glucose levels with rapidly alternating hyperglycemic and (often asymptomatic) hypoglycemic episodes.

• A new nomenclature for this diabetes type may undoubtedly support the acquisition of more accurate epidemiologic data, as well as the development of clinical guidelines on PTPDM treatment, including novel treatment algorithms and tailored therapeutic interventions aimed to improve the management and prognosis of a disease characterized by unique pathophysiological and clinical features that do not permit to treat it in the same way as other forms of diabetes.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The authors have no funding to report.