β-Cell Dysfunction in Chronic Pancreatitis

Abstract

Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by irreversible destruction of pancreatic secretory parenchyma, fibrosis, exocrine atrophy, and endocrine insufficiency leading to diabetes. Secondary diabetes occurring in CP subsequent to destruction of pancreatic β-cells is distinct, since it involves β-cell dysfunction amidst an inflammatory milieu. Even though considerable knowledge is available on the pathophysiology and clinical management of CP, relatively much less is known about the molecular events leading to β-cell dysfunction. Investigators have demonstrated that altered morphology, reduced β-cell mass, and β-cell numbers result in endocrine insufficiency. However, recent reports and our observations suggest that β-cell dysfunction develops in the early stages of CP while clinical diabetes manifests later, when there is profound fibrosis. In the early stages, altered internal milieu and physiology arising due to inflammation and release of cytokines might lead to deranged signaling pathways and islet dysfunction. Subsequently, development of fibrosis causes islet destruction. This suggests that endocrine deficiency in CP is multifactorial. Although the role of transcription factors (Pdx-1, MafA, NeuroD) on β-cell functions is understood, alterations in internal milieu of pancreatic tissue that affects β-cell functions in CP has not been elucidated. In this review, we summarize the factors that have an effect on islet functions. Understanding molecular events of β-cell dysfunction in CP can lead to the development of targeted preventive and therapeutic modalities.

CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

“…Although chronic pancreatitis is closely related to insulin insufficiency and diabetes mellitus (2), the molecular relationship between insulin secretion and chronic pancreatitis is unclear (17). This study demonstrates that CCR2-KO mice receiving long-term cerulein develop more severe chronic pancreatitis via 1) downmodulation of GLP-1R expression, 2) decrease in insulin release, and 3) hyperglycemia.…”

Long-Term Outcomes of Total Pancreatectomy and Islet Auto Transplantation for Hereditary/Genetic Pancreatitis

“…23,24 Patients often have transient pain relief, but due to the genetic defect there is diffuse involvement of the entire pancreas and pain eventually recurs in up to 50% of patients; 25–30 exocrine and endocrine insufficiency often develops over time. 7,31 Total pancreatectomy (TP) eliminates the source of the pain, and potentially eliminates risk of pancreatic cancer in this HGP group patients and IAT prevents or minimizes TP- related diabetes. Based on this natural history, it has been our practice at the University of Minnesota to offer TP-IAT rather than partial resection or duct drainage procedures in this group of patients, if they meet our criteria for TP-IAT.…”

Endocytosis of Secreted Carboxyl Ester Lipase in a Syndrome of Diabetes and Pancreatic Exocrine Dysfunction

“…Both cystic fibrosis and chronic pancreatitis are conditions associated with a loss of pancreatic endocrine function after the exocrine dysfunction has become manifest. The pathophysiological mechanisms in these syndromes are intricate, involving beta cell failure and destruction secondary to chronic inflammation and fibrosis (51). Notably, a recent study reported an increase in MAPKdriven cytokines in the duodenal juice of CEL-MODY patients (52).…”